Harvard's Thompson Targets Gut Circuits to Halt GLP-1 Weight Rebound

哈佛专家Thompson靶向肠道回路以遏制GLP-1体重反弹 停用GLP-1后的体重反弹源于代偿性内分泌激增，需要多靶点内镜介入或局部基因疗法以实现持久的代谢缓解。 Chris Thompson博士详细阐述了胃肠道如何充当代谢指挥中心，并说明了膳食纤维匮乏如何破坏黏膜屏障并加剧全身性内毒素血症。对话评估了GLP-1类药物的局限性——重点指出了患者脱落率高、肌肉流失以及停药后体重反弹等问题，同时探讨了如retatrutide等多受体激动剂。Thompson展示了突破性的介入技术，包括内镜袖状胃成形术（ESG）、十二指肠黏膜重塑术以及重塑神经内分泌信号传导的磁吻合术。对话最后讨论了抗阻训练等基础性生活方式前提，并展望了通过超声内镜递送的临床前营养响应型GLP-1基因疗法。 每月有超过100万名患者停用GLP-1类药物——由于胃肠道不耐受、注射疲劳或费用问题，约50%的患者在一年内停药——这通常会引发以脂肪组织为主的体重反弹，并伴有显著的瘦肌肉组织流失。 (30:20) 膳食纤维匮乏会迫使共生菌消耗宿主的保护性黏液层，导致肠道通透性增加，使细菌内毒素（LPS）渗漏至门静脉循环，从而诱发肝脏炎症和胰岛素抵抗。 (0:00) 十二指肠转流可在不依赖减重的情况下迅速缓解2型糖尿病，证实了抗肠促胰岛素假说，即阻止营养物质接触近端小肠黏膜可阻断驱动全身胰岛素抵抗的进化适应不良信号。 (104:28) 转化医学研究人员开发了一种通过超声内镜递送至胰岛β细胞的进餐响应型AAV GLP-1基因疗法，无需终身皮下注射或持续的全身激素暴露即可实现局部自分泌血糖控制。 (137:15)

Dr. Chris Thompson and Andrew Huberman explain that the gastrointestinal tract operates as a sophisticated endocrine organ rather than a simple digestive conduit, arguing that effective metabolic health and sustainable weight loss require protecting the gut mucosal barrier, identifying early markers of insulin resistance, and leveraging neurohormonal mechanisms through advanced endoscopic procedures and targeted therapies. Dietary Fiber, Fermentation, and Epithelial Barrier Integrity (0:00) Dietary fiber serves as the indispensable fuel for the colonic microbiome. Dr. Thompson emphasizes that when dietary fiber is absent, resident bacteria do not enter dormancy; instead, they consume the host's protective mucus layer. Through microbial cross-feeding, primary fermenters break down prebiotics into acetate and lactate, which secondary species convert into butyrate. This short-chain fatty acid powers colonocytes and seals epithelial tight junctions. A breakdown in this mucosal barrier triggers systemic inflammation and accelerates metabolic disease. Thompson notes that intestinal permeability is clinically demonstrable rather than theoretical wellness terminology. In studies of metabolic dysfunction-associated steatohepatitis (MASH), the tracer molecule Chromium-51 EDTA breached damaged barriers and drained directly into the portal vein toward the liver. Furthermore, chronic overfeeding structurally remodels gut architecture: intestinal villi elongate, mucosal walls thicken, and local inflammatory cells surge—including an 8-fold increase in natural killer cells and a 1.5-fold increase in macrophages relative to healthy controls. Early Detection of Metabolic Inflexibility and Insulin Resistance (68:47) Relying on body weight or standard glucose checks overlooks early metabolic breakdown. Citing longitudinal civil servant research, Dr. Thompson reports that elevated fasting insulin can signal future type 2 diabetes up to 15 years prior to clinical diagnosis. Moreover, cross-sectional NHANES data from UNC revealed that only 12% of American adults—and fewer than one-third of lean individuals—are metabolically healthy, proving that thinness does not guarantee metabolic wellness. When ectopic fat interferes with cellular signaling, homeostatic model assessment (HOMA-IR) scores exceed 2, precipitating metabolic inflexibility. Under this condition, measured by the respiratory exchange ratio (VCO2/VO2), the body fails to transition between carbohydrate and lipid oxidation. During fasting, it catabolizes lean tissue while fat stores remain locked away, culminating over time in pancreatic beta-cell apoptosis and overt diabetes. Clinical Realities and Adherence Limits of Incretin Therapies (30:20) While acknowledging GLP-1 receptor agonists as major breakthroughs for severe obesity, Dr. Thompson highlights a steep attrition curve: roughly 30% of patients abandon treatment within the first month, and nearly 50% discontinue within one year. This dropout rate is propelled by administration friction, needle fatigue, and severe gastrointestinal side effects caused by rigid dose escalation. Furthermore, synthetic therapies circulate at concentrations roughly 1,000-fold higher than endogenous biological bursts. Major clinical concerns include accelerated loss of lean tissue and cosmetic muscle wasting, making baseline DEXA scans and mandatory resistance training essential. Next-generation multi-agonists, such as the triple agonist retatrutide targeting GLP-1, GIP, and glucagon receptors, show unprecedented weight reductions of roughly 30% in Eli Lilly trials. Dr. Thompson explains that GIP provides an anti-emetic buffer against GLP-1-induced nausea, while glucagon signaling promotes hepatic lipid oxidation and spares muscle mass. Endoscopic Remodeling and Nutrient-Responsive Gene Therapies (128:13) Bariatric interventions operate through complex neurohormonal signaling rather than simple physical restriction. Thompson pioneered Endoscopic Sleeve Gastroplasty (ESG), which places full-thickness internal sutures to fold the stomach into a narrow tube. This activates mechanoreceptors that signal fullness through vagal afferents while delaying gastric emptying to suppress fundal ghrelin secretion. Auxiliary techniques, such as endoscopic fundal mucosal ablation using argon plasma coagulation, directly target ghrelin-producing cells. At the technological frontier, Thompson's laboratory is developing nutrient-responsive GLP-1 gene therapy. Delivered via endoscopic ultrasound directly into the tail of the pancreas, an adeno-associated viral (AAV) vector pairs the GLP-1 gene to an insulin promoter within beta cells. Rather than maintaining continuous supraphysiologic drug levels, the modified beta cells co-secrete insulin and GLP-1 only upon meal consumption. This episomal approach has demonstrated efficacy in preclinical rodent trials and entered early human trials in the Netherlands. Dr. Thompson concludes that while procedural innovations and gene therapies offer powerful alternatives to lifelong weekly injections, patient success remains anchored in non-negotiable lifestyle foundations—principally adequate dietary fiber to maintain the gut mucosal lining and resistance training to preserve lean mass. Unresolved questions remain regarding how to scale procedural access beyond specialized centers and how nutrient-responsive gene therapies will perform across long-term human clinical trials.

胃肠病学家与介入内镜专家 Chris Thompson 博士指出，消化道不仅是营养吸收管道，更是核心的内分泌与代谢调控器官；维护肠道屏障、及早监测胰岛素抵抗，并结合精准内镜或下一代靶向疗法，是攻克代谢疾病的关键。 肠道菌群底物与黏膜屏障完整性 (0:00) 膳食纤维是维持肠道菌群活性的基础底物。当宿主缺乏膳食纤维摄入时，肠道细菌会转而侵蚀宿主自身的保护性黏液层。结肠黏膜与血液循环之间的上皮屏障极薄，这一缓冲屏障的受损会破坏紧密连接蛋白，引发系统性炎症。结肠细菌通过发酵不可消化的碳水化合物，生成以丁酸盐（Butyrate）为代表的短链脂肪酸（SCFA），该物质是结肠上皮细胞的核心能量来源。 由于口服丁酸盐在到达下消化道前即被吸收代谢，人体依赖多阶段的“交叉喂养”（cross-feeding）机制：原发发酵菌将益生元纤维分解为乙酸与乳酸等中间代谢物，次级特化菌再将其转化为结肠局部的丁酸盐。此外，临床研究证实“肠漏”是明确的病理机制，在代谢功能障碍相关脂肪性肝炎（MASH）患者中，使用放射性示踪剂 51Cr-EDTA 测定显示其肠道通透性显著升高，革兰氏阴性菌来源的脂多糖（LPS）通过门静脉直达肝脏，加剧肝脏炎症反应。 排便基线与代谢不灵活性的早期诊断 (16:55) 排便模式是评估胃肠动力的直观窗口。临床健康基准为每天排便不超过三次、且两次排便间隔不超过三天，理想形态为成形软便；干硬球状便提示肠道蠕动迟缓与脱水，这在西方人群中通常源于膳食纤维严重不足。若排出黑色柏油样便（黑便），则提示上消化道存在氧化出血的急症风险。对于间歇性禁食，尽管存在禁食期细菌可能短暂侵蚀黏膜的假说，但 Thompson 博士认为其改善高胰岛素血症与促进胰腺休息的全身性获益远大于潜在黏膜侵蚀风险，早间限时进食可能更符合内源皮质醇和胰岛素节律。 在全身代谢层面，传统体检往往忽视早期指标。一项针对公务员的长达 10 至 15 年的纵向研究发现，空腹胰岛素升高可在临床确诊糖尿病前 15 年被检测到。同时，北卡罗来纳大学基于 NHANES 数据的分析表明，全美仅约 12% 的成年人代谢健康，且偏瘦人群中健康者不足三分之一。利用稳态模型（HOMA-IR > 2）可量化胰岛素抵抗，此类患者普遍存在代谢不灵活性（Metabolic Inflexibility）：空腹时无法有效分解脂肪，转而消耗肌糖原与肌肉；进食碳水后亦无法高效清除血糖，最终诱发胰岛 beta 细胞耗竭与凋亡。 GLP-1 药物局限、多靶点协同与生活方式干预 (30:20) 以司美格鲁肽和替尔泊肽为代表的 GLP-1 受体激动剂应用广泛，但面临严峻的依从性瓶颈。临床数据显示，约 30% 的患者在用药首月停药，一年内停药率高达约 50%，主要诱因包括注射疲劳、刚性剂量递增带来的严重恶心以及瘦体重流失。常规药物剂量在体内产生的激素浓度为人体自然生理浓度的约一千倍，导致许多耐受不良者转向非官方的“微量给药”（microdosing）。此外，快速减重易诱发少肌症（sarcopenia），甚至出现罕见的非动脉炎性前部缺血性视神经病变（NAION）。 新一代多受体激动剂（如靶向 GLP-1、GIP 和胰高血糖素受体的三激动剂 retatrutide）展现出约 30% 的减重效果。GIP 能增强胰岛素敏感性并缓冲 GLP-1 引发的恶心，从而提高耐受剂量；受控的胰高血糖素信号则促进脂肪分解并保护肌肉组织。Thompson 博士强调，患者在进行任何减重治疗前必须确立抗阻训练习惯以维持静息代谢率，并配合 Zone 2 有氧训练（优先氧化脂肪）与高强度间歇训练（HIIT，动员内脏脂肪）。饮食上应规避易氧化的高温多不饱和脂肪酸，并优先选择特级初榨橄榄油与足量 Omega-3。 前肠假说、内镜减重手术与基因治疗前沿 传统减重手术的机制并非单纯限制容积或吸收，而是深刻重构了神经内分泌通路。在 Goto-Kakizaki 糖尿病大鼠模型中，前肠排除（绕过十二指肠和近端空肠）可快速逆转糖尿病，支持了“抗肠促胰岛素假说”（Anti-Incretin Hypothesis）——即近端小肠存在过度活跃的拮抗胰岛素信号，阻断食物接触该区域即可恢复血糖稳态。长期过量进食会导致肠道黏膜代偿性肥大、绒毛延长，且局部自然杀伤（NK）细胞浸润增加 8 倍、巨噬细胞增加 1.5 倍，加剧局部免疫紊乱。 为避免传统胃旁路手术的高创伤，Thompson 博士于 2012 年开创了经口胃内缝合的内镜袖状胃成形术（ESG），利用全层缝合减少胃容量以激活迷走神经机械牵张感受器，并延长食物排空时间以持续抑制胃底分泌的饥饿素（Ghrelin）。部分中心还辅以氩离子凝固术（APC）破坏胃底黏膜以减少饥饿素分泌。前沿研究正转向超声内镜（EUS）引导下的靶向基因治疗：通过将连接胰岛素启动子的 AAV-GLP-1 载体单次注射至胰腺组织，使 beta 细胞仅在摄食血糖上升时同步分泌胰岛素与 GLP-1，实现生理性营养响应，避免全身超生理剂量的副作用。 该讨论展示了代谢疾病诊疗范式从被动机械限制向神经内分泌与分子靶向干预的转变。虽然经口内镜手术与前沿基因疗法有望克服当前外源性药物的耐受性缺陷与依从性断崖，但新型干预手段在更广泛人群中的长期安全性与有效性仍有待临床试验进一步确证。

[0:00] Dr. Chris Thompson: Feed your microbes. You know, they need to be fed. And what they eat is fiber. [18:28] Dr. Chris Thompson: Feed your microbes, or they're going to eat you. [47:44] Dr. Chris Thompson: Batman and Robin [60:44] Andrew Huberman: to deliver stuff, not take stuff [70:01] Andrew Huberman: Wagyu beef [82:08] Dr. Chris Thompson: more information is better almost in all circumstances [82:08] Andrew Huberman: Give it 20 months. This will be standard. [84:22] Andrew Huberman: Adapt or die—or your patients die. [102:45] Dr. Chris Thompson: Was it a coincidence? What the heck was that? Why is closing that little hole so important? [112:58] Andrew Huberman: made up by people in the Bay Area. [118:57] Dr. Chris Thompson: we should be treating like alcohol. [142:13] Dr. Chris Thompson: managing a slow demise

[0:00] There's all sorts of evidence that if [0:01] you don't have a lot of fiber, your [0:03] microbiome is not healthy. Feed your [0:05] microbes. You know, they need to be fed. [0:07] And what they eat is fiber. Okay? That's [0:10] what you want to eating. You want them [0:11] eating fiber. [0:12] >> And if you're not feeding them fiber, [0:13] they'll eat your mucous layer. Okay? And [0:15] we already talked about how thin that [0:16] barrier is. And all of a sudden, they [0:18] start eating your mucous layer. They're [0:20] they're not producing the butyrate you [0:21] need. And the butyrates needed to [0:22] maintain the tight junctions, right? So, [0:25] there's layers to this. It's like a [0:26] snowball effect that if you're not [0:29] feeding those micro the microbiome and [0:30] keeping it healthy, you're going to run [0:32] into all sorts of all sorts of trouble. [0:35] >> Welcome to the Hubberman Lab podcast [0:37] where we discuss science and [0:38] science-based tools for everyday life. [0:44] >> I'm Andrew Huberman and I'm a professor [0:46] of neurobiology and opthalmology at [0:48] Stanford School of Medicine. My guest [0:50] today is Dr. Chris Thompson. Dr. Dr. [0:53] Chris Thompson is a professor of [0:54] medicine at Harvard Medical School. He [0:56] is also the chief of interventional [0:58] gastroenterenterology at Mass General [1:00] Bighgam in Boston. He is a renowned [1:02] expert on the intersection of [1:04] gastroenterenterology, metabolism, [1:06] nutrition, and obesity medicine. And in [1:09] today's episode, Dr. Dr. Thompson [1:11] explains how to improve your gut health, [1:13] including the roles of your diet, gut [1:15] microbiome, and gastrointestinal [1:17] motility, as well as how your gut [1:19] communicates with the rest of your body, [1:20] which of course includes the gut [1:22] microbiome, but as you'll learn today, [1:24] much more. Dr. Chris Thompson is a guest [1:26] on this podcast because he's not just a [1:28] GI tract and obesity medicine expert. [1:31] He's also credited with having created [1:32] an entire new field of treatments and [1:35] perspectives on GI and metabolic health. [1:37] So the knowledge he shares today is [1:39] truly at the cutting edge and [1:41] applicable. Which is why by the end of [1:42] today's episode, you will have a clear [1:44] understanding of how your [1:45] gastrointestinal system works, and you [1:47] will have a set of new modern [1:49] evidence-based tools for improving and [1:51] maintaining your gut health. Before we [1:53] begin, I'd like to emphasize that this [1:55] podcast is separate from my teaching and [1:57] research roles at Stanford. It is, [1:59] however, part of my desire and effort to [2:00] bring zero cost to consumer information [2:02] about science and science related tools [2:04] to the general public. In keeping with [2:06] that theme, today's episode does include [2:08] sponsors. And now for my discussion with [2:11] Dr. Chris Thompson. Dr. Chris Thompson, [2:13] welcome. [2:14] >> Thanks so much. Good to be here. [2:16] >> A lot of us hear these days about the [2:18] gut microbiome, the gut brain axis. We [2:21] hear about GLP drugs that help people [2:23] lose immense amounts of weight and stop [2:26] feeling this food noise thing and on and [2:29] on. But could we start by just having a [2:32] conversation about this tube that is the [2:34] digestive tract and get real basic and [2:38] just educate people a bit on what [2:40] happens that stimulates them to want to [2:43] eat, why perhaps for certain periods of [2:46] day or night they don't want to eat and [2:48] then what the passage of food through us [2:50] looks like as a series of steps. This is [2:52] such a critical part of our biology and [2:55] our lives. It's becoming more and more [2:57] complex all the time, right? the gut and [3:00] it does a lot of things. So, it's [3:03] obviously involved in digestion, but [3:04] it's also an endocrine organ. You can [3:06] hear it called the second brain, right? [3:08] There's a lot of different ways we we [3:09] think about about the gut and it is [3:12] compartmentalized and each each area has [3:14] a different job. So, you first you have, [3:16] you know, the esophagus and its job is [3:18] to just kind of move the food into the [3:20] stomach safely and it's thick, right? [3:22] has different lining so it can handle [3:24] things that might be a little rougher [3:26] and uh it pushes sequentially, you know, [3:28] down into the stomach. So, it's taking [3:30] that food bolus and driving it into the [3:31] stomach and you can have all sorts of [3:33] problems in your esophagus, right? So, [3:34] each one of these organs has, you know, [3:36] things it's supposed to do and then [3:37] things that it doesn't do well. [3:38] Sometimes people don't swallow well. It [3:40] gets too tight at the bottom. There's a [3:42] condition called acalasia where it's [3:43] just the bottom of the esophagus doesn't [3:45] relax, right? And so we have procedures [3:47] we can do in my line of work where you [3:48] can tunnel down in between the layers of [3:51] that esophagus. It's very thin, you [3:53] know, a few millimeters you can tunnel [3:54] down into there and cut that muscle to [3:56] relieve the obstruction. So [3:57] >> what are the symptoms of that? [3:58] >> So inability to swallow. [4:00] >> So what do they do? They choke. [4:01] >> Yeah. They'd feel like they're choking. [4:03] So they'll they'll swallow food, it'll [4:04] get down and stop and then they'll feel [4:06] pressure. They'll feel really [4:07] uncomfortable. If they drank some fluid [4:09] with it, it might start coming back up. [4:11] It'll just stay there. And then [4:13] sometimes they'll have to, you know, [4:14] induce vomiting to remove it. [4:16] >> It's very uncomfortable for them. And [4:18] it's not a terribly common condition, [4:19] but it's coming more and more frequent. [4:21] I see it every week, right? So that [4:22] inability to swallow and you can get [4:24] that inability to swallow for other [4:25] reasons actually that are far more [4:26] common. Chronic heartburn. If someone [4:29] has reflux, you know, that burning [4:30] sensation, uh that can damage the line [4:32] of the esophagus and it can lead to [4:34] precancerous conditions called Barrett's [4:36] esophagus, which is something that, you [4:38] know, needs to be treated, looked at, [4:40] and and and uh kind of followed. But [4:43] with time, it can actually cause [4:44] scarring. So you get a stricture. So [4:46] it's kind of very firodic tissue there. [4:48] That's another reason why people might [4:50] have difficulty swallowing. There's [4:51] other reasons as well that are more [4:52] obscure, but so that's the job of that [4:55] esophagus just to move the the food down [4:57] safely and a lot of times it it doesn't [4:59] work. Then you have the stomach next, [5:01] right? First, what the stomach does is [5:03] is it stretches to accommodate and [5:04] accept a meal, right? So it stretches. [5:06] Normally it's like a tube in your, you [5:08] know, in in your abdomen. But then when [5:10] you start to smell food, it starts [5:12] stretching and becoming more like a bag. [5:13] >> Really just the the odor of food. [5:15] >> Yeah. It can it can stretch, relax to [5:18] accept that meal. And if it doesn't do [5:20] that properly, it's it causes symptoms [5:22] like nausea, right? So uh so then it [5:25] accepts the meal and uh it has to do its [5:29] job which is to break it down and pass [5:30] it on. So that the stomach now isn't [5:32] just transporting, it's breaking it [5:34] down. And it does that mechanically. So [5:36] and the the fundus the top of the [5:38] stomach is holding that meal. That's [5:39] what kind of stretched up to hold it. [5:41] And then the rest of the stomach is [5:42] working on it. So the body of the [5:43] stomach next segment is breaking it [5:44] down. It's grinding the food into [5:46] smaller bits. Acid is part of this as [5:49] well. The stomach secretes acid and then [5:51] the bottom of the stomach called the [5:52] anstrum will push the food out slowly [5:54] into the dudenum, right? That's the [5:56] first part of the small bowel. Satiety, [5:58] satiation all becomes part of this [6:00] because the stomach is what secretes [6:01] grein. We'll talk about that probably [6:02] more later, but the stomach secretes [6:04] ghrein. And so this is part of your [6:06] satiety signaling. All sorts of problems [6:09] with the stomach, right? So similar to [6:11] the esophagus, food might not leave uh [6:13] you know as it should in the right in [6:15] the right timing. So it can happen due [6:17] to ulceration in the stomach, scarring [6:19] or something called gastroparesis where [6:22] for a variety of reasons it might be [6:23] postviral, it might be due to diabetes, [6:26] uh neural hormonal um kind of origins of [6:29] this, the stomach just doesn't empty as [6:31] it should. People have nausea and [6:33] vomiting with that and other problems. [6:34] So then you get into the small bowel and [6:37] the small bowel's job now typically you [6:39] do a little digestion so early on cuz [6:41] you have pancreatic and bilary [6:42] secretions going in there but its main [6:44] job is going to be to absorb calories [6:46] right so that's absorbing calories and [6:48] moving it down it's very thin it's one [6:50] cell thick has about the surface area of [6:53] like a pickle ball court right [6:54] >> one cell thick [6:55] >> yeah one cell thick the lining is one [6:57] cell thick that's where the cell type [6:59] just to [7:00] >> interosytes [7:01] yeah must be some really sturdy cells [7:04] >> columnar epithel ium. Yeah. So, they're [7:06] pretty sturdy. Uh they they rely on more [7:08] than just the cell itself to to to [7:11] maintain that barrier. Um there's [7:12] certain cells called goblet cells that [7:14] produce mucin and that creates a nice [7:16] thick layer there uh that help as as as [7:19] another part of the barrier. They have [7:20] something called tight junctions right [7:22] between the cells which are complex [7:24] little structures that are part of that [7:26] barrier as well. And there's immune [7:28] cells in there. There's other elements [7:30] to that barrier but it is one cell layer [7:32] thick. So that's why the stomach's the [7:34] esophagus and stomach got a good job of [7:35] processing that processing that food so [7:38] that it's it's safe to go down through [7:39] the small bowel and be absorbed. All [7:41] sorts of issues with the small bowel. [7:42] Similarly you can have different [7:44] diseases that affect that you know [7:46] celiac disease uh Crohn's disease etc. [7:49] different inflammatory conditions. Um, [7:52] and uh, what we're learning now and [7:54] hopefully get get into is it plays a [7:57] central role we think in metabolic [7:58] disease. And that's kind of what's very [8:00] exciting is is its role in obesity, [8:03] diabetes, and other similar conditions. [8:06] And then eventually you have the colon [8:08] and that's where your microbiome is the [8:10] star, right? The colon uh, its job is to [8:12] usually just absorb water. Most of the [8:14] nutrients are gone by then. But it does [8:16] play an important role um as well and it [8:19] is working handinhand with your [8:20] microbiome to uh you know to to make [8:23] sure that um you producing it really [8:26] it's it's it's mostly butyrate I think [8:28] that's mostly involved there where the [8:30] microbiome is producing short chain [8:31] fatty acids and one of them the most [8:33] important probably is butyrate that has [8:35] a lot to say about your metabolism as [8:38] well that's involved in satiety [8:39] signaling and you have a lot of GLP1 [8:41] produced in the colon again so you're [8:43] you're getting these kind of endocrine [8:45] function function of your colon that's [8:46] very involved and then it passes. So and [8:48] again diseases in the colon colon cancer [8:50] is a big one right so colon cancer [8:52] screening is important people typically [8:54] now I think they moved the age back to [8:55] 45 everyone should start getting [8:57] screened uh to make sure you know they [8:59] don't have uh cancer you can do it [9:01] different ways there are genetic tests [9:03] you can do like colig guard and if you [9:05] do that you have to do it every every [9:07] few years but you can do that uh you can [9:09] do screening colonoscopy every 10 years [9:11] if it's normal and there's other things [9:13] you can do as well CT colonography is [9:15] not as common and other tests but those [9:16] are the two most common. It's important [9:18] important to do that. [9:19] >> How common is um colon cancer [9:21] >> in our line of work? Is the is the most [9:23] frequent cause of of cancer? [9:25] Unfortunately, [9:26] >> are more people being diagnosed because [9:28] of more diagnostic procedures and are [9:31] more people surviving colon cancer. [9:33] >> The survival rates are definitely [9:35] improving due to screening programs, [9:36] right? So that's that's important. So it [9:38] is definitely important to get screened. [9:40] Also screening earlier helps. So for [9:42] instance, starting at 45 is better than [9:44] many people who started at 50 and they [9:45] wouldn't get till 55 or 60, right? But [9:47] also if you have a family member that [9:49] has had cancer, you want to start at 40 [9:51] or if they were younger, you want to [9:52] start 10 years younger than when they [9:53] were diagnosed, right? So you want to [9:55] start that screening process really. [9:57] It's very effective. Um, you know, and [9:59] uh it's important to do it. And I think [10:01] that things like colag guard and other [10:03] genetic tests are going to keep getting [10:04] better and help because you don't have [10:06] to have that kind of very uncomfortable [10:08] screening procedure. colonoscopy is not [10:10] it's not a great way to do screening, [10:11] right? You shouldn't have to have a [10:12] relatively invasive procedure to be [10:13] screened for something, you know? It [10:14] should be something you just do a blood [10:16] test or a stool study or something like [10:18] that. And I think we're getting there [10:19] with technology and that will definitely [10:21] show dividends cuz you can have the [10:22] colonoscopy to remove the lesion, which [10:24] is something that we can do. It's it's a [10:26] newer technique where we can actually go [10:27] in and remove these very early cancers [10:30] endoscopically. So, we call it organ [10:32] sparing surgery. So, you don't have to [10:33] actually remove a piece of the colon [10:35] anymore. you can just kind of, you know, [10:36] take take the lining where that [10:38] precancer is residing. It's a [10:40] complicated procedure, but it's easy for [10:41] the patient. You know, they keep their [10:43] colon, they go home the same day. And [10:45] these tests, you know, are are easy ways [10:48] to to diagnose those patients and and [10:50] get them in for proper care. So, very [10:52] important. So, that's pretty much the [10:54] quick overview of of the gut. And uh it [10:57] plays one thing we haven't touched on [10:58] too much yet is its role in in really uh [11:02] you know satiety and and kind of how [11:05] it's involved in processing of food uh [11:08] in detail and the kind of endoendocrine [11:10] system that's involved. I'd like to take [11:13] a quick break and acknowledge one of our [11:15] sponsors element. 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I personally have used Lingo, [13:21] and it's been an invaluable tool for [13:23] improving my metabolic health. If you [13:25] would like to try Lingo, Hubberman Lab [13:27] listeners in the US and UK can save 10% [13:29] on a 4-week plan. Just visit [13:31] hellolingo.com/huberman [13:33] for more information. Terms and [13:35] conditions apply. Again, that's [13:37] hellingo.com/huberman. [13:40] Couple questions that uh no doubt will [13:43] resonate with people because they're [13:45] fairly common and you'll tell me if [13:47] they're of concern or not depending on [13:49] the frequency. We'll start at the the [13:50] top of the the GI tract. People will say [13:54] sometimes that they eat and some of the [13:55] food seems to go up their nose. They [13:58] know this because if they blow their [13:59] nose, they might get some food [14:00] particulate. It it sounds like something [14:02] that's not entirely uncommon based on [14:03] the number of questions I get about it. [14:05] What's going on there? Why would you [14:06] know I get asked a lot of questions some [14:08] of them truly weird and rare and some of [14:10] them um weird and less rare and I would [14:13] put it in the second category [14:14] >> that could be a variety of different [14:16] things and this is the area that I do [14:17] work in right so it can be an oral [14:20] fingial transfer problem where the the [14:22] hypoparrenx is transferring food into [14:23] the esophagus that can be you know ENT [14:26] thing it can actually be functional [14:27] medicine as well where you can work with [14:29] a speech pathologist that teaches people [14:31] how to swallow better they might have to [14:32] change the the quality of the food [14:34] they're eating to thicker food they [14:35] might have to turn a certain way to [14:36] swallow and there's ways they can [14:38] actually train people with with kind of [14:39] bio feedback to to learn how to swallow [14:42] better because that part's still under [14:43] your control a little bit. [14:45] >> They're not swallowing well. [14:46] >> Yeah. And with age that can happen, [14:48] right? With age that can happen. Now the [14:50] next thing that can contribute to that [14:51] is if they have high tension in the [14:53] first sphincter up above which is the [14:54] upper esophageal sphincter. That's the [14:56] the sphincter that separates the top of [14:58] your esophagus from your mouth [15:00] basically. And that can be have high [15:02] tension. And what I see a lot is [15:04] something called Zanker's diverticula, [15:05] which we haven't talked much about. [15:06] There's a few different little pockets [15:08] that can form high up on your esophagus [15:10] near that sphincter. [15:11] >> There's different names for how they, [15:13] you know, kind of where they where they [15:14] exactly occur. [15:15] >> And with time and with age, this this [15:18] this is like a herniation of mucosa [15:20] through the muscle and it creates a [15:22] pocket and that can actually trap food. [15:24] So when people are eating, the food goes [15:25] into the pocket and then comes back up [15:27] on can go out their nose or or sit in [15:29] there which is very uncomfortable for [15:30] them, right? That's another way you can [15:31] have problems swallowing [15:33] >> and that can be fixed very easily. We go [15:35] in through the mouth actually make a [15:36] tiny incision and just kind of take down [15:38] the septum that's part of that pocket [15:40] opening up the pocket so that the food [15:42] can leave. So it's important to do it [15:44] early too because people can actually [15:46] this it looks like an inconvenience [15:48] initially, right? It's you know you're [15:50] not swallowing well. foods, you know, is [15:52] is not where it's supposed to be [15:53] necessarily. The problem is when people [15:55] then aspirate and that food goes in the [15:57] lung and then it can lead to scarring in [15:59] the lungs and eventually it can really [16:01] cause problems. So, it is something that [16:03] should probably be taken seriously and [16:04] looked at even though it sounds funny, [16:06] you know, it is something that can be a [16:08] real problem. [16:08] >> There's a weird thing about GI tract and [16:12] bowel movements in particular, which is [16:14] the following. with babies, with puppies [16:17] and to some extent with ourselves, but [16:19] especially with babies and with uh [16:22] puppies, we sort of because they can't [16:24] speak, we have a couple of like key [16:27] readouts that we intuitively understand [16:29] reflect their health. One is the color [16:32] of their skin, the eyes, like if eyes [16:34] are looking glassy or tired, you know, [16:37] um and their and the uh quality or lack [16:40] thereof of their bowel movements, [16:41] quality, frequency, etc. But then [16:43] something happens where speech comes [16:45] online and we get uh you know uh toilet [16:50] trained and then everyone's responsible [16:51] for like understanding like their own [16:53] bowel movements, right? And then we're [16:55] never really told like what's healthy [16:57] bowel movements but we all kind of know [16:59] what's normal for us or not normal. I'd [17:01] be lying if I didn't say like these are [17:02] important metrics of health. Yeah. Well, [17:06] there's so much you can tell from bowel [17:08] movements. Okay. So the rule of thumb [17:10] is, you know, you don't want to have [17:11] more than three a day and you don't want [17:13] to go longer than three days without [17:14] having a bowel movement. So that's kind [17:16] of the general rule and you want it to [17:17] be one formed bowel movement, you know, [17:19] or a couple. You don't want little tiny [17:21] pebbles. That's called scibula stool and [17:22] that's that's a sign something's going [17:24] on. But there's a lot you can tell how [17:26] much are they taking enough fiber, [17:27] right? the World Health Organization um [17:30] uh published something in the Lancet [17:32] years ago on on fiber fiber synthesis I [17:35] think they called it and they found that [17:36] you know the vast majority of population [17:39] really doesn't especially western [17:40] countries just are not getting enough [17:41] fiber which is obviously concerning [17:43] because that that causes a lot of issues [17:45] long term right which we'll get into. [17:48] But if you're having these scibulus [17:50] stools, if you're if you are [17:51] constipated, meaning you're having a [17:53] bowel movement more than once every 3 [17:54] days and they're hard stools, that's a [17:56] sign you're not getting enough fiber. So [17:58] that's one thing you really have to to [18:00] think about, right? Additionally, [18:01] there's other things you can tell after [18:03] procedures. You know, if a if a [18:04] procedure if a if a bowel movement is [18:06] very dark, tarry, and shiny, that's sign [18:08] you have blood in your GI tract, right? [18:09] So there's different things you can tell [18:11] from from from the stool that are [18:13] important to keep an eye on. But in [18:14] general, that's kind of the rule of [18:16] thumb. uh you know uh with with uh with [18:19] bal having more than three a day is [18:20] probably leaning towards being too [18:22] loose, right? And if you're not having [18:24] one every three days, you're probably [18:25] bound up and and then you really have to [18:27] think about fiber. [18:28] >> As I recall, the recommendations were [18:30] for adult men 35 grams of fiber per day [18:33] and for women 25. And obviously that's [18:36] not accounting for variations in body [18:38] weight and height and all the rest. So [18:40] um does that sound about right? [18:42] >> Yeah, that's that's about right. And it [18:44] kind of depends on the quality, too. [18:45] There's a couple other really [18:46] interesting studies that came out [18:48] recently just within the last few years [18:50] uh looking at the importance of fiber [18:52] related to certain conditions like one [18:54] was fatty liver right and fatty liver it [18:56] was a interesting interesting study they [18:58] were using resistant starch like level [19:01] two so basically raw powdered um [19:04] potatoes something like that right uh [19:07] >> um and they were supplementing it I [19:09] think it was at 40 g and they found that [19:12] when they did that they actually saw a [19:14] significant improvement in fatty liver [19:16] which is phenomenal right and it was you [19:17] know relatively weight stable. So it has [19:20] important treatment effects. Another [19:21] group actually um studied it and looked [19:24] at insulin uh sensitivity. So they did [19:26] clamp studies you know where they they [19:28] would um kind of really be able to [19:30] detect insulin resistance and kind of [19:33] try to look at um kind of glucose [19:35] utilization and clearance. And they [19:38] found that with this RS2 type, you know, [19:41] resistant starch too, they were able to [19:43] improve insulin resistance and insulin [19:45] sensitivity as well. So fiber is very [19:48] important. It's not just about the bowel [19:49] movements, right? It's also about, you [19:51] know, really just having, you know, [19:53] health. [19:54] >> It probably helps the microbiome. [19:55] There's there's all sorts of evidence [19:57] that if you don't have a lot of fiber, [19:59] your microbiome is not healthy, right? [20:01] You get less diversity in your [20:02] microbiome. the different studies that [20:04] have looked at that. It is important to [20:06] have that fiber and that constipation is [20:08] an early window into it, right? It's an [20:10] early sign that maybe you're not getting [20:12] enough enough fiber. [20:13] >> Yeah, I make it a point to eat fruits [20:15] and vegetables because I like them. But [20:17] recently, I started supplementing with a [20:18] powdered pelium husk that and some of [20:21] them actually taste pretty good and my [20:23] expectation is I was going to feel [20:24] really bloated. It was quite the [20:26] opposite. It not that I had gut issues [20:28] before. if it was normally kind of like [20:30] hypernormalized things actually it made [20:33] uh postmeal um subjectively the [20:36] sensation just like feel good feel great [20:39] um and I didn't expect that I thought [20:40] okay more fiber I think a perception [20:42] people have is like more fiber more [20:44] regularity and more bloat [20:46] >> and I think that's a that might be true [20:48] for some people but it certainly wasn't [20:50] my experience and I think that if I feel [20:52] like the messaging on fiber to the [20:54] general public is pretty lousy meaning [20:57] people are told to take it that's Great. [20:59] They're told all the time, but I think [21:00] people think, "Oh, if I have a lot of [21:01] fiber, I'm going be really gassy. I'm [21:03] going to be really bloated." But as you [21:04] point out, it's not just about [21:05] regularity and speed of digestion. It's [21:08] about creating a healthy millu for the [21:11] gut. I think if more people knew that, [21:13] they'd probably make a move to consume [21:15] more fiber. [21:15] >> Totally. It's like feed your microbes, [21:17] you know, or they're going to eat you, [21:18] right? And it's kind of true, right? [21:20] Because they need they need to be fed. [21:23] And what they eat is fiber. Okay? That's [21:25] what you want them eating. You want them [21:26] eating fiber. And if you're not feeding [21:28] them fiber, they'll eat your mucous [21:30] layer. Okay? And we already talked about [21:31] how thin that barrier is and all of a [21:33] sudden they start eating your mucous [21:34] layer, they're they're not producing the [21:36] butyrate you need. And the butyrates [21:37] needed to maintain the tight junctions, [21:39] right? So there's layers to this. It's [21:41] like a snowball effect that if you're [21:44] not feeding those micro the microbiome [21:46] and keeping it healthy, you're going to [21:47] run into all sorts of all sorts of [21:49] trouble. [21:50] >> Raises some um interesting questions [21:52] about uh intermittent fasting. I think [21:54] very few people are doing long-term [21:56] fasts of more than a day or so. I mean, [21:58] it does happen, but most people a lot of [22:00] people do sort of timerestricted feeding [22:01] or they they'll skip breakfast. You [22:03] know, I'm I'm one of those people most [22:05] days just by default. I had a a [22:08] colleague friend at Yale who studied [22:10] microbiome and I said, "Oh, so does [22:11] fasting improve the gut microbiome." And [22:13] he said, "No, actually during the [22:14] fasting period, your microbiome starts [22:16] eating up your your digestive tract, [22:19] which is what you're But then he said, [22:20] but then the rebound often is puts you [22:22] at a slightly better place afterward. So [22:25] it's tricky. Should people avoid [22:28] intermittent fasting if they're having [22:29] gut issues? I know we don't want to make [22:31] any broad recommendations. It's highly [22:33] contextual, but based on what you said, [22:35] it it seems that it stands to reason [22:37] that you might want to avoid having your [22:39] stomach empty for very long periods of [22:41] time outside of sleep. [22:43] >> I don't see it as being a major issue. I [22:46] think the benefits of intermittent or [22:48] timerestricted eating, intermittent [22:49] fasting probably would outweigh that [22:51] risk. You know, you need to give your [22:53] pancreas time to relax. You know, you [22:55] need to have insulin come down. If [22:57] you're eating frequently, your insulin [22:58] levels are already up, always up, and [23:00] that that causes problems. So, I do [23:03] think the benefit of of of the the time [23:06] restricted eating definitely outweighs [23:08] that that potential risk. [23:09] >> Yeah, great to hear. um especially as [23:11] somebody who just by default doesn't eat [23:13] breakfast or and just don't get hungry [23:15] till 11. [23:16] >> I skip breakfast as well, but there's [23:17] studies because initially they actually [23:19] used to say, well, you have a cordal [23:20] sauce spike in the morning and you know, [23:23] you know, you're more likely to star the [23:25] uh the food you take in if you if you if [23:27] you eat in the morning. Turns out maybe [23:29] that's not so true. It might be better [23:30] to actually have you know, eat earlier [23:32] and then have your fasting window start [23:34] in the afternoon, right? I think doing [23:35] is better than not doing it. I still I [23:37] still skip the breakfast. The topic of [23:39] fermented foods, low sugar fermented [23:40] foods as a possible benefit for gut [23:42] health has come up um since Justin [23:45] Sonnenberg and colleagues have published [23:46] that the study. It there's a small [23:49] number of people in that study [23:50] admittedly, but um that taking in some [23:53] low sugar fermented foods really helped [23:55] lower the inflamm. They didn't look [23:56] specifically at as I recall uh symptoms [24:00] of gut irritabil irritation or things of [24:02] that sort, but what are your thoughts on [24:03] fer low sugar fermented foods? So, we're [24:06] not talking beer. We're talking kimchi, [24:08] sauerkraut, brine. [24:10] >> I think they're they're important. Um, [24:12] and they're missing in the western diet, [24:14] which is an issue. And I think there's [24:16] the study you referred to actually, I [24:18] think they compared it to to fiber, [24:19] right? It was it was fermented foods to [24:21] fiber. [24:22] >> And with the fermented foods, you had uh [24:24] reclaimed some diversity in in the [24:26] microbiome, which was great, as well as [24:28] the reduced inflammatory markers where [24:30] the fiber didn't seem to do that. And [24:32] you saw all these benefits in these [24:33] other other fiber trials that we're [24:34] we're talking about with the resistant [24:36] starches, right? So, it stands to reason [24:38] that we'd probably see that as well as [24:40] we do more research into the fermented [24:42] foods. They're beneficial for a variety [24:44] of reasons. You know, one, they're [24:47] prebiotic, right? So, you're feeding [24:49] your microbiome things they want, which [24:51] is phenomenal. And it's already kind of [24:52] started. It's a little partially [24:53] digested, which is really helpful. And [24:56] um and they're also a little bit of a [24:58] probiotic as well because you do have [25:00] some, you know, some live cultures in [25:03] there, right? And um they usually have [25:05] bifidto bacterias for lactobles or [25:07] something like that in in them and a [25:08] variety of other things as well. So it [25:11] gets the ball rolling, right? So it's [25:12] sort of like when you're you're trying [25:13] to grow something, you want to plant the [25:15] seeds but also have the fertilizer and [25:16] whatnot. And this this is what um [25:18] fermented foods do for you. So I think [25:21] you know that that's that's very [25:24] helpful. And it's all about maintaining [25:26] this this kind of healthy microbiome [25:29] that can produce things like butyrate [25:30] which have a lot of a lot of benefits we [25:32] can talk about. You can't just take [25:33] butyrate and then it's not going to make [25:35] it to the colon, right? It needs to be [25:36] in the colon to have its to have to have [25:38] its effect. And so what these bacteria [25:41] do is they kind of they they will um [25:45] kind of crossfeed in a sense, right? So [25:47] you have those first layer of bacteria [25:48] that will take the fiber and break it [25:50] down and they create acetate and lactate [25:52] and whatnot. And then that can then be [25:54] used by other bacteria. So you're [25:56] feeding the other the other bacteria [25:57] that can then turn that into butyrate, [25:59] you know, and things like that. The [26:01] butyrate is magical, right? So that will [26:04] feed your colon cells. Your colon cells [26:05] live on that with butyrates needed for [26:08] those tight junctions. Butyrate, you [26:10] know, does all sorts of things via GLP-1 [26:12] pathways and satiety pathways. So it has [26:15] a lot of different uh a lot of different [26:17] roles that it's playing. Additionally, [26:19] it keeps your bowel acidic, right? So [26:22] like these short- chain fatty acids and [26:24] you know acetate and whatnot and that's [26:27] great to to make sure you are protected [26:30] from certain pathologic organisms might [26:32] want to take take root, right? So the [26:35] aerobic organisms and the the other [26:37] organisms that you don't want don't [26:39] survive as well in an acidic [26:40] environment. [26:41] really important to to to take these [26:44] fermented foods in addition to fiber. [26:46] >> Do you make it a point to consume them? [26:48] >> I do. Yeah. I I Yeah, I like keer or [26:50] kefir and everyone say that, right? I [26:52] like I like that. I think it's [26:53] phenomenal. Yeah, it's good. [26:55] >> Kimchi is good, you know, sauerkraut. [26:57] >> Um there's all different types. Yogurt, [26:59] you know, um there there different types [27:01] I think that everyone should be able to [27:02] find. Kombucha, you know, [27:05] >> um and it's certainly missing in our [27:06] diets. So I think it's it's important to [27:08] to to to recommend that the folks do [27:12] >> cankera sores and ulcers u my [27:14] understanding for a long time is they [27:15] were caused by stress or wounds to the [27:17] mouth and then you know couple folks won [27:20] a Nobel prize for identifying a [27:22] soilbased bacterium that causes ulcers [27:24] and I loved that Nobel Prize year you [27:27] know as a scientist like some people [27:28] watch the Super Bowl like you know like [27:29] who you know who won the Nobel Prize and [27:31] it's never surprising who wins it's at [27:33] least for the scientists right um it's [27:36] often surprising who doesn't but let's [27:37] leave aside that uh that component but [27:39] that was a very surprising set of [27:42] findings right like a gut bacterium is [27:44] causing ulcers and I I love the findings [27:47] but at the same time I think many many [27:50] millions of people hundreds of millions [27:53] billions across history would say stress [27:56] gives people ulcers so there's something [27:58] going on there that's more than [28:00] soilbased bacterium right [28:02] >> yeah definitely you know and that that's [28:03] the problem with these you know the way [28:05] the media covers these findings like [28:07] it's not all that you ingested the wrong [28:09] soil. Stress can give you ulcers, right? [28:11] Or am I am I missing something? [28:13] >> Stress can play a role. Um, you know, it [28:16] is it is certainly complicated. So Barry [28:18] Marshall was phenomenal in Australia and [28:20] he found H. pylori could cause gastric [28:22] ulcers, right? And he had to consume, no [28:24] one believed him. He had to consume [28:25] himself consume it and and then he had [28:27] gastric ulcers. [28:28] >> I love it when scientists do self [28:30] experimentation. [28:30] >> That's crazy, right? So, but that was [28:32] phenomenal, right? And he he proved H [28:34] pylori and we need to treat that, right? [28:36] >> And uh and that that actually H pylori [28:38] was actually found even in AI the [28:39] iceman. I don't if you remember AI the [28:41] ice man. He was this uh [28:44] >> 5,000y old, you know, homo sapien in the [28:46] in the Italian Alps. He was found [28:48] frozen, right? So you could actually get [28:49] into his stomach and see what's in [28:51] there. [28:51] >> He died stressed. He had h pylori in his [28:53] stomach. That thing's been around a long [28:55] time. It's kind of interesting. There's [28:57] other lessons there like like a loss of [28:59] of of diversity of the microbiome, [29:02] right? with industrialization, we have [29:04] far fewer species and less genetic [29:06] diversity in our microbiome. But [29:08] regarding ulcers, so I I actually did [29:12] study this in gastric bypass patients a [29:14] good bit, right? And uh it was not a [29:17] bacterium that was causing it, right? [29:18] Sometimes it was a relative eskeeia. [29:20] Type two diabetes causes uh kind of [29:23] microvascular eskeemia. Smoking can [29:25] cause microvascular eskeeia. In gastric [29:27] bypass patients, the small bowel doesn't [29:30] uh it's it's a distal part of the small [29:31] bowel from lower down that's connected [29:33] to the stomach and it doesn't have [29:35] bicarbonate uh that's being secreted [29:37] from the pancreas in in the area. So [29:39] there's no way of neutralizing acid. So [29:41] if the pouch which you know we can get [29:43] into the anatomy here, but if the pouch [29:44] of of the gastric bypass is too large [29:46] and makes acid the douadinum now has no [29:49] the junum actually has no natural [29:51] defense against that. So acid clearly [29:54] plays a role and if you're stressed it [29:56] can produce more acid, right? So [29:58] generally there's probably multiple [29:59] hits. We don't fully understand things, [30:01] but clearly it's not just an infectious [30:03] organism and it kind of depends on [30:05] individual circumstances um and [30:07] susceptibilities, but ulcers are [30:10] certainly something that can occur short [30:11] of a bacteria. [30:12] >> So important for people to hear that, [30:14] you know, because one thing can cause [30:16] something, it doesn't mean it's the [30:18] always the case that [30:19] >> Yeah. So, let's talk about metabolic [30:21] health, hunger, obesity, weight loss. [30:23] These are areas that went, you know, [30:25] square in your wheelhouse. Can't have [30:27] this conversation without talking about [30:28] the GLPS. Um, most everyone has heard of [30:30] these things nowadays. Millions and [30:32] millions of people I've heard, I don't [30:35] know if this is true, as many as 20% of [30:37] of uh people 18 and older have taken or [30:40] are currently taking a GLP or either, [30:43] you know, Zen Picjaro soon, Red True [30:45] Tide will be out to market. What's your [30:47] thought on these compounds? are they the [30:50] perfect solution to weight loss? [30:52] >> Well, I'm grateful we have them, right? [30:54] Um, obesity is is a serious problem and [30:59] all the all the metabolic issues that [31:01] that are kind of there with obesity [31:04] uh need to be addressed and we weren't [31:07] doing much with it unfortunately until [31:08] the GLP1s came around. So, GLP1s are [31:11] fantastic from that standpoint. They're [31:13] not perfect, you know, there's [31:14] limitations, but they're it's much [31:16] better to have them than not have GLP [31:18] ones, for sure. There's issues with with [31:21] certainly um adherence, unfortunately. [31:24] Right. So, there's a there's a number [31:25] over a million people a month are coming [31:27] off GLP-1s, right? And that's for a [31:29] variety of reasons. About 30% come off [31:31] GLP-1s in the first month and then 50% [31:34] or so by by the end of the year, right? [31:37] So, and it's not specific to GLP1s. You [31:39] see that with any medicine. You see that [31:41] with with blood pressure medicines? You [31:42] see that with cholesterol medicine? [31:44] >> What's the Can we say what the primary [31:46] driving force is in the case of GLP1? Is [31:48] it the side effects? Is it they don't [31:50] like having to pin themselves? [31:52] >> I I think because the numbers so [31:53] curiously similar to all the other [31:55] medicines, maybe there's some underlying [31:56] thing where people just don't like [31:58] taking medicines frequently. [31:59] >> That might be part of it. I think that, [32:01] >> you know, sticking yourself is is a is [32:03] probably for some people they don't want [32:05] to jab themsel once a week. That might [32:07] be something. They needle fatigue. [32:08] That's probably there. I think when you [32:10] take a medicine orally every day, it [32:12] gets hard to remember to take it. And [32:14] then I think there are issues with with [32:16] how you ramp them up to the effective [32:17] dose and side effects. I think there's [32:19] ways you can do that, you know, safely [32:21] going step by step. But nausea is an [32:23] issue with some of these. You know, [32:24] muscle loss is an issue. There's [32:26] different features there. And then [32:27] additionally, you know, long-term this [32:30] this is, you know, you're taking a super [32:33] physiologic dose of something and we [32:35] don't know what the long-term [32:36] ramifications could be. So even though I [32:40] believe the benefits outweigh the costs, [32:42] right? You're treating obesity. We know [32:43] obesity is a problem. We don't know you [32:46] GP1 to be a problem long term. That does [32:48] weigh heavy on some people's minds and [32:50] that might be why they stop as well. So [32:52] in my practice where we do endoscopic [32:54] therapies, uh over 85% of people have [32:56] already been on a GLP-1 and either [32:58] they're struggling on it or they've come [32:59] off. [33:00] >> 80 85%. [33:02] >> Wow. [33:04] Yeah. Um we again we don't want to get [33:06] too far into the sociology and [33:08] psychology of of uh uh medication [33:11] adherence but it is interesting that so [33:13] many people come off meds but then there [33:15] are meds like SSRIs and things like that [33:17] which I think can benefit certain people [33:19] like people with like full-blown [33:21] clinical OCD extreme they save lives [33:24] right but but then they're [33:25] overprescribed I feel like especially in [33:27] the United States people like their [33:29] prescription drugs so if they're [33:31] stopping I feel like there's got to be a [33:33] reason. I mean, aren't we the biggest [33:34] consumer of prescription drugs in the [33:36] whole world? Like, people love their [33:38] drugs. Like, I you know, I've heard [33:40] about the nausea. I I don't [33:42] >> There are a number of people now who are [33:43] quote unquote micro doing the GLPS and [33:46] finding that they're getting some [33:47] benefits without taking the the the [33:50] prescribed amount. I'm not recommending [33:52] people do that. Uh, you know, I guess [33:54] talk to or don't talk to your doctor. [33:55] They probably won't approve. But I know [33:57] people are doing that. I think initially [33:58] it was because of cost and actually pen [34:00] sharing. Um but also people feeling like [34:02] oh I get the same effect. So is your [34:05] sense that when because the way clinical [34:06] trials are done there aren't often there [34:09] aren't like really nice dose responses [34:10] that you're just kind of comparing [34:12] they're so expensive to do these trials [34:14] that they're going you know two doses [34:16] you know moderate high versus placebo [34:19] and then the that's what the doctors [34:21] have to work from. Do you have any [34:23] knowledge of whether or not the lower [34:25] dosing brings takes people away from [34:28] side effects and then you're seeing [34:30] fewer of them? [34:30] >> I think it's actually very useful. So [34:33] that's you know the approved dosages are [34:35] kind of just an effect of our regulatory [34:38] system as as you've alluded to, right? [34:39] And it's too expensive to do different [34:41] different doses. Plus it takes it takes [34:43] away personalization. You know we're all [34:45] trying to get to precision medicine and [34:47] personalized medicine and that's what [34:48] micro dosing allows you to do. The first [34:50] time I I heard about micro dosing was [34:52] one of my patients and he was a [34:54] physician and he came in and he he said, [34:56] you know, I it's a it's too expensive, [34:59] you know, b I don't feel great on it and [35:01] c I'm doing this thing where I take the [35:04] pen and I inject it into a sterile vial [35:06] and they use a an insulin syringe and [35:08] I'll take a small amount out and I'll [35:10] give it to myself. And he said, I'm [35:12] doing great. You know, I don't feel [35:14] nauseous. My weight is staying off. and [35:16] you know he was a physician so he's he [35:18] was familiar with with you know the the [35:20] equipment if you will and that was the [35:22] first time I came across it I was like [35:24] wow that's actually that's a great idea [35:26] so a lot of my patients actually do [35:28] micro dose these things uh and you know [35:30] generally you get up to the the point [35:32] where you want to lose weight you get to [35:33] that dose you're losing weight you're [35:34] losing weight and then for maintenance [35:35] rather than just stopping it because if [35:36] you stop the jp1's there's problems [35:39] right this is not meant to to be stopped [35:41] these are kind of lifelong medicines [35:42] instead of stopping it just go to micro [35:44] dosing and you'll find a spot hopefully [35:46] you know, not everyone does, but you'll [35:48] find a spot where uh you keep the weight [35:50] off, you feel good, and you're not [35:52] you're not taking as much of the med. [35:54] Now, the problem with coming off of them [35:56] is especially with the the the original [35:59] drugs, you know, like simaglletide's an [36:01] example, right? Where when you lose [36:03] weight, about a third of the weight you [36:04] lose would be lean mass, right? So, most [36:06] muscle, right? Maybe some bone, etc. And [36:09] the problem is when you cycle on and [36:11] off, right? So, say you come off of it [36:12] and you put your weight back on. You're [36:14] not putting the lean mass back on, okay? [36:16] You're putting the fat back on. So, now [36:19] you've shifted your body composition to [36:20] be less favorable than before you run [36:22] the GLP1. And then you go on it again [36:24] and you lose weight again and you lose a [36:25] little more muscle. And then you go off [36:27] and you put more fat on, not more [36:29] muscle. So now, basically, you're taking [36:31] your your your body composition and [36:32] shifting it, you know, worse every every [36:34] cycle. So, there has to be a game plan. [36:37] If you're coming off the JLP1, you need [36:39] either to micro dose it or have a [36:41] bridging plan to a procedure or [36:43] something else which uh you know will [36:45] keep the weight off for you. [36:47] >> Are there any good studies um showing [36:49] that resistance training can offset the [36:51] muscle loss um from a standard or micro [36:54] dose of of one of these GOP drugs? [36:56] >> Yeah, resistance training definitely I [36:58] I'm not familiar with that where that [36:59] was the primary outcome of the focus, [37:01] right? But you can actually see that [37:02] that does play a major role in [37:04] maintaining muscle and that's with [37:06] anything. It's not just GLP-1 [37:07] medications. It's with the first [37:09] generation medications. It's with any [37:11] surgical procedure or endoscopic weight [37:12] loss procedure. You know, you if you're [37:15] doing resistance training, you tend to [37:16] maintain your muscle because the body [37:18] realizes, hey, I need this muscle. I'm [37:20] not going to I'm not going to get rid of [37:21] it as the person's losing weight, right? [37:23] So, when there's a caloric deficit, the [37:25] body is looking for what it can do to, [37:26] you know, uh, you know, to to to uh [37:29] maintain, you know, energy levels, if [37:31] you will. And you don't want it chewing [37:33] up the the muscle to do that. The side [37:36] effects that I see getting the most [37:38] coverage are um increased feelings of [37:41] apathy. Um general, you know, food noise [37:45] is down, al alcohol appetite is down, [37:48] appetite for life is down. You hear [37:50] this, but I don't know that how accurate [37:52] that is, right? Social media is a weird [37:54] place cuz certain things get amplified [37:56] it um out of proportion to the the real [37:59] data often. The other one is that GOPs [38:02] um can cause blindness. these GLP drugs, [38:05] but turns out that's in a very very rare [38:08] set of individuals that have this uh [38:09] optic nerve head kind of eskeemic [38:12] opportunity. So like so yes, the GLPS [38:15] can make certain people blind, but yes, [38:18] also it's a very small number of people. [38:20] So you want to get screened for this um [38:22] structural thing in the eye, but it's [38:24] not true that like GLPs are making [38:25] people go blind all over the place. So [38:27] what I'd like to ask is like when [38:29] patients come to you and they say like, [38:30] "I didn't like the GLP or it wasn't [38:32] working for me." Are they telling you [38:34] why? Are they saying, "Look, it made me [38:36] feel nauseous." Certainly, you know, if [38:37] it they lost their vision because of it, [38:39] but is there some resounding themes [38:41] there? There are. I think that muscle [38:43] loss honestly is is one of the bigger [38:45] ones, right? Um and it might just be [38:47] subtle like ompic face, ompic butt, [38:49] right? You're losing some muscle in [38:51] places where it's noticeable. Other [38:53] people actually truly develop [38:54] sarcopenia, I think, right? Where you [38:56] have significant loss of muscle. It's [38:58] rare, but those are people that they're [39:00] not really exercising a whole lot when [39:02] they take it and they might have had a [39:03] predisposition to it in the beginning, [39:05] right, to start with. [39:07] >> So, in people that I'm concerned about [39:08] that, it's good to get a DEXA scan [39:10] beforehand, right? Make sure you have [39:11] adequate muscle mass. And if you don't, [39:13] you really have to think twice about if [39:15] you want to do the GLP1, right? Or if [39:17] you want another another avenue to try [39:19] to lose the weight and you definitely [39:21] have to start hitting the gym. I think [39:22] that's the most common thing is is [39:24] muscle loss in obvious places or [39:26] sarcopenia developing. The other one's [39:28] nausea. A lot of folks do get nausea on [39:31] the higher doses and they will not lose [39:34] weight on the low dose, right? And if [39:36] they go on the high dose, they feel [39:37] nauseous. So that's another issue. Some [39:40] people say it stops working and that [39:42] might be because you know of of that of [39:44] that similar issue. They don't tolerate [39:45] the higher doses. Those are the primary [39:48] reasons that I that I hear. U maybe we [39:50] can move a bit towards some of the [39:51] surgical procedures. And um I always uh [39:54] like to remind people there's basically [39:55] two ways you can affect your your brain [39:57] and body. You've got chemical methods [39:59] and mechanical methods. So uh you know [40:02] um and when I think of quote unquote [40:04] stomach stapling, I think of that purely [40:06] as a mechanical thing. You're making the [40:07] stomach smaller. Make people feel full [40:10] earlier in the meal is my naive view of [40:13] this, right? But of course it stands to [40:14] reason that you're also removing tissue [40:16] and so you're going to change the [40:17] chemical millu of the environment. I'm [40:18] sure that you'll tell us that the you [40:20] know both things are involved and what [40:22] we had this thing called stomach [40:23] stapling for a long time. Why did we [40:25] need the GLPS? Now, some people say, [40:27] well, that's a surgery. But I think in [40:30] today's conversation, hopefully we'll [40:32] convince people that uh surgeries can be [40:34] done less and less invasively now and [40:37] can be done with tools that make it seem [40:39] a lot more like a a dental cleaning, [40:42] maybe a bit more than the idea that, you [40:44] know, you're cutting open the body and [40:46] taking things out, laying them out on a [40:47] table, putting back in this kind of [40:48] thing. Cuz people's minds go all sorts [40:50] of crazy places, trust me, including [40:52] mine. When we hear surgery, why did we [40:54] ever need the GLPS? We had stomach stay. [40:57] >> So surgery, it really started back in [40:59] the 50s. University of Minnesota, I [41:01] think, was the first place they did it. [41:02] And the first procedures were focusing [41:04] on malabsorption, right? So the idea was [41:07] they're going to bypass a portion of the [41:09] small bowel so that you don't absorb [41:11] your calories. Okay? And it was called a [41:14] juno ilial bypass. But this procedure [41:17] was awful, right? So the people did lose [41:19] weight, but the problem was they created [41:20] a long blind limb. So there was there [41:23] was no actual food going through the [41:25] limb. Okay. So you connected the junum [41:28] which is the kind of early small bowel [41:30] to the very bottom small bowel and the [41:32] rest of the small bowel was still in [41:34] there but it wasn't no food was going [41:35] into it. [41:36] >> So you had bacterial overgrowth in [41:38] there. [41:39] >> You had all sorts of problems. You had [41:40] the fat that was being malabsorbed was [41:42] binding calcium. And so calcium you [41:44] didn't have calcium in the bowel. So [41:46] what happens is the oxalate which [41:47] normally binds calcium gets absorbed and [41:49] then it binds calcium in the body in the [41:51] kidneys. So you're having all sorts of [41:52] renal failure issues and it was a [41:55] disaster went on for years right because [41:57] you know people were desperate but it [41:59] was a very bad procedure and it was [42:01] replaced by something called gastric [42:03] bypass and I think that came about [42:04] probably in the in the mid to late60s [42:06] and Mason I think was the was the [42:08] surgeon that came up with this. So his [42:09] goal was to avoid the problems with the [42:12] ji bypass and um you know still get a [42:16] treatment effect and he did right so he [42:18] thought of this as restriction. So when [42:19] you eat stomach stapling the stomach is [42:21] smaller so you'd have some element of [42:23] restriction and then also an element of [42:25] bypass where you're not absorbing all [42:26] your calories. Turns out that's not [42:28] really how this thing works really but [42:30] that's what he thought was going on. [42:32] >> And then from there you keep moving [42:34] forward you have all these other [42:35] procedures. lap bands, adjustable [42:36] gastric bands that was just purely [42:39] restrictive. It it worked. True stomach [42:41] stapling which was I think the VBG and [42:43] now the sleeve gasterectomy. So these [42:44] are the real surgeries and you know they [42:47] were created at the time just [42:48] conceptually thinking about either [42:50] restriction or thinking about [42:52] malabsorption but they work entirely [42:54] different than what they thought. [42:56] >> I have a question about your profession [42:58] generally. I'm guessing there are not [43:01] large-scale clinical trials of each of [43:03] these surgeries like they're doing you [43:04] know 5,000 of these surgeries comparing [43:07] to the existing surgery. So, how much [43:10] license do physic do surgeons have? Say, [43:12] you know what? I'm very familiar with [43:14] this tissue. Maybe I just like graft [43:17] these two, cut out the middle. That's [43:19] the part that absorbs stuff. Oops. Okay. [43:21] Actually, big problems and modify. And [43:22] then cuz I mean there's [43:24] >> there are other things, but there are [43:27] few things greater in terms of trophies [43:29] for a physician knowing some physicians [43:32] aside from the great feelings they get [43:34] from healing patients and saving lives. [43:35] Let's let's be fair. having a procedure [43:37] named after you that saves lives like [43:40] that seems to me like that's like the [43:41] ultimate thing. So there's got to be a [43:43] huge incentive for um physicians to do [43:45] it on that basis which might sound all [43:47] like ego but there's another facet to [43:49] this which is no and we know this from [43:51] science too like you can read about the [43:53] brain but if you get your hands on [43:55] brains record from them slice them up [43:57] look at them under a microscope [44:00] you just like a familiarity with the [44:02] tissue of interest especially in the [44:04] context of the whole person who's coming [44:05] back and saying I don't know I'm still [44:07] hungry less hungry but I got this pain [44:09] on my left side you know what that pain [44:11] could [44:12] Are there any procedures that you would [44:13] love to be able to do? Cuz you have the [44:15] sense that it could really help people, [44:17] but the red tape is just too thick that [44:20] it doesn't even make sense to try and [44:22] develop that procedure. [44:23] >> I don't think so. I think the proper [44:25] channels are workable. I do think that [44:28] there are compassionate use cases where [44:31] you need to make exceptions and then [44:32] they have expedited protocols for that. [44:34] I remember one time I had a person that [44:36] was bleeding and it was was bleeding [44:38] that was chronically going on and [44:40] couldn't be stopped and we needed [44:41] something that was not yet approved in [44:43] the United States. was approved in [44:44] Canada and the person they had no other [44:47] option right and so we were actually [44:49] able to get within you know 12 hours [44:51] approval to use it as compassionate use [44:53] and it worked for the patient so there's [44:55] even pathways for that right so I think [44:57] there's always you know there's always a [44:59] way to use that it slows it down yeah [45:00] you're excited to do something right and [45:03] it does slow things down but um but I [45:06] think it's always workable now there are [45:07] other examples of where you have a [45:09] device that's approved for one thing [45:12] that the company doesn't want to get it [45:14] approved for everything. So, it would [45:15] have no money to do that. So, you use it [45:17] off label. That happens every day in [45:18] every hospital. [45:19] >> Just like drugs are used off label. [45:20] >> Yeah. Right. Same thing, right? So, so [45:23] um like we use wires when we're when [45:24] we're accessing a bile duct to remove a [45:27] stone, right? That wire has not been [45:28] approved for that. It was approved for [45:29] some vascular indication, right? And [45:31] we've been using it that way forever [45:33] because no company ever went through and [45:34] did it. So, the whole field is based on [45:36] this, but it was never approved for [45:37] that. So, so there are examples where [45:39] you use your clinical knowledge and use [45:41] a device that's approved. it's approved [45:43] but just not approved for that [45:44] indication necessarily. And so there's [45:46] there's that. Um and that does require [45:48] medical judgment happens on a daily [45:50] basis. Um but if you're developing [45:52] something truly new, generally the [45:54] proper channels are very workable. And [45:55] actually a lot of times they give you [45:57] even better ideas like oh why don't you [45:58] think about checking these studies like [45:59] if you're doing this check this gut [46:00] hormone, right? So they have uh you know [46:03] a lot of times they they give good [46:04] feedback that helps the study um you [46:06] know improves the study. [46:07] >> I'd like to take a quick break and [46:09] acknowledge our sponsor AG1. AG1 just [46:12] launched their newest formulation called [46:14] AG1 Pro. And right now you can get an [46:16] extra 20% off your first subscription. [46:19] AG1 takes the clinically backed AG1 [46:21] formula, which is a blend of vitamins, [46:23] minerals, probiotics, and adaptogens, [46:26] and adds three important new [46:27] ingredients: creatine monohydrate, [46:29] calcium HMBB, and zinc carnosine. It has [46:32] 5 grams of creatine monohydrate to [46:34] support muscle strength and performance [46:35] along with brain health. Calcium HMBB to [46:38] support muscle recovery and reduce [46:39] muscle breakdown. and zinc carnosine to [46:42] support and improve the lining of your [46:43] gut. Some of these ingredients I [46:45] personally was already taking separate [46:47] from the AG1 formula. So, it's great to [46:49] see all three of them now in the new AG1 [46:52] Pro. As you may know, I've been taking [46:54] AG1 every single day for about 14 years [46:56] now. That means I discovered it and [46:58] started taking it daily long before I [46:59] even knew what a podcast was. I continue [47:01] to take it and back it here on the [47:03] podcast because it is an excellent [47:05] formula and it's now even better with [47:07] the AG1 Pro formula. For a limited time, [47:10] you can get an extra 20% off your first [47:12] subscription to AG1 Pro by going to [47:14] drinkag1.com/huberman [47:16] and using the code backtoine. So that's [47:19] with the numeral 2 back numeral 2 [47:21] routine. Just go to [47:22] drinkag1.com/huberman. [47:25] When it comes to the chemicals [47:27] associated with hunger and satiety, we [47:30] could just kind of like list out the the [47:32] big players. So we're talking about the [47:33] GLPS, which obviously play a role in [47:35] satiety and other things, hence the side [47:38] effects. So what are some of the big [47:40] ones that we don't hear about so so much [47:42] anymore because of the GLPS? [47:44] >> Yeah. [47:45] >> Well, it starts grein's a big one. [47:46] That's the hunger hormone, right? So [47:48] that goes up and it is produced in the [47:50] fundus of your stomach. And uh when that [47:52] >> the fundus is the uh [47:53] >> the very top of the stomach, the top [47:55] thin part of the stomach, right? The the [47:57] kind of where the esophagus comes in and [48:00] a lot of the ghre is produced there. And [48:03] when that's how you feeling hungry, [48:04] >> so it leaves the gut, travels to the [48:06] brain. [48:07] >> Yeah. and stimulates hunger. What a [48:09] beautiful mechanism. You're the top of [48:10] the gut. You're like, I haven't seen [48:11] food in a while. I'm still, you know, I [48:13] I have to say I'm proceverating in the [48:15] background about this this thing that [48:16] the gut expands in anticipation of food [48:19] and that that's odorbased. So, does that [48:22] mean that the alactory neurons are [48:23] communicating with the gut directly? Are [48:26] they talking to insulin goes up and then [48:27] the gut expands? Does [48:28] >> insulin actually does go up, too. So, [48:30] insulin is before you eat, you'll have a [48:32] little spike in insulin, too, right? So [48:34] I don't I don't know if they ever [48:35] figured out exactly that mechanism by [48:38] which uh smell you know tasting food [48:40] early on um uh triggers or seeing food [48:44] potentially right triggers this whole [48:46] process to start but before you swallow [48:48] any food right you already have insulin [48:50] coming up a little your stomach's [48:51] already starting to stretch to [48:53] accommodate the meal so maybe some of [48:55] it's learned as well I don't know but [48:57] I'm not sure those mechanisms but it's [48:59] very interesting how it's a critical [49:01] role right it certainly is involved [49:03] >> when Was it grein discovered? I I should [49:05] know this. It was this is like over 30 [49:07] years ago. [49:07] >> Yeah, it was it was it was a while ago. [49:09] Yeah. So after grein that's your hunger [49:11] hormone, right? When you eat it drops [49:13] and then you know it comes back again [49:15] sometime after the meal. So grein is one [49:17] to watch cuz we actually we actually use [49:18] ghrein. We work with ghrein. It's one of [49:20] the mechanisms we we use to to um get [49:23] our treatment effects with endoscopic [49:25] procedures and with surgical procedures [49:26] too. So that's ghrein. So then after it [49:28] kind of the food leaves the stomach, [49:30] right? Then you have your CCK which goes [49:32] up, right? Which um CCK will cause the [49:35] the gallbladder to dump bile, but it [49:37] actually also will be a satiety signal [49:39] as well. And um it that that's secreted [49:42] from the the first part of the the dueum [49:44] there. And you also have peptide Y and [49:46] GLP1. Of course, they're big ones. [49:49] Before you get there, I guess G GIP from [49:51] the K cells approximately too. GIP is [49:53] like GLP-1. It's kind of similar. It's [49:56] not it's not quite as potent. um people [49:58] think of as Batman and Robin with JLP1 [50:00] and GIP, right? [50:01] >> People might um be curious to know that [50:03] this drug retorew tide that the more [50:05] cavalier peptide curious folks are [50:07] already getting off from compounding and [50:10] gray market, black market reat, as I [50:13] understand promotes GLP, GIP and [50:16] glucagon [50:18] um to I think the clinical trial Lily [50:20] ran showed a 30% reduction in body [50:22] weight, which is really striking. So, [50:24] it's kind of curious that this GIP never [50:26] really took off as a drug, a druggable [50:29] thing, but you know, GLP seems to be [50:32] like the heavy gun, but now by combining [50:34] with other things, maybe you actually [50:35] get some synergistic effects. [50:37] >> It does help. I think it helps with [50:39] nausea. So, it allows you to have higher [50:41] doses potentially of GLP-1 with less [50:43] nausea. So, CIP, I think, plays that [50:45] role. It has a role in insulin [50:47] sensitivity as well. And it does some of [50:49] the same stuff JLP1 does, and it's [50:51] synergistic, I think. But what's [50:53] interesting about the glucagon is [50:55] potential muscle sparing there, right? [50:57] So glucagon among other things. So, you [51:00] know, glucagon is usually up when your [51:01] insulin is down and vice versa, right? [51:04] And its job is is is to say burn fat, [51:07] right? That's it main job. It also [51:09] causes you to to dump your your um [51:11] glycogen out of your liver a little bit, [51:12] but the main job with glucagon being up, [51:14] it says burn fat, right? It's kind of [51:16] nice that uh they're adding that as a [51:19] muscle preservation as well as as a way [51:21] of helping to burn some of the fat [51:22] potentially. [51:23] >> Yeah, these uh pharmaceutical companies, [51:25] however a bunch of people might hate [51:27] quote unquote big pharma, I mean they're [51:29] putting hundreds of millions of dollars [51:31] into the the research. There's kind of [51:33] an amazing case of the of like 20 years [51:35] ago there was nothing for for druggable [51:38] for for obesity as I understand and what [51:41] was there was mainly stimulant based [51:44] >> like the finine and like the valve [51:46] issues but you had well you had [51:47] fentamine right which was a [51:49] sympathomimedic really um and [51:52] >> speed [51:53] >> yeah basically [51:54] >> mother's little helper kind of thing [51:55] right I mean and nicotine you know [51:58] there's a whole set of conversations [52:00] there some people think that when we you [52:02] know basically abolished smoking. Um, [52:04] people started eating more and then [52:07] America got fat. Then snack foods and [52:09] highly palatable and there are a lot of [52:10] things, right? Moving more, eating more, [52:12] highly palatable foods and less fiber. [52:15] But um, now nicotine's back in oral [52:18] forms is back big time, mostly with men, [52:20] but also with women. And um, a lot of [52:22] people like it because it's an appetite [52:24] suppressant. I'm not a fan for a bunch [52:26] of reasons. Raises blood pressure, [52:27] highly addictive, and so on. But it's [52:29] interesting, right? Like people have [52:30] struggled for forever to like how can I [52:35] eat enjoy food but not eat too much [52:38] whether it's a compound that we norm you [52:41] know a drug that increases a compound we [52:44] already make like gip or we're taking [52:46] something to make us move around more [52:48] and like you said sympathy medics it's [52:50] like stimulants it's like a human [52:52] obsession why can't we just eat enough [52:54] and not too much [52:55] >> I think it's uh obviously metabolic [52:57] dysregulation and there are of it. The [53:00] processed foods which you touched on [53:01] certainly is an element to it, right? [53:03] There was a study done I believe it was [53:04] in Bethesda NH study when they had they [53:08] had like 20 subjects and they randomized [53:09] and crossed it over and they could [53:11] either have whole foods or they could [53:12] have processed foods and the people that [53:14] were eating the processed foods they [53:15] could eat at will. They were eating like [53:16] 500 calories more a day. So it is [53:19] something that you do in in your normal [53:21] environment if you're eating stuff in a [53:22] wrapper and you're eating it you're [53:24] inclined to eat more of it. And not only [53:25] are you eating more of it, right? It's [53:27] easier to digest, right? You're getting [53:30] bigger glucose spikes and you have a [53:32] lower thermogenic effect of food, right? [53:34] So, it really is it's probably also not [53:36] doing great for your microbiome because [53:38] there's less fiber in it. And so, that [53:40] is playing a big role. It starts [53:42] starting the ball rolling for sure. [53:44] >> And then there's different there's [53:45] different layers to it. Then you have [53:47] your your PY and your and your GLP-1 [53:49] which the GLP1 um you know it's [53:53] triggered by anything but glucose tends [53:55] to trigger more of it, right? And then [53:57] the PY, um, that's more, you know, your [53:59] proteins and your fat. And it does [54:01] something similar. You stay full longer, [54:03] I think, and with a with a big heavy fat [54:05] and protein meal, probably because of [54:06] the the PY. Um, uh, that's something [54:10] that's been very hard to drug, right? [54:12] They didn't have a Hila monster to solve [54:13] the problem that the GLP1 did, but uh, [54:16] it's it's also very potent. And they [54:18] both come from the L cells in the distal [54:20] small bowel and the colon. And, uh, [54:23] those are those are kind of all the the [54:24] major players. You also have leptin in [54:26] the background. Now, that's more of a [54:28] thermostat, if you will. It gets [54:29] involved in it set point and things like [54:30] that. And it's that's secreted from your [54:32] fat cells. Uh, and if it's in almost [54:35] proportionate to fat. So, if it's high, [54:37] you know, generally you're going to [54:38] probably eat less. If it's low, you're [54:40] going to eat more. But there's all sorts [54:41] of problems with leptin resistance and [54:43] other things like that, too, that [54:44] complicate it. I remember coming up [54:46] through science like leptin was all the [54:48] rage. um it's discovery, it's cloning, [54:52] and everyone thought, okay, there drugs [54:53] gonna are going to come along to mimic [54:56] or stimulate leptin and we're going to [54:58] solve the obesity or overweight issue, [55:02] but it didn't really pan out. Why was [55:04] that? I think leptin never panned out in [55:07] large part because of leptin resistance, [55:09] right? I think the hypothalamus and the [55:11] uh the brain itself is is just becoming [55:14] resistant to it because it's so high in [55:16] people with obesity for so long, right? [55:19] And [55:19] >> there's just saturated. They got a lot [55:21] of fat, a lot of leptin receptors are [55:22] are clogged. [55:23] >> There's low rate inflammation we know in [55:26] in in those tissues and and you [55:28] eventually just yep you don't respond to [55:30] it anymore. And so [55:32] >> so the the drugs just didn't pan out. I [55:34] think that um with with the GLP1s it's [55:37] another story, right? I think you know [55:39] incrretins in general we've talked about [55:41] incrretins we've been talking about [55:42] these these hormones that are produced [55:44] in the gut they go into the blood and [55:45] they do something. So the concept first [55:47] came about in the 1930s and it was in it [55:50] was in London and they basically were um [55:54] grinding up animal um douadinums. Okay. [55:57] And they're emulsifying it and injecting [55:59] it back into the animal in the vascular [56:01] system. [56:02] >> Science in its not crudest form history. [56:05] This is 1930s folks said science is not [56:07] that old you know real science [56:09] >> right nittygritty right and the idea for [56:12] that was secretin. So someone had found [56:14] secretrretin right and that is that [56:16] that's a hormone produced in the [56:17] dueadium that goes to the pancreas and [56:19] says secrete fluids for digestion. So [56:21] extorine function of the pancreas. So [56:24] this person thought well wow if the [56:25] dueium secretes secretrretin maybe it [56:27] secretes something else. So he they did [56:30] this study and in the animal the blood [56:33] glucose fell and like holy cow right [56:36] this something in the dudenum is causing [56:38] glucose to fall phenomenal. I'll call it [56:41] Inkrretton because you have Sacretton [56:42] I'll call it Incretton. So that was that [56:44] was where it started 1930s, right? And [56:46] then there's another lab uh Sheila [56:49] Sherlock's lab in in London and she was [56:51] famous for being one of the kind of you [56:53] know founding physicians that that that [56:55] started the field of hepatology and she [56:56] was trained in some medicine and some [56:59] some internal medicine some surgery and [57:01] they had this concept but what they had [57:03] access to was this new tool which is [57:05] where you see innovation right they had [57:06] access to this way of actually detecting [57:09] and measuring insulin and so they did a [57:11] very interesting study where they gave [57:13] subjects a set amount of glucose [57:16] introvenously and then they measured the [57:18] amount of insulin that was produced. [57:19] Then they gave them the exact same [57:21] amount of glucose orally and they found [57:23] they produced much more insulin. All [57:25] right, so this was something they they [57:27] they coined the incrretin effect. But is [57:30] that based on taste? So they had no [57:32] idea, right? But they knew the insulin [57:35] was going up and they thought it [57:37] probably because the only other research [57:38] that was out there was from this this [57:40] old 1930s study where it was coming from [57:42] the dudenim. was probably due to that [57:44] inkerton. Then there's other studies [57:46] that come after that that get get closer [57:48] and closer to it. Right. So eventually [57:50] what ends up happening is uh in in the [57:53] uh um Lily Labs I believe it was there [57:56] was there's a physician named Bell who [57:58] actually he he the pre-p pro glucagon he [58:02] ends up you know cloning that and then [58:04] from that you get GLP1 and GLP GLP2 [58:08] right and so he now he now we now have [58:10] GLP1 we've identified it and then there [58:13] was this a physician um uh Blossom I [58:16] believe was the name in in London again [58:19] this guy did some phenomenal work. So [58:20] what he ended up doing is now we had [58:22] GLP-1 so he could actually study it. He [58:24] found GLPM1 was in the bowel where we [58:26] thought it was. He also um found out [58:29] that when you actually gave glucose GLP1 [58:31] increased in the blood and then he [58:32] actually infused GLP-1 and found that [58:34] when he infuses it insulin goes up, [58:36] glucose goes down. So now all of a [58:38] sudden we had a real sign that what what [58:41] what this incretin was and it was GLP-1. [58:44] Very exciting work. The problem was you [58:46] had to infuse it, right, for it to work [58:48] because it gets chewed up really quickly [58:50] by dipepadil peptidase. It chews it up. [58:53] There's something on the end terminus of [58:56] it that is susceptible to that. And uh [58:58] that's the part that binds the receptor [59:00] so you can't really get rid of it. Uh [59:02] and then it was in the Bronx in the '9s [59:04] when there's a Dr. Ang and he's studying [59:07] Hila Monsters and in Hila Monster he [59:09] finds this thing in the Hila Monsters [59:11] Venom that looks very much like GLP-1. [59:14] has one uh substitution like second [59:17] second uh yeah amino acid in from the [59:19] inside otherwise looks just like it'll [59:21] bind a receptor. The C is a little [59:23] longer and different but this is um you [59:26] know uh extending 4 uh and basically [59:30] this is the the molecule he he discovers [59:32] and this is what ends up becoming all [59:34] the GLP ones. [59:35] >> These healer monsters don't have to eat [59:36] very often so it makes a good candidate [59:39] to to stay. [59:40] >> So you do surgeries of various kinds. um [59:43] the people are coming to you, they have [59:45] they all tried GLPs and they don't like [59:47] them or they're not working for whatever [59:49] reason or they'll micro dose it but it's [59:51] not solving the problem and um what [59:54] sorts of surgeries were you trained to [59:56] do and then at what point did you become [59:58] the doctor I referred to earlier uh who [60:00] seeks out IRB approval to build [60:02] something better like like I'm a I guess [60:05] if there are multiple themes in today's [60:06] discussion but one of them is if the [60:09] really great physicians look at a [60:11] problem they look at the tools they've [60:13] got to solve that problem and if they're [60:14] not working for any number of patients, [60:17] they build something better or different [60:19] or they they increase the array of of [60:22] tools. So tell us that story. How does [60:24] that where where did that start and [60:26] where are we at? Where are you at now [60:28] with that? [60:28] >> Really for me it started in in um [60:31] fellowship. So I moved to Boston to to [60:34] learn interventional gastronurology, [60:37] right? So this is not you know [60:38] colonoscopy and whatnot. It's doing [60:40] procedures mostly focusing on [60:42] pancreatobilary. So pancreas and bilary [60:44] conditions and the big problem at the [60:47] time was really pancreatic cancer [60:48] diagnosis. And so I was moving there to [60:51] learn a new procedure uh that they [60:53] called endoscopic ultrasound. So you'd [60:55] be able to put a scope in the mouth into [60:57] the stomach and small bowel and then use [60:59] the ultrasound probe that's embedded in [61:01] its tip to see the structures just [61:02] outside the lumen and you could gain [61:04] access to them. You could put a needle [61:06] in them and that held a lot of promise. [61:08] You could maybe ablate lesions with it. [61:10] You [61:11] >> So you're feeding a needle through a [61:12] tube. You're watching it on a screen, [61:14] right? So you're not you're not using [61:16] the you're you're not opening up the the [61:18] abdominal cavity. [61:19] >> Yeah. So you can do it through this [61:21] through the mouth. So it's a natural [61:22] orifice. You're going through the mouth [61:24] rather than opening up which for [61:26] pancreatic cancer a lot of times that's [61:28] how they would do it. They would go to [61:29] surgery, open the belly up, and get the [61:31] biopsy, right? To see what it was. Uh [61:34] cuz it's really hard to make the [61:35] diagnosis. And so I wanted to learn this [61:37] new technique where you just the patient [61:40] goes home the same day. They don't feel [61:42] anything, right? So I thought it was [61:43] phenomenal. When I got there, I I'd done [61:46] a masters in health evaluation science [61:47] at Penn State before before going and I [61:50] thought that I would be doing [61:51] epidemiologic research. And when I got [61:53] there, the my my my uh mentor, Bill [61:56] Buggy at the time was a pioneer in this [61:58] ultrasound. And um he he he gave me a [62:01] needle and said, "Hey, this thing [62:03] doesn't work to make the diagnosis of [62:04] pancreatic cancer. I need you to try to [62:06] fix this. Right. And he was right. The [62:08] thing didn't work. Unfortunately, like [62:10] we had about a 50/50 chance of getting a [62:11] diagnosis with the needle. And it's [62:13] because it was it was designed like a [62:15] hypodermic needle. Like you get an IV [62:17] placed, right? The IV is not taking [62:19] chunks of tissue out of you. It's [62:21] designed to atroatically split the [62:23] tissue. And that's needles we were [62:24] using, right? So for [62:26] >> to deliver stuff, not take stuff. [62:28] >> Yeah. Yeah. So I kind of figured out [62:30] what the problem was. They didn't know [62:31] the solution honestly, but I gave him my [62:33] report and the company thought it'd be [62:34] too expensive to fix and we didn't [62:36] really do much with it. But it still [62:37] went on. when I was a couple years into [62:39] practice on faculty there and you know [62:42] we still had the problem of you know you [62:45] you take these FNAS final aspirations of [62:48] it and you wouldn't have an answer and [62:50] you know you'd have people that wouldn't [62:52] want to have a major surgery having [62:53] their pancreas taken out without an [62:56] answer and then they'd have worsening [62:57] cancer and then by the time you'd be [62:59] able to make the diagnosis it'd be too [63:01] late to treat them and help them. So [63:03] that's where I started kind of uh you [63:05] know entrepreneurial stuff right and so [63:07] my first um my first company I guess [63:10] you'd say was based on that and uh I [63:14] needed a team you know and one of the [63:16] engineers had the brilliant idea of how [63:18] to change that bevel design helped raise [63:20] the money I knew what the clinical [63:21] problem was and and and that and whatnot [63:24] but you needed a team to fix it. So we [63:25] hired engineers and we got together and [63:27] we came up with a needle that could bind [63:28] to the pancreas without causing [63:29] pancreatitis or any problems and it has [63:33] been wonderful because that that really [63:35] became very instrumental in helping a [63:37] lot of people to get the diagnosis [63:38] earlier. So we're saving lives with [63:40] that. But now we look forward to the the [63:42] fact we have preserved cell cellular [63:44] architecture. So you could do you know [63:46] precision medicine. You can actually uh [63:48] test different drugs on the tissue and [63:50] see what it's going to respond to. you [63:51] can do immuno staining and uh it's a lot [63:53] better than just having a few shaved [63:54] cells. So that was the first time I [63:56] really get involved in in trying to [63:58] solve a problem like you say and that [64:00] was before I started diving into [64:01] metabolic disease where I've spent [64:03] really a large part of my time but that [64:05] was what started it off. So just like [64:07] earlier I you know I was saying the [64:10] mechanical influences and chemical [64:11] influences over our health and biology [64:14] for what I call like reading from the [64:16] body like people get a sleep score or [64:18] your heart rate or blood pressure that's [64:19] reading obviously you're not writing to [64:21] the body but you have a structure and [64:23] you have functional readout so like if [64:24] you know someone goes I have a pain in [64:26] my side and you go okay well you you uh [64:29] give them an ultrasound there's a [64:30] massive thing there like you got a [64:32] structure there that doesn't belong [64:33] there then then you can decide to cut [64:34] open right What I hear biopsy, people [64:38] hear biopsy, they go, "Oh boy, you're [64:39] getting poked with a needle." this kind [64:40] of thing. But I might shock a few [64:43] people, but if you told me that I could [64:45] come into the clinic and spend one long [64:46] day under anesthesia and get completely [64:50] non-damaging biopsies of every single [64:53] one of my major organs to grab a few [64:55] cells here and there through the mouth [64:57] or heck, even if they have to make a [64:59] small incision one place and then zip me [65:02] back up and send me home and I can just [65:03] say, "Okay, like I'm let's just look at [65:05] all the cells. Let's see what's you [65:07] know, let's see if I have any issues." A [65:08] lot of people be like, "Why would you do [65:10] that?" Well, I'd rather do that than [65:12] walk into the clinic at 72 and go, "I've [65:14] got this pain or I'm not sleeping well [65:16] or I'm sweating or I have this bump [65:17] here." I mean, in the end, we end up [65:19] diagnosing ourselves. Well, we either [65:21] drop dead, diagnose ourselves, or [65:22] someone else diagnoses us, right? And [65:24] so, with a procedure like yours, I'm [65:28] kind of inclined to say like, would you [65:30] just get it? You seem healthy. Have you [65:33] done it to yourself? Can I come in and [65:35] get it just for uh checking things out? [65:37] We take blood tests now. People go, [65:39] "What's my testosterone, my estrogen, my [65:41] uh luteinizing hormone, my lipids, my, [65:44] you know, small uh, you know, LDL, [65:46] APOB." 20 years ago, if you wanted to [65:50] get a blood test 15 years ago and you [65:52] didn't have a problem to motivate that, [65:55] it was thousands of thousands of dollars [65:56] at best. It was very hard to find people [65:58] that give you these. Now, it's triv [66:00] trivially inexpensive for most people. [66:03] Um, so I feel like we're kind of going [66:05] that way with biopsy. So how soon are we [66:09] um going to just be doing biopsies with [66:11] non-damaging procedures? [66:12] >> So I think a lot of times with biopsies, [66:14] you have to be very targeted to get the [66:16] tissue of interest, right? So even in [66:18] the pancreas like like we said earlier, [66:20] you know, you could be even in the area [66:21] that looks like a lesion like a tumor [66:23] and not getting cancer cells out. So I [66:25] think that you have to be very very [66:27] targeted, but then once you do get the [66:29] tissue, you can do all these stains and [66:31] you can really figure out what's going [66:32] on. Is there a gen genetic [66:33] predisposition to it? Is there some way [66:35] it'll respond to one drug over another? [66:37] I think that's phenomenal. But I would [66:39] like to see the diagnostic studies [66:42] become less and less invasive so they [66:44] can scale easily. So the the one problem [66:47] with uh procedure-based diagnosis, I [66:50] like procedure- based treatment. I love [66:52] it. It's better than surgery. Um you [66:54] know going through the mouth and rather [66:56] than making an incision in the abdomen I [66:57] think has has benefits for the most [66:59] part. But when you get diagnostic [67:01] studies similar to colonoscopy, there's [67:03] a scaling problem, [67:04] >> right? So when when a patient has to [67:07] come in and spend an hour with a doctor [67:09] or two hours, that doctor is taking care [67:11] of one patient for two hours and he's [67:12] outnumbered, right? Everyone needs [67:14] screening and it becomes very [67:16] complicated. So, I would love to see [67:18] innovation in technology go where we [67:19] have minimally invasive ways of [67:21] diagnosing things, whether it's via your [67:23] smartphone and AI or it's via minimally [67:25] invasive scans and and uh um blood tests [67:28] are great because it it's quick and easy [67:30] to do. And we're not even doing talk [67:32] about metabolic health. You know, [67:34] there's several things we could be doing [67:35] non-invasively at home right now that [67:37] we're not doing that catch it much [67:39] earlier. So, [67:40] >> well, so an example is most of the time [67:43] we're waiting for hemoglobin A1C, right? [67:45] And that's the the marker of diabetes [67:47] and that's the going to be the thing [67:48] that you know once you have an A1C or a [67:51] high APOB which they're probably not [67:52] checking maybe you know an LDLC or [67:54] something right once those are high we [67:56] know there's a problem however there are [67:59] signs much much earlier than that and so [68:01] so metabolic dysregulation follows a a [68:05] fairly predictable sequence right first [68:07] it's calorie excess right so it's it's [68:10] in the western diet it's usually glucose [68:12] right so you have too much glucose [68:13] around you have too much saturated fat [68:15] but too much glucose and then at too [68:17] much glucose uh you could catch that by [68:20] doing a CGM right so that's one way you [68:22] could do it a continuous glucose monitor [68:24] you could then see if you have [68:25] particularly glucose spikes to certain [68:27] foods and if your glucose is shooting up [68:28] to 200 with certain meals you know [68:30] you're sensitive to that and maybe you [68:31] should change how you're eating it try [68:33] to eat it after having something fatty [68:34] maybe avoid it right so because we know [68:36] this is part of a sequence that's going [68:38] to lead to problems and this goes back [68:40] to the white hall 2 study which um to to [68:43] give relevance here so the whiteall two [68:45] White Hall 2 study was on British civil [68:47] servants. It was a prospective kind of [68:50] longitudinal thing and they found that [68:52] um they followed all sorts of metrics. [68:54] One of them was insulin. Fasting insulin [68:56] was one thing that they followed. They [68:57] followed other things as well. And they [68:58] saw that if someone had high fasting [69:00] insulin, they're more likely to get [69:01] diabetes long term. So, so and it was a [69:04] long period of time. It was like a 10 15 [69:06] year time. They could detect this thing [69:08] 15 years earlier. They could do [69:10] something about it, right? But no one [69:12] does because no one looks for fasting [69:13] insulin. And the other thing that's very [69:14] relevant here is there was another study [69:16] was the UNCC NHANE study. Okay. And um [69:19] that's another large database. It's more [69:21] cross-sectionally looking at at a at a [69:23] point in time. And what they found was [69:25] that less than a third of people that [69:27] are lean are are metabolically healthy. [69:30] That's crazy. 12% of the whole [69:32] population, less than a third of lean [69:34] people are metabolically healthy based [69:35] on their parameters. And the parameters [69:36] looked at waist circumference and [69:37] glucose and blood pressure and whatnot. [69:39] Right? So looking at metabolic signals. [69:40] The word there is start looking early [69:42] and don't look with the traditional [69:44] things. Okay, we have to look at other [69:45] things. Getting back to you know [69:46] metabolic syndrome ideas. So first you [69:49] could check for glucose. So glucose [69:50] spikes a CGM can do that. I wouldn't say [69:52] wear it all the time. Get one for a [69:54] month or two. Learn what spikes your [69:55] glucose. See if something spikes your [69:57] glucose and adjust it. Next you have [69:59] fasting insulin. Okay. So the next thing [70:01] that happens is first in anybody they [70:03] have the insult of excess calories. The [70:05] excess calories comes. That's what [70:07] happens. Insulin's job is to take that [70:09] sugar and push it into the cells because [70:10] glucose is really bad for the body. We [70:12] know this. If you look at endstage [70:14] diabetes where they can't control their [70:15] glucose anymore, they go blind. You [70:17] know, they have kidney failure. It's [70:18] killing the vasculature. It's sticky. [70:20] Glucose is sticky. It glycates things. [70:23] It causes problems. So, the insulin's [70:24] got to get it out of the bloodstream. [70:26] So, next in the sequence of metabolic [70:28] dysregulation is high insulin levels. [70:30] Fasting insulin goes up. So, you can get [70:33] a fasting insulin level. That's the next [70:35] thing you check, right? It's not a lot [70:36] to ask for. It's an inexpensive test and [70:38] you can see if you've if you've evolved [70:40] into that problem where now you have [70:42] chronically high insulin levels. And [70:44] part of that honestly is due to eating [70:46] too frequently and could be eating you [70:47] know certain things that are uh you know [70:49] high fructose corn syrups or things that [70:51] that basically u you know have a high [70:54] glycemic index or load that's going to [70:55] cause your sugar to spike. So and the [70:58] problem is if you're eating every few [70:59] hours insulin goes up and it spikes. It [71:01] drives the glucose out of your blood but [71:03] then the insulin stays high. Okay, it [71:06] doesn't go right back down. It stays [71:07] high for a few hours. So, if you're [71:08] eating every few hours, you always have [71:10] this high insulin. That's going to lead [71:11] to other problems. And the next thing [71:12] that happens is ectopic fat, right? So, [71:16] your fat exists in different areas. You [71:18] have subcutaneous fat. That's where it's [71:20] supposed to be. That's your depot for [71:22] energy and uh it's healthy there. Has [71:25] different ways of growing. Then you have [71:26] visceral fat, which is really in your [71:28] your momentum. You know, it's a it's in [71:31] the abdomen and uh in your mezzentary in [71:33] the abdomen that's around the bowel. [71:35] Okay, so that's that kind of your [71:37] visceral fat. Then you have your organ [71:39] associated fat. You have some fat around [71:41] the heart. You have some fat around the [71:43] kidneys, etc. It's kind of supposed to [71:44] be there. They're all adiposicides. [71:46] They're all fat cells. Their job is to [71:47] store fat and release it, right? That's [71:50] what they do. Then the last bucket is [71:51] ectopic fat. And ectopic fat is where [71:55] you have fat in cells that is not their [71:57] job to store fat, right? Like liver [71:59] cells or muscle cells or pancreas cells. [72:02] And that becomes that becomes a problem. [72:04] >> It's like Wagyu beef. [72:06] >> Yeah. It's like Wagyu beef. [72:08] >> Yeah. Those cows are over they're not [72:10] they don't move. They're overfed. It's [72:12] >> Yeah. [72:13] >> And and that that's you know that's [72:15] another problem. Right. So that's the [72:16] next phase of metabolic dysregulation. [72:18] And they've done all sorts of great [72:19] studies that have shown exactly from [72:21] each step what happens and how you get [72:23] there. Right? And so that's when you get [72:25] fat in your muscle and you get fat in [72:27] your liver and that's bad. Fatty liver [72:29] is very bad. And then that is what goes [72:32] on to insulin resistance. Okay. So for [72:34] the fat, how can you look for that? [72:35] Well, you can do a waist circumference [72:37] measurement, waist to height ratio. You [72:38] can get a DEXA scan that'll tell you if [72:40] you have visceral fat or you know if you [72:42] have a lot of subcutaneous fat, a CT [72:44] scan MRIs, other things will do it too. [72:46] Um or an ALT, look at a liver test [72:48] measurement, right? Uh that's [72:50] amotransferase in your liver. Um and [72:53] usually, you know, that'll signify some [72:55] inflammation. So you know that's the [72:58] next level, right? And then you have [72:59] insulin resistance, which that's a [73:01] little harder to check. That's a [73:02] combination of there's a formula that [73:04] you can do to look at that. It's a it's [73:05] a a fasting blood glucose and a fasting [73:08] insulin level. And you multiply those [73:10] and divide it by a constant. And if it's [73:12] greater than two, you have insulin [73:13] resistance. So that's the next next [73:15] phase of it. And then finally, you have [73:17] metabolic inflexibility. Your body is [73:20] supposed to change between calories, [73:21] right? What is burning? If you're [73:23] fasting, it's supposed to be burning [73:24] fat. And if you're eating, it's supposed [73:26] to be burning some element of carbs [73:27] depending on what you eat. But if you [73:28] have carbs in it, it should be burning [73:30] the carbs, right? And so you can develop [73:33] metabolic inflexibility as the next [73:35] phase of this once you have insulin [73:36] resistance where when you're fasting, [73:38] you're not really accessing your fat [73:39] anymore. Your fat's still there. It's [73:41] burning more your glycogen stores and [73:43] god forbid it's chewing up muscle, [73:44] right? But it's it is no longer [73:46] accessing the the fat stores is supposed [73:49] to be accessing. And then when you eat, [73:51] it doesn't shift over to burn the carbs [73:52] well either. kind of just it doesn't [73:54] know what to do. So that's a loss of [73:56] metabolic flexibility. And by then [73:58] you're getting near the time when all of [73:59] a sudden something's going to happen cuz [74:01] once you have a loss of metabolic [74:02] flexibility, they've shown in studies [74:04] that you're more likely to gain weight [74:06] and develop obesity. You're more likely [74:08] to start losing beta cells. You start [74:09] burning out your beta cells and they [74:11] became apoptic and you lose beta cell [74:12] mass and you start having all sorts of [74:15] other problems. So this is a very kind [74:17] of typical sequence that you see. It can [74:19] happen in other ways, but that's a [74:20] typical sequence that's backed by [74:22] science and different clinical trials. [74:24] And each each step of that way, you have [74:26] a study you could do to find out about [74:28] it. The last one, the metabolic [74:30] flexibility is a little harder because [74:32] you you have to do kind of go and do a [74:34] breath study for that where you're [74:35] looking at gas exchange and it's very [74:38] accurate actually because we know that [74:40] there's a respiratory exchange ratio. [74:42] Um, athletes do this to optimize [74:44] performance. You can do this where you [74:45] get a DEXA scan. A lot of places they'll [74:47] tell you how many calories you're [74:48] burning or what you're burning. And [74:50] basically it's you know first law of [74:52] thermodynamics and you're burning [74:53] calories but it's a ratio of a volume of [74:56] carbon dioxide divided by volume of [74:58] oxygen. When you eat carbohydrates [75:00] carbohydrates have an equal number of [75:01] carbon and oxygen. So it doesn't require [75:04] much oxygen to to burn the [75:05] carbohydrates. But when you burn fat it [75:07] requires more oxygen. So if that ratio [75:09] is like 7 uh so it's it's carbon dioxide [75:13] oxygen that means you're using more [75:15] oxygen. That means you're burning fats, [75:16] right? And if it's one, you're burning [75:18] carbs. And then there's an in between. [75:19] And so this is a great way to see if [75:21] you're metabolically flexible. Eat fat, [75:22] see what happens. Eat carbs, see what [75:24] happens. Do it fast, see what happens. [75:25] Right? And you sit in a chair, and you [75:26] breathe for half an hour. There's [75:28] companies that are actually developing [75:29] at home method that's doing this, too. [75:30] There's a few of them. And actually, one [75:32] of them recently, I think, now has one [75:33] that does both the oxygen and the carbon [75:35] dioxide. [75:36] >> I've seen this like a little box that [75:37] you breathe in, too. [75:38] >> So, I mean, you can do everything, [75:39] right? So, and then or you can just wait [75:41] until you have diabetes and your A1C [75:43] goes up. And so, yeah, there's a lot of [75:45] things we should be doing before we do [75:47] the standard test of looking at your [75:48] fasting glucose and looking at your [75:51] hemoglobin A1C. [75:53] >> I'd like to take a quick break and [75:55] acknowledge our sponsor, Function. [75:57] Function provides over 160 advanced lab [76:00] tests to give you a clear snapshot of [76:02] your bodily health. This snapshot gives [76:04] you insights into your heart health, [76:06] your hormone health, autoimmune [76:07] function, nutrient levels, and much [76:09] more. They've also recently added access [76:12] to advanced MRI and CT scans. Function [76:15] not only provides testing of over 160 [76:17] biomarkers key to your physical and [76:18] mental health. It also analyzes these [76:21] results and provides recommendations for [76:23] improving your health from top doctors. [76:25] For example, in a recent test with [76:27] function, I learned that some of my [76:28] blood lipids were slightly out of range. [76:31] As a result, I decided to start [76:32] supplementing with nattokinise, which [76:35] can naturally help reduce LDL [76:36] cholesterol. And it did. In a follow-up [76:39] test, I could confirm that this strategy [76:40] worked. My blood lipids are now back [76:42] exactly where I want them. Comprehensive [76:44] lab testing of the sort that function [76:46] offers is just so important for health. [76:48] I mean, how else are you going to know [76:49] what's going on under the hood? And [76:51] while I've been doing blood work for [76:52] years, it used to be timeconuming, [76:54] complicated, and expensive. In fact, I [76:56] used to spend thousands of dollars per [76:58] year trying to get this kind of data. [77:00] And the data, frankly, were not all that [77:02] good. But now with Function, it's [77:04] extremely easy and affordable. A [77:06] function membership is only a dollar a [77:08] day, $365 a year. And if you think about [77:11] the information it provides and the [77:12] health challenges it helps you avoid and [77:14] the proactive things that it can do for [77:16] you to enhance your health, I truly look [77:18] at it as a savings. To learn more, visit [77:21] functionhealth.com/huberman [77:23] and use the code hubman for a $50 credit [77:26] towards your membership. Again, that's [77:28] functionhealth.com/huberman. [77:31] It's gratifying to hear that you put the [77:33] CGM uh pretty early on that list. Very [77:37] early, in fact. I mean, I I don't I want [77:40] to be clear. I'm neither complaining [77:41] about nor am I um trying to turn you [77:44] against your colleagues. But I'm going [77:47] to just be really blunt from and these [77:49] are my words and my words only. I want [77:50] people to understand this. Like I mean, [77:53] I've gone public many times saying, [77:57] "Hey, like as the cost of blood testing [77:59] comes down, this is awesome. you get a [78:01] window into uh lipids, hormones, things [78:04] that can be very informative whether you [78:06] have issues or not. And the push back on [78:08] that from the medical community, not all [78:11] cuz I have friends in the medical [78:13] community who will quietly say, "Yeah, I [78:15] totally do that test. I take that test, [78:17] you know, but many of them just say, [78:18] "Oh, great. Now patients are going to be [78:20] coming to me saying like, I need to do I [78:22] need to be worried about this? Do I need [78:23] to be worried about this?" I said I [78:25] actually put a post out recently that as [78:27] the cost of of whole body MRI comes out. [78:30] It's going to be interesting to see what [78:32] happens. I have neurosurgeon friends who [78:34] tell me about life-saving procedures [78:36] they they do all the time. The [78:37] neurosurgery community was super angry. [78:39] It generated some press this week. [78:41] Actually, uh this is how the the tables [78:43] kind of turn. There's a celebrity, I [78:45] forget their name, who took a one of [78:46] these types of scans from a company I [78:48] have no affiliation with, by the way. I [78:50] took a POVO scan and um identified a a [78:54] malignant issue that could be cut out [78:56] and very likely saved their life or at [78:58] least extended it. So, I get it on the [79:00] one hand why a lot of physicians are [79:02] worried about people walking around with [79:04] a lot of data. I heard the same about [79:07] CGMs. Okay, I'm gonna try not to rant [79:09] here. It was like, "Oh gosh, who needs [79:10] to know their glucose goes up, glucose [79:13] comes down in the absence of diabetes or [79:15] pre-diabetes?" Like, you can have a [79:17] glucose spike. We don't want people [79:18] walking around neurotically worried [79:20] about eating a grape, which I totally [79:22] understand. Your body can manage these [79:24] things. But now that CGMs have been out [79:26] for a couple of years, I don't hear much [79:28] push back. Yeah, somebody wants to use a [79:30] CGM for a couple weeks and see how they [79:32] react to different foods post exercise, [79:34] post poor sleep, etc. Cool. So, it's [79:37] kind of wild to me that physicians don't [79:40] want patients to have data. But here, [79:42] I'm hearing something very different. [79:44] You're saying, "Yeah, it's I think [79:45] people should pay attention to how [79:46] they're regulating their blood glucose." [79:48] The problem with medicine is it moves [79:50] very slow, right? So, a lot of people [79:53] are going to want you randomized control [79:55] trial, another randomized control trial, [79:56] maybe a few more, and then a meta [79:58] analysis, and maybe understandably, but [80:01] from a patient perspective, people want [80:03] data now. if they can get it [80:05] inexpensively. And by the way, these are [80:07] are they called elective or elected [80:09] >> procedures? They're elective. If they're [80:11] elective procedures, so no one's saying [80:13] you have to get this done. [80:14] >> It's an option. [80:16] >> Yeah. [80:16] >> I don't get it. Can't wrap my head [80:18] unfortunate. It's it's it's unfortunate [80:20] that um there's there's a reason for it. [80:23] Obviously, do no harm, right? There's a [80:25] reason for it. But by the same token, it [80:27] does not necessarily [80:30] um do the patient any favors by waiting [80:33] for something that's that that is [80:35] logical and makes sense, right? And [80:37] there's enough evidence for this [80:38] sequence of events, if you will, for [80:40] metabolic illness all the way back to [80:41] syndrome max in the 80s, right? We know [80:43] there's this constellation of things. [80:44] And we also know that if you don't act [80:46] early, you're much less likely to have a [80:48] good treatment effect. If you start [80:50] treating someone once they have [80:51] diabetes, it's much harder to get them [80:53] back to healthy and normal. They've [80:54] already lost beta cell mass [80:56] >> or peripheral nerve. I mean they could [80:57] have loss of their fingertips and toes [80:59] or sensation, excuse me, in their [81:00] fingertips and toes. [81:01] >> And now before I mean we might not have [81:03] had access to things. We had access to [81:05] fasting insulin, right? But think about [81:07] this. So say you don't get the CGM and [81:09] you have fasting insulin, right? And the [81:11] fasting insulin is normal. You don't [81:13] know if step before that is a problem [81:15] and you're going to have problems with [81:16] fasting insulin or if it's abnormal, you [81:18] need the CGM to learn how to eat, right? [81:20] Because that fasting insulin is high for [81:22] a reason. you're spiking your insulin or [81:24] you got to figure out why you're spiking [81:26] it, right? So, so then you go back to [81:27] the CGM and you learn and I don't I [81:29] don't have any stock in the CGM company [81:31] either. You got to learn how to eat to [81:33] not spike your insulin in that case. [81:35] Now, if you're taking a bunch of, you [81:36] know, saturated fat, that's not great [81:38] either. You can't be on super high [81:39] saturated fat with an Ape B through the [81:40] roof. But, you know, either way, it's [81:42] not good, right? So, most of the time in [81:44] Western countries is it's the glucose [81:46] and insulin that are the problem. And [81:48] it's the very beginning of it. So, why [81:50] not learn about yourself? take some [81:52] responsibility, right? Learn and and [81:54] prevent these diseases from from going [81:56] on. And I do hope physicians are are [81:59] more open to kind of encourage this as [82:01] well. Um where we start acting earlier. [82:04] It's going to it's going to be better [82:05] for the, you know, for the population in [82:07] general. [82:08] >> Yeah. Because I could see why physicians [82:10] would be very reluctant towards [82:11] self-directed interventions. I get it. [82:14] But here we're just talking about [82:15] getting data and it's voluntary. The [82:18] costs are coming down. And as you point [82:20] out, having data early is better than [82:22] having data late when it comes to um [82:25] physician guided interventions. So what [82:27] I've what I've heard in this regard is [82:30] um you know I with in conversations is [82:33] well the problem is a patient's going to [82:35] then figure out they can eat junk food [82:37] like like a like something that's really [82:39] bad for them. you know, some greasy [82:41] fatty thing that's unhealthy for them, [82:43] going to, you know, put their, you know, [82:45] APOB through the roof and they'll think [82:48] it's okay cuz it's not showing up in [82:49] their CGM. I think it's not giving the [82:51] patients enough credit because generally [82:52] if you're getting a CGM, you probably [82:54] are are trying to do the right thing. [82:55] So, I think it's how will they use the [82:57] information? Could they accidentally not [82:59] be informed enough to to use that [83:01] information appropriately and could they [83:02] do the wrong thing? But again, I think [83:05] more information is better almost in all [83:06] circumstances with diagnostic stuff. [83:09] Now, I agree with this MRI thing being [83:10] concerning because you might have a lot [83:12] of little lumps and bumps there that now [83:13] you're doing diagnostic studies for that [83:15] could increase risk, [83:16] >> right? So, because diagnostic studies [83:18] could increase risk and also could be a [83:20] burden on the health care system, but [83:23] >> more information I still think more [83:24] information is better. We just have to [83:26] find better ways of doing the followup [83:28] confirmatory diagnosis. there might be [83:30] other ways we can do it. Looking for [83:31] metabolic activity of tissue like PET [83:33] scans or what doing other things rather [83:35] than a biopsy and and something that [83:37] would increase risk. [83:39] >> Okay. Well, thank you. I wasn't asking [83:40] you to take my side in the argument, but [83:42] since you threw out CGMs first, I just [83:44] kind of took that as an opportunity. I [83:45] think uh my um I won't name names, but [83:48] let me put it this way. Whenever I get [83:50] that sort of push back, I'll go to [83:52] people I know in the field and I and [83:53] I'll say I'm not looking for [83:55] confirmation that I was right and they [83:57] were wrong. to tell me what what I'm [83:59] hearing here. What what's beneath what's [84:01] the layer beneath what I'm seeing? And [84:03] almost inevitably they say the same [84:05] thing. Give it 20 months. This will be [84:07] standard. And that happened with CGMs. [84:09] No one bulks at the idea of a CGM. Yeah, [84:11] you want to put that thing on, you can [84:12] afford, you want to get some data. Like [84:13] most people, most physicians I know now [84:15] are comfy, but at the beginning it was [84:16] like all the push back in the world. [84:19] That's really wild how. So wait 20 [84:22] months and and this will be a non-issue [84:24] is what I keep hearing again and again. [84:26] Well, even when you have procedures that [84:27] have gone through rigorous, you know, [84:30] evaluations and they have FDA approval [84:33] and, you know, they're they're ready. [84:36] You have so many people that are [84:38] reluctant to send patients for them, [84:40] right? [84:40] >> Why is that? [84:42] >> Yeah, I think it's it's in the culture. [84:43] >> Are they afraid they'll do it wrong? [84:45] It's like a new skill to learn. [84:46] >> That could be. So, some of these [84:47] procedures, you can't learn them in a [84:49] weekend course. You know, you have to [84:50] spend a year or or longer learning some [84:52] of these things. And so for a physician [84:55] who wants to add something to their [84:57] practice, that's they're not going to [84:59] dedicate a year to it. They might do a [85:00] weekend course and realize it's it's too [85:02] hard and then they don't they don't [85:04] adopt it. The problem is the people that [85:06] do adopt it and they're not ready. So [85:07] then doctors that are referring go, [85:09] "Huh, this procedure's been around for 6 [85:12] months or a year. It really has great [85:14] data in the clinical trials, but does [85:16] the guy down the street know how to do [85:18] this after doing a weekend course?" And [85:19] so they were reluctant maybe for that [85:21] reason. So just give it time. and wait [85:22] until it's maybe insurance not covering [85:24] it yet, right? Wait to see if the [85:26] insurance companies think it's it's it's [85:27] a good idea, then maybe we'll start [85:29] sending patients. So, it just it's it [85:31] moves slowly. [85:32] >> Yeah. Well, I don't want to you hover on [85:34] this too long, but I have a friend who's [85:35] really into cars and uh he told me that [85:38] in the mechanic and automobile [85:41] community, a similar thing like as [85:42] things became more and more [85:43] computerized, there was a lot of push [85:44] back because it makes it hard for auto [85:46] shops to do their um their work. You [85:50] know it changes the the field changes [85:52] and you need more tools. Sometimes those [85:55] tools are expensive. You need training [85:56] and people like to hold on to the way [85:58] they were trained. This is absolutely [86:00] true of most every field. Adapt or die [86:03] or your patients die there. Um that's my [86:07] you know if you don't adapt your [86:08] patients will die. I have to imagine [86:10] that there are good surgeons there are [86:12] mediocre surgeons and there are [86:13] exceptional surgeons. Are there places [86:16] where you've brought in devices or [86:18] machines that could offset the mediocre [86:22] and um lousy surgeons or surgeons by day [86:26] sleep a little sleep deprivation? So I'm [86:28] not just saying like bad surgeon good [86:29] surgeon but there so what has come into [86:32] the field that's allowed you to do your [86:34] work more effectively and others to do [86:37] the work more effectively. [86:39] >> Most devices we see are kind of [86:41] incremental improvements. a little bit [86:43] of better wire, you know, devices a [86:44] little more ergonomic. But what I see [86:48] kind of happening more recently is AI [86:50] starting to have an impact where it can [86:52] actually coach you through procedures, [86:54] which is kind of work. You have an [86:55] earbud in or something [86:56] >> uh on the screen itself, it's like a [86:57] heads-up display, right? On that [86:59] heads-up display, uh it will actually [87:01] give you information so you're not just [87:03] seeing the images you're working on. It [87:04] can actually highlight certain [87:05] structures you want to work on. It can [87:07] actually point to something where you [87:08] want to put your stitch, right? And it [87:10] can count the stitches as you're placing [87:11] them and tell you if they're close [87:12] enough together. It can change the shape [87:14] of the stomach as you're working on the [87:15] stomach to let you know if you're having [87:16] a good treatment effect. This is [87:18] something that we we never could have [87:20] have done before in real time. [87:21] >> Real time. Yeah. Which is phenomenal. [87:23] Right now it's not widely available yet. [87:25] This is in research centers, right? But [87:27] you actually can see this happening in [87:29] real time and um it's it's phenomenal. [87:32] So you see that in more and more it's [87:34] happening in different surgical [87:34] procedures where AI is kind of real-time [87:36] coaching you and in endoscop endoscopic [87:38] procedures. Additionally there's the [87:41] hope for robotics to help as well and [87:43] we've done a lot of research in our lab [87:44] on robotics and how it can take trainees [87:47] that are learning a new very complicated [87:50] procedure and shorten the learning curve [87:52] dramatically. And we'll randomize the [87:53] trainees and have them do the [87:55] traditional way like this is usually [87:57] resecting a tumor from the colon leaving [87:58] the colon in place. That's a very [88:00] complicated procedure and or from [88:03] somewhere else in the in the stomach or [88:04] whatnot. And the fellows will learn [88:06] they'll spend a couple of weeks training [88:07] in both modalities and then they will [88:09] struggle horribly with the original way. [88:11] That's why it takes two or three years [88:12] to learn how to do it. They'll sit down [88:14] with the robot and be almost good as an [88:15] expert. So robotics are very interesting [88:18] and now in the future we haven't done it [88:20] yet. But when you start layering on AI [88:22] and automation with the robots, now you [88:25] might have a big win. And we we've seen [88:26] this before with different surgeries as [88:28] well with the with you know intuitive [88:30] surgicals robots when they first came [88:31] out years ago. It democratized the [88:34] field. It took mediocre surgeon it made [88:36] them excellent and the excellent [88:37] surgeons were still excellent right but [88:39] it really helped the ones that were [88:41] struggling. [88:41] >> How the excellent surgeons feel about it [88:43] in keeping with our previous discussion. [88:45] >> Seriously like are is it is it is part [88:48] of it's like is it like athletics like [88:50] it people want to be they want a [88:52] hierarchy of performance um for [88:54] themselves. they don't want patients [88:56] dying at the hands of poor surgeons. But [88:58] I would think that um if do no harm is [89:01] really the the uh the true um central [89:05] cord of medicine, then every person in a [89:08] field would want more people being [89:10] healed independent of their own stature [89:12] as a physician. Yeah, I think they're um [89:16] supportive of robots, but I think that a [89:19] truly exceptional surgeon is probably [89:21] just going to be better without the [89:23] robot and just, you know, the robot is [89:25] just it's going to it's going to make [89:26] you worse. [89:27] >> How do I know if I'm getting a truly [89:28] exceptional surgeon? [89:30] >> That's a good question. [89:31] >> Understanding do am I getting the best [89:33] physician for this thing is really hard [89:36] to determine. [89:38] >> Yeah, that's common across all medicine, [89:41] right? And even as I'm looking for a [89:43] doctor for something, it's hard to find [89:44] the right person. I'm in a massive [89:46] medical center, you know, and have great [89:48] connectivity. But knowing who truly is [89:50] the best is complicated, right? So some [89:52] things we rely on are volume, case [89:53] volume, and historic case volume. So how [89:55] many procedures do they do? That's [89:57] important. And probably more important, [89:59] how many have they done over the course [90:00] of their career. So if you're having a [90:02] procedure, you want to know volume [90:03] because volume is important. It's not [90:05] the whole story, but volume is [90:06] important, right? And we need in [90:08] medicine honestly to move more towards [90:10] objective metrics. And this is one thing [90:13] AI can do for us. Right? I'm involved in [90:15] a um a healthcare delivery platform. [90:17] It's called Everself. And what it does [90:19] basically is the doctors that are doing [90:21] these procedures are held to a certain [90:24] metric. Right? So it starts with just [90:27] collecting the data, you know, finding [90:28] out what their weight loss outcomes are, [90:31] finding out how many stitches they place [90:32] per procedure, looking at their [90:34] procedure time, looking at their [90:35] complications. So, you're grading all [90:36] that, but the next layer is putting this [90:38] AI on top of it where the AI, not only [90:40] can it coach you through the procedure, [90:42] it can give you a grade at the end of [90:43] the procedure. It can be very specific [90:45] and it can tell you you placed this many [90:48] full thickness sutures versus this many. [90:50] You want 100% of your stitches to be [90:51] full thickness. Maybe the doctor's [90:52] putting in 70. They're full thickness. [90:54] That's not good. This number of sutures [90:56] were close enough together. Some were [90:57] too far apart. It will give you a grade. [90:59] This is the pattern used. This is the [91:00] volume of stomach you reduce it by. [91:02] It'll give you a grade at the end of [91:04] that procedure. And that grade is [91:05] incredibly important. And then the the [91:08] idea next would be is to share that data [91:10] so people know kind of what grade you're [91:12] getting. It'd be great to share that [91:14] with governing bodies that do [91:15] credentiing. So people that are truly [91:17] underperforming, maybe they should get [91:19] refresher, right? It would be nice for [91:21] patients to be able to select, you know, [91:23] who they're going to go to based on [91:25] objective metrics. And AI can do this [91:26] probably across the board with other [91:28] things as well. So that's part of it. [91:30] We've seen this a little bit with ADR, [91:31] edenoma detection rates in colonoscopy [91:33] where they used to publish that and they [91:35] stopped doing it. So doctors were [91:37] expected to have a certain number of [91:38] polyps they'd see per colonoscopy and [91:40] they'd report that. That was something [91:42] that was another way. But then the [91:43] problem was all the patients wanted to [91:45] go to the one or two doctors that had [91:46] the highs and their weight times became [91:48] enormous, [91:49] >> right? And then patients couldn't get [91:50] access to them. That's a problem as [91:52] well. But there should be a reasonable [91:54] cut off where a certain level of [91:57] expertise is required and um you know I [92:00] think AI you know hopefully will help us [92:02] get there. I'm excited by what you told [92:04] me about how AI can um provide real time [92:08] data and perspective data about how the [92:10] stomach will change shape in with the [92:14] opportunity to make the adjustments as [92:15] you go as opposed to having the patient [92:18] heal up and have to have to come back in [92:19] for another surgery. years ago, I saw [92:22] something amazing. A a neuroopthmologist [92:25] um friend allowed me to sit in on a on [92:27] something. He said, you know, people [92:29] forget that surgeons wear microscopes on [92:30] their eyes, right? They they wear these [92:32] like um uh optics that allow them to see [92:35] things bigger obviously, but then there [92:37] are all these new tools that you know [92:39] like a little drop of florosine, a [92:41] little bit of like innocuous uh liquid [92:44] that creates a contrast for the for the [92:47] surgeon or for the eye doctor to see [92:50] what what is what and not cut the wrong [92:52] tissue. It seems like a like such an [92:55] obvious thing, but I was told that for [92:58] you know a hundred years the same [92:59] procedure had been done without that. [93:01] And so eye surgeons had to essentially [93:03] guess based on their intuition, their [93:05] training of what was tissue to uh [93:07] preserve what was healthy, what was [93:08] unhealthy tissue. I mean these what seem [93:10] like kind of simple to us now [93:12] technologies have improved the margins [93:16] of safety have improved the you know [93:19] outcomes tremendously. And so the idea [93:20] that you would have AI combined with [93:23] really good microscopes either worn on [93:25] the eyes or you're looking down a [93:26] microscope better surgical tools to me [93:28] it just seems obvious like yes yes and [93:30] yes [93:31] >> but a lot of people hear AI they hear [93:33] robot and they hear surgery and they go [93:35] oh my goodness like what if the they go [93:37] to the extreme I think with AI people [93:39] think it can go rogue has a mind of its [93:41] own so I don't want you to give false [93:44] assurance that that's not going to [93:45] happen but when you sit down to do a [93:47] procedure and you're getting information [93:48] from AI where does your trust come from [93:51] that um it's giving you good information [93:53] as opposed to faulty information. [93:55] >> Yeah. So the AI is is trained on [93:57] thousands and thousands of procedures, [93:59] right? So more than I' I've done, right? [94:01] So [94:02] >> which is good and so it recognizes [94:04] patterns. So you have to use your [94:06] clinical judgment and you're not doing [94:08] you're not using this AI kind of [94:09] blindly. You're using your clinical [94:10] judgment and you might ignore it [94:12] sometimes. You don't have to follow it. [94:14] Now, if it becomes the time where you're [94:16] automating [94:18] operative robots using AI, [94:20] >> like suture placement, [94:21] >> that'd be different. If it's doing it [94:22] itself, that's different. But for this, [94:23] where it's just suggesting where you put [94:25] a stitch or showing where a blood vessel [94:27] is, I think it's a huge advantage. So, [94:28] we do these procedures that are very [94:30] technical where where you tunnel, you [94:32] know, you're creating a potential space [94:34] in the esophagus. So, back to that [94:35] earlier um person that couldn't swallow, [94:38] right? They had trouble swallowing [94:39] because they had acalasia. So the [94:40] procedure how we do that is we go in [94:42] through the mouth. We inject a little [94:44] fluid under the mucosal layer to to lift [94:46] it with a with a pocket of fluid. We [94:48] make an incision in that and we take the [94:49] endoscope. We slide under in between the [94:52] mucosal layer and the muscle. We dig all [94:54] the way down to the bottom of the [94:55] esophagus and then we cut through the [94:57] muscle. When you're doing that, there's [94:59] vessels in there and they're hard to [95:00] see. AI can actually see those vessels [95:02] because it's got pattern recognition and [95:04] color them for you so you don't hit the [95:06] vessels as you go, reducing your chances [95:08] of hitting a blood vessel. Right. [95:09] Beautiful. So that's just one example of [95:11] something that's a very complicated [95:12] procedure and you're certain you're [95:14] you're you're making certain aspects of [95:15] it a little easier. We think that [95:17] >> physicians are looking at the equivalent [95:19] of a medical textbook with coloring, but [95:22] it's not. It's black and white and gray [95:24] and beige and there are certain [95:26] structures that look different that are [95:27] contrasty and look different. So now [95:29] with with endoscopic ultrasound, it's [95:32] not even color. It's all gray. So when [95:34] we're doing endoscopic ultrasound, we [95:36] talked about looking for a pancreas [95:37] tumor. It's all gray. It's just [95:39] different shades of gray. There's no [95:40] coloring to it. Now, you can you can [95:42] turn on a button to see if there's blood [95:43] flow, right? But it's all gray. So, I [95:46] years ago in my lab, I was trying to use [95:48] image registration. So, I could take a [95:50] CT PET scan and I could link it to the [95:52] the angle of the probe and you could see [95:55] a CT scan fluctuating in the probe of [95:57] the ultrasound and lay the overound the [95:59] ultrasound over it and then you get an [96:01] idea of the tumor you're looking for, [96:02] the leion you want to biopsy or [96:03] whatever, right? [96:04] >> It was too hard to do. it would take [96:06] three hours of preparation to be able to [96:08] set that up. You could never scale that. [96:09] Now with AI, other groups are doing [96:11] similar work now and it's it's almost [96:14] automated. So I'm hoping that we'll see [96:16] image registration with these very [96:18] advanced imaging tools that are being [96:20] used help us with diagnosis and [96:22] hopefully even with therapy too. They're [96:24] they're doing something now called [96:25] hyperspectral imaging and they're doing [96:27] it in surgery as well. There's several [96:29] groups doing this. One group in Lond is [96:30] doing phenomenal work. They're using all [96:32] these narrow bands of wavelengths, just [96:34] tons of wavelengths, and they're finding [96:36] out that each tissue actually has a [96:38] fingerprint. So, you can actually use [96:40] this this hyperspectral imaging to [96:42] fingerprint tissue, and you can actually [96:44] see margins of tumors with this. And [96:46] it's very interesting without giving a [96:47] die anymore. So, you still might want to [96:49] give it for lymph node testing or [96:51] whatever. Sometimes they'll inject [96:52] something into a tumor and then look to [96:53] see if it gets into lymph nodes. That's [96:55] different. But this is for actually [96:56] looking for margins or for lesions. And [96:58] it's just with light technology, it's [97:00] amazing. So that's what LEDs are doing, [97:02] right? In different kind of cameras, [97:04] right? So instead of CCD chips, you have [97:07] CMOS, right? And so with newer [97:09] technology, even though it seems [97:10] incremental, with LEDs being able to flu [97:12] kind of fluctuate the wavelengths of [97:13] light and your chips being able to read [97:15] it faster and better, we're able to make [97:17] better diagnosis. [97:19] I'd like to take a quick break to [97:20] acknowledge our sponsor, Our Place. Our [97:23] Place makes my favorite pots, pans, and [97:25] other cookware. Surprisingly, toxic [97:27] compounds such as PASES or forever [97:30] chemicals are still found in 80% of [97:32] non-stick pans as well as utensils, [97:34] appliances, and countless other kitchen [97:36] products. As I've discussed before on [97:38] this podcast, these PASES or forever [97:41] chemicals like Teflon have been linked [97:42] to major health issues such as hormone [97:45] disruption, gut microbiome disruption, [97:47] fertility issues, and many other health [97:49] problems. So, it's very important to [97:51] avoid them. 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So, if you're looking for [98:35] non-toxic, long-lasting pots and pans, [98:37] go to fromourplace.com/huberman [98:40] and use the code Huberman. With a [98:42] 100-day risk-free trial, free shipping, [98:44] and free returns, you can try HourPlace [98:47] with zero risk, and you can see why more [98:49] than 1 million people have made the [98:50] switch to HourPlace kitchen wear. I feel [98:53] like uh one structure that we could um [98:56] conceptual structure that we could put [98:57] on things. I'm realizing today is [98:59] medicine has a couple of different ways [99:01] to determine what's going on, for better [99:03] or worse. One is the stuff that comes [99:05] out of the body. And we do this with [99:06] babies, like, oh, their their mucus [99:09] looks really green. We do this maybe I [99:10] have a sinus infection it comes out of [99:12] the body or with bowel movements or [99:14] we're not so good at gauging the color [99:16] of blood kind of things or then we have [99:18] surface of the body power of skin how [99:20] the eyes look do we see you know uh [99:23] stuff that we don't normally see and [99:26] then you know the age-old story where [99:28] like was like phronology which was like [99:30] you know complete bogus but it was like [99:31] oh can we figure things out from the way [99:34] things are changing at the level of the [99:36] the shape of the skull is complete [99:37] nonsense right but as we go in. We're [99:40] still trying to do this, right? X-rays [99:42] let us see, you know, fractures and [99:44] things with, you know, you don't want [99:46] too much X-ray uh radiation, but the the [99:49] goal has always been to get more [99:50] information with with less uh in [99:53] invasive procedures. And I feel like now [99:55] we have blood tests so you can pull [99:57] stuff out of the body. And it's kind of [100:00] wild that in 2026, [100:02] this is where we're at. I think it's [100:04] super exciting, but you know, hasn't I [100:08] mean, 50 years ago, the tools were [100:09] really crude there, but I think they [100:11] might still be kind of crude now [100:13] compared to where they are in 10 years. [100:15] Are you hopeful that in 10 years you can [100:17] go into a tube, 20 minutes later, walk [100:20] out, and we might be able to scan with [100:23] good enough resolution. Do you have any [100:24] tumors anywhere? Compare that to a blood [100:27] test and um you're good to go. [100:30] >> I don't know if we'll get there. Um I'm [100:31] hoping right because we are seeing [100:33] capsule technology improve. We're seeing [100:35] imaging technology improve and blood [100:36] tests improve and there's all sorts of [100:38] things you can do with with kind of [100:40] genotyping things and whatnot. I think [100:41] that's exciting but where we are seeing [100:43] improvements I think are in learning [100:46] about physiology and how things work and [100:48] then being able to do a targeted [100:49] approach. So you're not just doing that [100:51] with drugs where GLP1 is actually GLP1 [100:54] isn't really targeting a deficit [100:56] necessarily. There's different ways you [100:57] can treat things. You can either find a [100:59] pathology and treat the pathology, [101:01] right? Like cutting a tumor out. It's [101:02] kind of like treating a pathology. It's [101:03] not supposed to be there. Or you can [101:05] take normal physiology and augment it, [101:07] right? And that's what they're doing [101:08] with GLP1. There's not like some [101:09] horrible GLP1 deficit. That's that's [101:11] totally clear, right? [101:12] >> But they're ramping things up [101:13] thousandfold over what they would be [101:15] even the healthiest person. Most people [101:17] don't know that, by the way. They think [101:18] that like the GLPs are bumping things up [101:20] like two or four fold. It's like no, [101:22] never before in human history, at least [101:24] to my knowledge, have people walked [101:26] around with this level of GLP-1 [101:28] circulating in their blood. [101:29] >> Yeah. You're supposed to have a little [101:30] tiny amount that's produced in response [101:33] to a meal, right? And then it goes away, [101:35] you know, and it's kind of like, you [101:36] know, relatively speaking, not this is [101:39] super physiologic doses. You're bathing [101:41] the area postrea in this chemical, [101:43] right? And it's like it's not [101:44] functioning like in a physiologic way. [101:47] Our GLP1 is secret. It's nutrient [101:48] responsive. It's secreted from L cells, [101:50] right? And then it does its job. It goes [101:52] to the pancreas, says produce insulin. [101:54] It goes to the stomach, it says slow [101:55] emptying. It goes to the brain, it says [101:56] you're full. It does things like that, [101:59] right? And it does it in response to a [102:00] meal and it's in much smaller doses like [102:02] you've said. So medicines have done this [102:05] for a while where they kind of see [102:06] something as a mechanism they can [102:08] augment or they see a pathology they can [102:10] treat. But that augmenting is very [102:12] interesting. And surgery for a long time [102:15] wasn't doing that. They were just [102:16] thinking, "Oh, I'm going to make you [102:17] malabsorb calories. I'm gonna make this [102:19] tight so you feel full quicker. But now [102:21] that we're understanding mechanisms and [102:24] there's some great research that have [102:25] gone into this, we can actually develop [102:27] targeted therapies. And I think that's [102:30] what's very excited. It's more so even [102:32] than than a new device. It's being able [102:34] to do targeted therapies and get better [102:36] outcomes with that. And where I started [102:39] with this is um in fellowship. So I saw [102:44] you know I saw a patient with a gastric [102:46] bypass. So they have a gastric bypass [102:48] anatomy. They have a small gastric pouch [102:49] like I mentioned and a bigger stomach. [102:52] And a patient was sent to me that had [102:54] bad reflux. They had weight gain after [102:57] the gastric bypass. And their diabetes [102:59] came back. Their diabetes was gone, but [103:01] now it come back. So the surgeon [103:02] basically said, "Hey, take a look at [103:04] this patient. See if they have an ulcer. [103:05] What's going on? They're having all this [103:06] pain and heartburn. Find out what's [103:08] going on." So I went and looked and [103:09] there's this little hole between the [103:11] pouch, the new stomach and the old [103:13] stomach. And I thought, well, maybe the [103:15] acid is produced in the other side. [103:16] Maybe the acid's coming up through that [103:18] fistula. And we had a new device. It was [103:22] a suturing device that you could [103:23] actually put in through the mouth and [103:25] put stitches in. I thought maybe the [103:27] suturing device I could use it to close [103:28] that hole, right? So I waited until I [103:31] was on faculty a few months and I talked [103:33] to the surgeon. He was supportive. So [103:35] again, this is kind of that thing. Are [103:36] you inventing something? The procedure [103:37] is FDA approved. The device is FDA [103:39] approved. The procedure is not. No one's [103:41] closed official with us. But we talked [103:43] to the patient, you know, we told them [103:45] we weren't sure if it was going to help [103:46] or not. We tried to do it. They were [103:48] willing and we did the procedure, closed [103:50] the fistula. And so I was hoping the [103:52] reflux would stop. The reflux stopped, [103:54] but the person started losing weight and [103:56] their diabetes went away almost [103:57] immediately again. And that was for me, [103:59] and this is 2003, 2004, 2003. I was like [104:03] >> flabbergasted, you know, was it a [104:05] coincidence? What the heck was that? Why [104:07] is closing that little hole so [104:08] important? Right? So that's what got me [104:11] involved in understanding these the gut [104:14] hormones honestly and because we we were [104:16] able to now if I learned about the gut [104:18] hormones and why we saw this treatment [104:20] effect we could potentially manipulate [104:21] them to get a to get better results. [104:23] Right. So that was the beginning of it [104:26] for me and uh there was shortly after [104:29] that uh one of my friends and colleagues [104:31] actually did some uh animal work. He had [104:33] a rat model and they're called GK rats [104:35] and they're rats with diabetes that [104:37] don't have obesity. Okay. And they were [104:40] a great model for this because you [104:41] didn't want weight loss to confound [104:42] things. And so he did two surgeries for [104:46] gut and hind gut method, right? So the [104:48] the one surgery he basically excluded [104:51] the for gut. So he excluded the [104:52] douadinum and the very first part of the [104:55] digunum. Okay? And he did he did a [104:57] little bypass surgery there so no food [104:59] could get in the dueum. Went from the [105:00] stomach and it went to the the very [105:02] first part of the dudenum and then boom [105:04] down into the junum. Not touching that [105:05] for gauging that bowel. The other one he [105:08] did a gastroadunal anesmosis. So stomach [105:10] two small bowel but he left the rest [105:12] open. So food could go either way. He [105:13] could go into the douadum like it [105:14] normally would in the fore gut or go to [105:16] the hind gut dropping down into the [105:18] distal bowel. [105:20] What he found was these were diabetic [105:23] rats. He did glucose uh tolerance tests [105:26] on them and he found that the ones that [105:27] had the exclusion, their diabetes got [105:30] much much better. The ones that didn't [105:31] have exclusion didn't get better at all [105:33] even though you were dumping stuff into [105:34] the distal gut. Very interesting. So he [105:37] thought there was something very [105:38] important about for gut exclusion and he [105:40] hypothesized there was something called [105:42] an anti-incretin in that bowel that [105:44] would maybe protect against hypoglycemia [105:46] but there was something in there that if [105:48] you exclude it you got a better [105:49] treatment effect. So that was, you know, [105:52] my fish work and then his his very [105:54] interesting animal work got us going [105:55] down that path. And it kind of fed well [105:59] into something that actually was done uh [106:02] in the 1980s that that was from uh a [106:05] continuation of that work that Sherlock [106:06] had done looking at incurrins and this [106:08] famous publication by no and uh what he [106:12] did is he looked at the same the same [106:14] study that that Sherlock did in London [106:16] where they were giving glucose to look [106:18] at the insulin response but he did it in [106:20] diabetics and he did in a normal [106:22] population normal healthy population. [106:24] The normal population had that exact [106:25] same incrretin response where you gave a [106:27] certain amount of glucose introvenously [106:29] little spike same amount of glucose [106:31] orally big spike. Diabetics didn't do [106:33] that and they had already tied it maybe [106:35] to GLP1 and maybe in the in the in the [106:37] bowel. So very exciting. So maybe by [106:40] excluding this for gut you're playing a [106:43] role you're having something to do with [106:44] that or maybe not. So that was the [106:46] beginning of trying to understand the [106:47] procedures for me. And um with that I [106:51] then did another study where I closed [106:53] those fistulas right and uh and where we [106:56] closed the fistulas 60% of people had [106:58] resolution of their diabetes. If we [107:00] didn't close it no one got resolution of [107:02] diabetes. So okay that's a good thing. [107:04] So we learned there's some important [107:06] element to to for gut exclusion. Then [107:09] there's various device companies that [107:10] start getting involved in the space [107:12] because there's this there's this [107:13] information out there that excluding the [107:14] for might be important and a company [107:16] comes up with the idea of putting a [107:17] liner in endoscopically. So it's like a [107:19] little sleeve you anchor it has a little [107:21] dent that springs open you anchor it in [107:23] the first part of the small bottle. It [107:24] covers the dueum protects it. It's [107:27] implant so it has to come out right at [107:29] some point in time maybe a year later. [107:30] But it was very interesting because uh I [107:32] was I was part of those those those [107:34] clinical trials and we found you had a [107:36] one point in diabetics you have a [107:37] onepoint drop in A1C that's fantastic [107:40] and you lose weight about seven 7% total [107:42] weight loss. So clearly it's doing [107:44] something and it's it's important. The [107:46] problem is it's an implant. It's got to [107:48] come out but it's exploiting this [107:50] mechanism potentially. [107:51] >> So you're essentially um cinching down [107:53] this compartment of the the gut or [107:55] you're create you're creating more [107:56] compartmentalization along the the tube. [107:59] >> Yeah. the douadinum, right? And then [108:01] there's a liner that you place in it. [108:02] So, this is like a stent. So, it springs [108:04] open and holds its form inside it. And [108:07] then it's a sleeve that kind of goes [108:09] down. So, you can still get all your [108:10] secretions that go on the outside of the [108:12] sleeve and track down, but it's right [108:14] after the pyloris, the outlet of the [108:16] stomach. So, all the food is going in [108:17] the tube. So, the food is inside the [108:19] sleeve. The digestive enzymes are [108:21] outside the sleeve and they don't mix [108:22] for a few feet down. So, that's very [108:25] interesting and it worked. The problem [108:26] is it's it's still in clinical trials, [108:28] been around for a while, but it's an [108:30] implant. So, it's just like taking a [108:32] drug. Eventually, it has to come out. [108:34] >> But then there was a there was a [108:35] brilliant idea that came about one of my [108:36] colleagues at at the Bighgam. He's a [108:38] cardiologist, right? And he knew I was [108:40] trying to do something that was so I [108:42] traveled to Brazil, right? And I was [108:44] doing surgery endoscopic procedures in [108:46] Brazil and there was a doctor in a room [108:47] nearby and that doctor was doing a very [108:50] novel experimental surgery called ilial [108:52] interposition. And what he was doing, [108:54] this was a lean diabetic. So they they [108:56] weren't suffering from from obesity. [108:58] They had type two diabetes. And he was [109:00] taking this the small bowel, the distal [109:02] small bowel, kind of the opposite a [109:04] little bit of what Rabbino had done. [109:05] Took the distal small bowel and he moved [109:07] it up, kept it on his mezzentan blood [109:09] flow. He resected it out of the out of [109:12] the out of the distal small bowel near [109:14] the colon and he moved it up and he put [109:15] it near the dudinum. And his idea was, [109:18] you know, the concept was that GLP was [109:20] denser in that part of the bowel and it [109:22] was also denser, you know, down lower. [109:24] And if you moved that up higher, you'd [109:26] get a more immediate icon effect from [109:28] GLP-1. So you'd hit GIP and then [109:30] immediately GLP-1 and you'd have this [109:32] amazing effect. And he did. It was [109:34] incredible. Right? These people, their [109:35] diabetes went away and they didn't lose [109:37] any weight cuz he didn't actually have [109:38] any blind areas. The food, he didn't [109:41] change anything. There's no restriction. [109:42] There no absorptive change. He just [109:43] moved that part of the bowel up. That [109:45] was phenomenal. So I was trying to do [109:48] that endoscopically by harvesting uh [109:50] tissue from the illium via colonoscopy [109:53] creating stem cells and then injecting [109:54] it in the fore and getting him to take [109:56] and hopefully getting an effect that [109:58] wasn't successful but one of my [110:00] colleagues is a cardiologist and he [110:02] actually said why don't you just burn [110:04] the douadinum you know ablate the [110:07] douadinum there's different ways you [110:09] could do it you could do it with steam [110:10] hot water um etc just ablate it and see [110:13] if you can reset those stem cells [110:14] because the duadinum is sick Okay. And [110:17] this is very interesting research to [110:18] prove the dudim is sick. We should [110:19] probably talk about but you know the [110:21] dunium is sick. If you can reset the [110:23] duodum it might work. And I said why [110:25] don't you do it and he did and he [110:26] started a company and it's been great. [110:27] So and that that that is something that [110:29] we're studying more and more of. And now [110:31] you don't have a sleeve in place. You [110:32] don't reroute any bowel. You just ablate [110:35] the douadinum. Okay. And what happens is [110:37] your A1C drops by over a point. You [110:39] don't lose a lot of weight by just [110:40] ablating the douad, right? But your A1C [110:42] corrects. That's a a potent a potential [110:44] treatment for diabetes. They've also [110:46] done some studies. Uh I don't believe [110:48] these are published yet, but I think [110:49] that is showing that when someone comes [110:51] off a GLP1, if you use this treatment, [110:52] it keeps them from regaining their [110:54] weight. So, you can take a GLP-1 and [110:56] then have your douad kind of reset, if [110:59] you will, the stem cells come back and [111:01] uh you've maybe heal those tight [111:03] junction and other problems that you're [111:04] having. So, [111:05] >> so it regenerates. [111:06] >> It regenerates. Yeah. It comes back more [111:07] healthy and more normal. [111:09] >> And the rationale for that comes from a [111:11] lot of very good research. Right. So [111:13] there were studies that showed uh in [111:16] mice that if you feed mice, you overfeed [111:19] them, an overfeeding study and you have [111:21] a control group, you don't overfeed. [111:23] When you take them to the necropsy and [111:25] you look at their their bowels, the [111:27] bowels in the in the the overfed mice [111:29] are longer. They're heavier. The vill [111:31] are longer. They've adapted. They've [111:33] adapted. They've upregulated the ability [111:35] to absorb calories. And then these [111:37] studies have been repeated in humans [111:38] where people getting gastric bypass, [111:41] they're already going to be doing [111:42] surgery on them. So they resect part of [111:43] their small bowel and someone getting [111:45] cancer surgery is a control patient that [111:47] resect their small B. They look at the [111:48] differences and there's extreme [111:50] differences, right? The villa are [111:52] longer, it's thicker, there's more [111:53] inflammation in people with obesity or [111:55] type two diabetes. A lot more [111:56] inflammatory cells. The natural killer [111:58] cells are up eightfold. Uh macrofasages [112:01] up 1.5fold in these studies, right? So [112:03] you have more inflammatory activity [112:05] going on in these patients. The only [112:07] thing that's different is really [112:08] obesity, right? Additionally, if you [112:10] look at those patients and you you do uh [112:14] amuno staining for like zonula including [112:16] like tight junction protein, scaffolding [112:18] proteins and proteins, you'll see that [112:19] those are much lower and they're [112:20] disorganized. Two questions. So, if I [112:22] understand correctly, if people overeat, [112:25] the villi, like basically little [112:26] finger-like protrusions inside the gut [112:28] that can sense things but also collect [112:31] nutrients, right? They're growing to [112:33] adapt to the elevated levels of [112:35] calories. And so then essentially, [112:38] you've changed the digestive tract in a [112:40] way that yes, they can make more use of [112:42] of those calories, but that also creates [112:45] a more pro-inflammatory environment. Do [112:47] I have that correct? [112:48] >> That's absolutely correct. Also because [112:50] they're changing in configuration and [112:52] you're using that energy, the cells are [112:54] using energy to do other things, your [112:56] tight junctions are dep prioritized. [112:58] >> Okay. Right. So then there's this um [113:00] secondary uh or parallel effect of the [113:03] the tight junctions. We haven't really [113:05] talked too much about tight junctions [113:06] here, but um I'm not by no means an [113:08] expert, but I'm familiar with them from [113:09] the bloodb brain barrier. Like like [113:11] cells need to stick together. And some [113:14] tissues you want things sticky but not [113:16] too sticky. Some tissues you want them [113:18] really sticky. And my understanding is [113:21] that the tight, as the name uh suggests, [113:24] tight junctions, the goal is to keep [113:25] stuff inside the gut, not let bacteria [113:28] out. [113:29] Is leaky gut a real thing or is leaky [113:32] gut? Because I've heard it's sort of [113:33] like chronic fatigue syndrome that a lot [113:35] of the standard medical community, they [113:37] hear a chronic fatigue syndrome and they [113:39] go, "Okay, that was made up by people in [113:41] the Bay Area." I'm only half kidding [113:42] here. I'm from the Bay Area. But that's [113:44] how a lot of physicians react online to [113:48] this phrase leaky gut. But we've had a [113:52] fair number of people come on here and [113:54] talk about tight junction deficits, [113:56] bacteria getting out of the gut. This [113:58] isn't good for the body, inflammation [114:01] going up, bacteria circulating places [114:03] they shouldn't be is not good. So, is [114:05] leaky gut real? [114:06] >> Well, increased gut permeability is 100% [114:09] real. [114:10] >> But that's I mean, I'm not pushing back [114:11] on you. That sounds like like that [114:13] sounds like a different language for [114:14] leaky gut. [114:15] >> Yeah. So it is. [114:16] >> So why so why is this phrase leaky gut [114:18] so um no pun intended so irritating to [114:21] the medical community? [114:23] >> So I think if you say leaky gut it could [114:25] have other connotations that you don't [114:27] know what it means to the person. [114:29] Someone might think that leaky gut means [114:31] that it's responsible for a certain [114:33] constellation of symptoms potentially [114:34] >> like irritable bowel or Alzheimer's like [114:38] they can take a leak. [114:39] >> Yeah. Yeah. cuz cuz you see in in in lay [114:41] literature, right, they'll in other [114:43] literature they say leaky gut is [114:44] associated with XYZ, right? And it's not [114:48] clear that that that phrase leaky gut is [114:51] is is really talking the same thing I'm [114:54] talking about. Now, is leaky gut the [114:55] same thing? Yes, I'm still talking about [114:56] leaky gut in a sense, right? But the [114:58] danger is calling something leaky gut [115:00] when people already might have a [115:01] definition for leaky gut in mind like [115:03] it's responsible for for all these other [115:04] problems, right? But let me tell you [115:06] what leaky gut is to me or what [115:07] increased gut permeability is. And I'll [115:10] tell you that it's very real and it is [115:11] actually tied to metabolic illness. Uh [115:13] we can start with a study that used uh [115:16] small bile biopsies, right? And this was [115:19] recent just last year and they did small [115:21] bile biopsies and then they they [115:23] actually were able to from the stem [115:24] cells grow little or organoids, right? [115:26] And then organoids are like [115:28] threedimensional cultures that they they [115:30] behave as they should. as this the cells [115:32] kind of populate out of there they take [115:34] their normal form and structure and they [115:35] had a control group and they had a group [115:37] with MASH obesity and MASH right so [115:39] which is a metabolically associated uh [115:42] stat hepatitis so these two groups they [115:46] looked at the organoids and they found [115:47] that the tight junctions were far less [115:50] well-developed and more disorganized in [115:52] the mash patients compared to the [115:53] control patients additionally they did [115:55] transcripttoics on it and they found [115:57] that they weren't even producing a you [116:00] know the the the proteins. They weren't [116:02] even making the RNA to produce the the [116:05] tight junction proteins. So clearly at [116:07] transcriptional level, they were [116:09] downregulating the the the tight [116:11] junction proteins. [116:13] So with the imunoshistochemical staining [116:16] and then transcrytoics, they found that [116:18] the tight junctions just weren't weren't [116:20] functioning as they should in people [116:21] with MASH. So if you don't have tight [116:23] junctions, it stands to reason you might [116:25] have quote unquote leaky gut. So another [116:27] group actually looked at something [116:29] similar, right? They had same population [116:32] patients with MASH and they actually [116:34] studied they can there's different test [116:36] tests you can do to look for a leaky [116:38] gut. You can give something that's very [116:39] small but it should not get through [116:41] those tight junctions, right? There's [116:42] different tracers you can use. 51 [116:43] chromium EDTA is one that they use and [116:46] that's one that was used in this study [116:48] and so they give it. It's not supposed [116:49] to get into the blood bloodstream. in [116:51] patients with MASH, zipped right in, [116:53] much higher levels than there should be. [116:55] And in patients without MASH, it wasn't [116:56] getting in. Additionally, in patients [116:58] with celiac disease that was treated, it [117:00] wasn't getting in. But in patients with [117:02] with fatty liver disease, it was getting [117:04] in and it's probably playing a role, [117:06] right? So, if you think about it, the [117:08] gut, the first place it goes is the [117:10] liver. There's a portal circulation and [117:12] the gut goes to that portal circulation. [117:14] Everything that goes through there has [117:15] to stop by the liver with the exception [117:16] of fat. Fat gets into the lymphatics and [117:18] dumps out of the thoracic duct. doesn't [117:20] have to actually go to the liver. So if [117:23] you have bacterial products uh uh LPS, [117:26] lipopolysaccharide, [117:27] it's a portion of gram negative [117:29] bacterial cell membrane, right? If that [117:31] gets through these tight junctions, it [117:33] causes all sorts of problems. It is [117:35] going directly they're inflammatory. [117:37] They interact with um to receptor 4 and [117:41] uh you know that that goes um you know [117:44] starts all sorts of inflammatory [117:45] cascades. So um it goes via NFC B [117:49] signaling etc. That can be problematic. [117:52] Another group proved that was [117:53] problematic but actually this was done [117:54] in Duke. They actually took LPS and they [117:57] injected it into healthy people and they [117:58] found that their inflammatory markers [118:00] went through the roof and they found all [118:01] sorts of other problems out including [118:03] they did clamp studies in these [118:04] patients. They found it induced insulin [118:05] resistance. So yes, I think leaky gut [118:08] can be involved in all this stuff. And [118:10] that gets back to our very early [118:11] discussion about fiber and about, you [118:13] know, fermented beverages and how [118:15] important it is to keep your microbiome [118:18] healthy because that microbiome and that [118:20] butyrate is critical to producing [118:22] healthy intercases. That's first and [118:24] foremost, right? As well as healthy [118:26] tight junctions, a healthy mucin layer. [118:28] All the and and and actually it also [118:30] works together. Butyrate and and the the [118:33] microbes and the byproducts of the [118:34] microbes work with your immune system, [118:35] your innate immune system and it tells [118:37] them what to recognize and what not to [118:38] recognize which is just as important [118:40] because your your your bowel is full of [118:42] bacteria, right? So absolutely very [118:45] important and you do see where this [118:47] increased gut permeability is associated [118:50] hardcore good science evidence with real [118:52] illness. So absolutely is a problem. [118:55] It's just I don't want to blame it for [118:56] everything. [118:57] >> Right. Right. I get it. I I think that [119:00] the you know earlier we were talking [119:01] about CGMs and there's sort of a kind of [119:03] a common theme here which is the general [119:06] public now because of online health [119:08] information good and bad is starting to [119:11] um create their own nomenclature and I [119:14] could see why that would scare [119:15] physicians but I think that a more [119:17] symbiotic relationship between like the [119:19] public's under like knowledge of their [119:20] own data questions about like maybe it's [119:23] leaky gut you know um and being able to [119:26] approach their physician with with these [119:29] things in mind and still acknowledging [119:31] that the physician is the physician, [119:33] right, could be really helpful. I have a [119:35] couple of questions that feel free to [119:36] pass if these are aren't meaningful. Um, [119:39] I get a lot of questions about [119:40] artificial sweeteners and negative [119:42] effects on the gut microbiome. Seems [119:44] like they're marginal to zero effect on [119:47] insulin and resting uh blood glucose [119:49] from artificial uh lowc calorie [119:52] sweeteners in a way that like would lead [119:55] people to say these are bad. There's no [119:56] reason to run out and use them if you [119:59] don't want to. But the weight loss data [120:00] say people who drink diet sodas instead [120:02] of w water actually lose more weight. [120:04] I've seen those data, but this is not an [120:06] incentive for people to start drinking [120:08] diet sodas. [120:09] >> It sounds like, you know, saccharine and [120:11] Splenda are probably worse for you than [120:13] stevia and aspartame. Like where are you [120:16] at with these things in terms of their [120:17] potential negative effects? And if you [120:20] know of any positive effects, I'd be [120:21] curious. [120:21] >> I think they're better than high [120:22] fructose corn syrup for sure. Right. I [120:25] mean that I think we should be treating [120:27] like alcohol, right? Yeah. I think [120:29] fructose and fruit is fine. I'm not [120:30] worried about fructose and fruit [120:31] fructose in general because it comes [120:33] with a matrix around it. It's not it's [120:35] not like a rush of c of of of fructose [120:38] into your liver. But fructose can only [120:40] be processed by the liver, right? And so [120:42] it's busy as it is now. It's got to take [120:44] the burden out of of uh you know a [120:47] beverage which is absorbed very rapidly [120:49] goes directly to the liver and it has to [120:51] be has to be dealt with. um and you know [120:54] it gets trapped in the liver very [120:55] quickly and that's the only place I can [120:56] really process it. So I think that [120:58] fructose is something to watch. Um again [121:01] not if it's in fruit even in juices it [121:03] can be kind of juices are processed [121:04] fruit right so it's similar just [121:06] minimally processed stuff is better I [121:09] think the problem with sweeteners [121:10] artificial sweeteners is they come in [121:15] foods that are uh that are highly [121:17] processed as it is right and you can't [121:19] separate the two I think that's for a [121:21] while why people were so down on on [121:23] polyunsaturated fats right because [121:26] they'll come in a in a bar full of a [121:28] bunch of other stuff that's not good for [121:30] So well I guess the polyunsaturated fat [121:31] is also bad for you in some way right [121:33] that was like a recent phenomenon. Well, [121:35] no, the food that it's in is bad for [121:37] you, but the polyunsaturated fat has [121:38] been shown to reduce LDL and has as has [121:40] health [121:40] >> benefits or essentially translation for [121:43] people like seed oils basically [121:45] >> that yeah, there's some still debate [121:46] about whether or not the processing of [121:48] them can make them worse, but um yeah, [121:50] it's it it's hard to uh Well, I know did [121:53] you see this recent avocado uh oils [121:56] thing out of UC Davis? Uh this is wild. [121:59] UC Davis went and analyzed like all [122:01] these avocado oil containing products [122:03] are supposed to be like healthier. You [122:05] know how much avocado oil these products [122:07] contain? [122:08] >> Zero. [122:08] >> Oh no. [122:09] >> And the push back has been that maybe [122:11] they're looking at the wrong metabolites [122:13] of of of avocados. I don't know how this [122:16] is going to play out, but if it this [122:19] could this could potentially do more [122:20] damage to the I just call the non olive [122:23] oil uh community, right? Because in my [122:26] mind, like the safest thing is you just [122:27] use olive oil, a little bit of butter if [122:29] you here and there, right? Like, okay, [122:31] no one debates olive oil. It's kind of [122:33] wild. No one debates. Everyone knows [122:34] it's good for you. No one thinks it's [122:36] bad for you. But the seed oil lard [122:38] thing, they go back and forth and it's [122:39] kind of like professional wrestling. I [122:41] feel like it's all kind of made up for [122:42] entertainment, but both sides are really [122:44] adamant. It's just kind of stupid. Olive [122:47] oil, butter, right? Or you're the [122:48] physician. Tell me, am I thinking about [122:50] this wrong? [122:50] >> I do the same. No, Olive oil is the [122:52] best, obviously. Then small amounts of [122:53] butter. I don't think, you know, large, [122:55] bad, and small amounts. I think the [122:56] problem is it's overall amount of [122:58] saturated fat, right? Um, but [123:00] polyunsaturated fats have a lot of proof [123:01] that they're very safe. Where you get [123:02] into problems is if you have a big [123:04] container of it, like a huge container, [123:05] you're not going to use it in a [123:06] reasonable amount of time and sitting in [123:08] the sun or something and you get oxid, [123:10] you know, it oxidizes. That's a problem. [123:12] You don't want to take an oxidized oil [123:13] into your body, right? Or you're deep [123:15] frying with it and you're frying over [123:16] and over again, you start generating [123:17] trans fats. [123:19] >> That's a different story. [123:20] >> But in general, I think, you know, I [123:21] think they're fine. Um, and and I don't [123:24] even think you need this omega 3 to [123:25] omega 6 ratio people used to worry [123:27] about, right? I think you need a certain [123:29] minimal amount of omega-3s, right? You [123:31] know, if you eat fish once in a while, [123:33] you're getting all you need. [123:34] >> Do you strive to get like some fatty [123:36] fish in your diet? [123:36] >> I do. Yeah. I love I love fatty fish. [123:38] It's It's good for you. Try to do it a [123:40] couple times a week. [123:40] >> I take Lavaza, the highdosese omega-3 [123:44] >> pharmaceutical, because I don't want the [123:46] mercury. It's cleaned of mercury. I [123:48] don't know. My blood markers are where I [123:49] want them to be, but I'm I'm curious. [123:51] What's your read of the data on omega-3s [123:53] for metabolic health and cardio uh [123:55] cardiovascular? [123:55] >> It's mixed. I mean, it's probably better [123:56] for Alzheimer's, right? If someone's [123:58] starting to show signs of Alzheimer's, I [124:00] think it's it's better for that. The [124:03] data I think the problem is universally [124:06] supplementing is not necessarily the way [124:08] to go. You want to find a deficit and [124:10] then supplement, right? So, even with [124:12] vitamin D, you know, most people [124:13] probably are deficient, so they benefit [124:15] from it, but there's no point in really [124:16] doing it unless you're deficient for [124:18] most things. And I think with omega-3s [124:20] is it's similar. You want to get your [124:21] daily allowance if you will. And again, [124:23] if if you're a vegetarian, you can do it [124:25] from algae, the original source. The [124:26] fish are just consolidating, right? Um, [124:29] so, you know, you don't have to eat the [124:30] fish, but uh that or get that in some [124:33] kind of, you know, supplement form. [124:34] >> You heard it here from Chris Thompson. [124:35] Fish are just consolidated algae. I'm [124:38] just kidding. I put those words in your [124:39] mouth. I love that. For all the people [124:41] who are like, "No, you can't get [124:42] omega-3s from non-animal sources." I [124:44] mean, I think you put it beautifully. I [124:46] don't like eating fish, so I take the [124:48] lavaza. Yeah, I don't like I don't like [124:50] that. But I'm not on the east coast. You [124:51] guys tend to have better seafood. It's [124:53] delicious. Yeah, I know. I got to get [124:55] out. But it's too cold out there. Then [124:57] you have to take vitamin D out here. You [124:58] don't I'm just kidding. Um what else do [125:01] you recommend to your patients as they [125:02] start to move away from obesity? So [125:06] obviously fiber, some fermented foods. [125:10] Um uh it sounds like resistance training [125:13] might be in the list given that they're [125:15] they're they're at risk of uh re [125:17] becoming um thin but more jelly tissue [125:21] than uh lean lean mass. Do you do you [125:24] prescribe resistance training? [125:26] >> Absolutely. So all my patients I ask [125:29] them to do resistance training um even [125:31] you know before they start losing weight [125:33] before they go through a procedure. It's [125:35] essential. Uh zone 2 cardio is great [125:37] right? It's good for fat burning. you're [125:38] in that zone where you're burning fat [125:40] and you know not you know carbs as much [125:42] right HIT is great. So highintensity [125:45] interval training is great for [125:46] mobilizing visceral fat because your [125:48] visceral fat we haven't talked a whole [125:49] lot about it but it has betadronurgic [125:52] receptors on it. It also has [125:54] gonadotropic hormone receptors on it as [125:56] well. So um it's responsive to to stress [126:00] like acute stress. So it will mobilize [126:02] when you're going you know through the [126:04] stress of of of high you know high [126:06] intensity interval training. So, it'll [126:08] mobilize. It won't be burned right away, [126:09] right? Because you're burning carbs at [126:10] the time. You're burning your your liver [126:12] glycogen and uh and your muscle [126:13] glycogen. You're burning that, but you [126:15] mobilize the fat at least. And that's [126:17] kind of what it's designed for. That's [126:18] why you have some visceral fat there. [126:20] Um, so I included I I I try to have them [126:22] do those things. Hit little zone 2 and [126:25] then resistance training. I think those [126:26] are the most important things long term. [126:28] Do they do it? [126:28] >> This is very interesting. So, I think [126:32] they try and depending on how they lost [126:34] the weight determines if it's effective, [126:36] right? So it's it's theory of set point, [126:38] right? Which is something that's very [126:40] important. Back to back to metabolic [126:41] health. So it's it's not a point [126:44] necessarily. It's a defended range if [126:46] you will, right? So you have this [126:46] defended range of what you think your [126:48] weight's supposed to be. And that's set [126:50] by a variety of things. Leptin is part [126:51] of it, right? And your thyroid hormones [126:54] and whatnot. And you think you're [126:55] supposed to be a certain weight. And [126:56] then what you do is you do a crash diet. [126:58] You lose a bunch of weight. Like the big [127:00] biggest loser was a great example of [127:01] this, right? You lose a bunch of weight. [127:03] So now you're fighting several factors, [127:05] right? So, one factor is your body is [127:07] smaller, so it burns less weight. Okay? [127:10] So, you have to eat less to just [127:12] maintain the same weight you're at now, [127:14] this lower weight. That's a bit of a [127:15] problem. You downregulate your gut [127:17] hormones. We talked about a bunch of gut [127:19] hormones. You're producing less GLP-1. [127:22] You're producing less P Y. You're [127:25] producing GIP is here neither here or [127:27] there. Little less CCK. So, your satiety [127:29] hormones are being produced less. Your [127:30] grein goes through the roof. If you do [127:32] this with diet and exercise, your [127:34] grillin goes through the roof, right? So [127:37] that in addition to the fact that your [127:39] muscles become more efficient, I think [127:40] they become 25% more efficient in doing [127:42] a similar task. They're going to burn [127:44] less fuel to do the same task. It's [127:45] amazing, right? Your kind of non [127:48] exercise energy expenditure, right? So [127:51] just kind of daily activity, your basil [127:52] malbach rate as well, they all kind of [127:55] go down. So you're burning less calories [127:57] at rest. So we've shown this study study [127:59] after study. So, your whole body is [128:01] fighting you, okay? It wants to go back [128:03] to that weight, whatever it thought it [128:05] was supposed to be at. The biggest loser [128:06] was a great there was a kind of an NIH [128:08] follow-up study to that, and they found [128:09] that they were burning 500 fewer [128:11] calories per day after that. So, and [128:14] there's other studies that have shown [128:16] this as well if you lose weight that [128:17] way. So, that's why it's so important. [128:18] GLP1's helped fight part of that, right? [128:20] You're replacing the GLP1 that's you're [128:23] not you're not addressing the ghrein or [128:24] other things. So, time will tell if we [128:26] can have long-term weight loss, but it [128:28] does it does. So ground isn't the whole [128:30] story, right? So like with with our [128:32] procedures, so we're addressing these [128:33] very targeted with procedures and one [128:36] bridge into that is is the ESG [128:38] procedure. So this is the procedure I I [128:40] I developed in 2012. So you go in [128:43] through the mouth, someone's sleeping [128:44] obviously with a little scope and you [128:46] fold the stomach on itself. Now the goal [128:48] of that was to do two things, you know. [128:50] Uh one was to augment the stretch [128:53] receptor so it's a smaller pocket. So [128:55] when food hits that the stomach [128:56] stretches quicker and you have the [128:58] veagal aerence now that go up to the [129:00] noto's ganglia and then you know uh NTS [129:03] and then you know boom into the um [129:06] hypothalamic area [129:07] >> you tell the brain we're full. Yeah, [129:08] exactly. We're full, right? Stretch [129:10] fast. Boom. So when you stretch, you get [129:12] that signal. Boom. And you're full. [129:14] That's part of it, right? That's [129:15] phenomenal. The other part of it is you [129:17] suppress ghrein because food stays in [129:19] the stomach longer, right? And so it's [129:21] suppressing grein. So it's doing two [129:22] different things. Now, when those people [129:24] lose weight, they don't have to worry [129:26] about their ghrein going up because it's [129:27] been suppressed. So it's easier to keep [129:29] the weight off for 10 years or longer [129:31] because you're not fighting that part uh [129:33] you know of of the counter measures that [129:35] the body will do to defend this [129:36] potential you know potential range. [129:39] We're not doing anything with that [129:40] necessarily to to GLP GLP1 and other [129:44] another dudal hormones but you'll see it [129:46] actually it actually you have ways of [129:48] dealing with this. So how do you augment [129:50] weight loss? You have all these [129:51] different targets right? So one thing [129:52] we're doing now is we talked about how [129:54] grein resides in the fundus. Now, in [129:57] addition to that ESG where we tighten [129:58] the stomach, someone developed an idea, [130:00] I think they were in Germany where you [130:01] can actually ablate those fundal ghrelin [130:04] cells because they live in the mucosal [130:06] layers. You can get to them. So, you can [130:08] they use argon plasma coagulation. [130:10] There's different ways to ablate it. You [130:11] just kind of spray this over the fundus [130:13] and it kills off the grein producing [130:14] cells. They grow back and there's not [130:15] much of them, right? So, now all of a [130:17] sudden, you can suppress ghrelin as [130:18] well. So the weight loss goes from about [130:20] 18% with DSG alone in a in a top center [130:23] goes up to way over 20% maybe 25% if you [130:25] start ablating the gre [130:28] inhibit ghrein. [130:30] >> No not not effectively. Yeah. So and [130:33] then you add to it right. So now if [130:34] you've delayed gastric emptying your CCK [130:36] is not spiking as much as it was etc. So [130:38] but you're not getting which which is is [130:41] a subtle countermeasure potentially [130:42] right? It will still spike but GLP1's an [130:44] issue. So now what if you combine that [130:46] with a small bowel procedure right? And [130:48] there's different small bowel procedures [130:49] that we've come up with using magnet [130:51] magnetic anastmosis is one we published [130:53] about 10 years ago. We did it in the [130:55] Czech Republic where we used endoscopes. [130:57] It was a hard way to do it. Went from [130:59] below a colonoscopy. My partner did [131:01] that. I went from above. It released [131:02] these two magnets and we connected the [131:04] jigunum the first part of the jigunum to [131:06] the the lower part of the illium. [131:07] >> We should probably tell people what anos [131:09] is is basically uh when you connect two [131:11] tubes. [131:11] >> Exactly. [131:12] >> Right. Is that right? You're basically [131:13] just So you're basically like liating a [131:15] tube. Y we're using more nomenclature. [131:17] You're you're bridging in two tubes. [131:19] >> Bridging them, right? Yeah. And they did [131:21] it originally with sutures. You cut a [131:23] hole and you suture the tubes together, [131:24] right? And then they did staplers and [131:26] staplers that do it, but they're big and [131:27] bulky and hard to position. So So our [131:29] lab developed magnets, right? And these [131:31] are ring magnets. So they come out, [131:32] they're they're magnets encased in nit [131:35] so they can take a certain shape. So you [131:36] put them through a tube. In this case, [131:38] it's an endoscope. You could put them [131:39] through a laparoscope or whatever else [131:40] you want to put it through. And they [131:42] come out and they form a ring. Right? So [131:45] we went from the top endoscope we formed [131:46] a ring in the junum and the bottom we [131:48] formed one in the illium way downstream [131:50] and then we had an anastmosis that would [131:53] allow the food to directly pass there [131:55] and what we found is you get these big [131:57] spikes in GLP1. So now what people are [131:59] doing I'm conflicted and can't do this [132:01] part of the procedure but what they're [132:03] doing is they're doing that in aosis and [132:05] they're doing uh suturing procedure [132:07] endoscopically and together you're [132:09] really replicating a full gastric [132:11] bypass. You're having a GLP-1 hind gut [132:13] spikes. you're getting that sense of [132:15] restriction and the veagal aerant [132:16] signaling. You're getting uh you know [132:18] ghrein to be suppressed and you're [132:20] getting really amazing weight loss. So [132:22] what we can do now is take a procedure [132:24] that was really big. It started off as a [132:25] big open procedure that had certain [132:27] risks to it. We didn't know how it was [132:28] working and it did a bunch of different [132:30] things and we're targeting different [132:31] aspects of it. And the goal moving [132:33] forward is to even be more precise and [132:35] find out what someone is going to be [132:37] more responsive to and then just do the [132:38] least you need to do. Maybe they just [132:40] have ghrein that's driving them just [132:42] ablate the ghrein, right? Maybe they [132:44] need something more. And people are [132:46] actively studying that. Um they're [132:48] studying the phenotyping of obesity. [132:50] It's quite exciting. [132:51] >> I'm sensing another theme here. Um this [132:54] procedure that you co-developed or [132:56] developed, [132:57] >> which one? [132:58] >> This this uh bridging of um [133:00] >> So that was my lab. So yeah, that was my [133:02] lab. I'm the PI, but I have a whole team [133:04] obviously. Yeah. [133:05] >> Yeah. So, it's increasing GLP, but I'm [133:08] guessing it's not increasing it [133:09] thousandsfold like a GLP drug would. [133:13] It's got some other positive [133:14] consequences that help cure the obesity. [133:17] I'm I'm kind of sensing a theme here, [133:19] right? Like we have this these drugs [133:22] like Ompic, Monaro, etc. that blasted [133:26] GLP's through the roof, helped a lot of [133:28] people that needed help, but there were [133:29] a lot of side effect issues. Then along [133:31] comes this other drug reatride which is [133:33] like okay well let's increase GLP but [133:35] let's also kind of bump up the GIP [133:37] system a nudge or two let's also bump up [133:40] the glucagon system and lo and behold we [133:42] get a much better effect muscle sparing [133:44] and actually better weight loss so kind [133:47] of a perhaps a lesson to us that like [133:49] you don't really want to push really [133:51] hard on one lever in biology or take any [133:54] one thing out maybe the more [133:57] combinatorial approach is the better [133:59] approach [134:00] speculating here but there seems to be a [134:02] you know parallel theme. [134:04] >> Oh definitely. I think that um you can [134:07] mitigate risk by doing that by not [134:10] giving too much of one thing and I think [134:12] it's it's it's hitting again using [134:14] multiple levers is definitely a way to [134:16] get a treatment effect without exposing [134:17] the body to potentially the harms of [134:20] going too too big on one thing. [134:22] >> So that'd be the argument for these kind [134:24] of multimodal approaches. Then you can [134:26] also combine these procedures with the [134:27] drugs, right? So you do an endoscopic [134:29] procedure like a tighten tighten the [134:31] stomach and then give a drug and see if [134:33] you get much more weight loss [134:34] >> or at a lower dose and get the [134:36] >> lower dose. Right. [134:37] >> Yeah. This was what years ago on this [134:39] podcast we looked at the whole ADHD [134:40] thing and the effects of these drugs on [134:42] ADHD and you know like parents who get a [134:45] great effect of a of a you know an [134:47] Adderall or a Vivance for their kid that [134:50] couldn't focus. It's I have friends with [134:51] a kid like this and you know they're [134:53] just like it's remarkable but they're [134:55] worried about the reduced uh growth [134:57] effects. They're worried about the sleep [134:59] effects and and you know so they're in [135:01] this trade-off and and that's where I [135:03] think you it doesn't it's not always an [135:04] eitheror. We forget it could be well [135:06] maybe this child could get by with a [135:08] lower dose of medicine if they're also [135:10] doing some things behaviorally if [135:12] they're also doing some things with [135:14] nutrition etc. Obviously, the [135:16] constellation of things will differ, but [135:18] we we don't often think like that. [135:20] Americans want the drug that fixes the [135:22] problem. We love that. And then we get [135:25] all pissed off when we're like, we had a [135:27] generation of kids raised on [135:28] amphetamines. Well, it's like maybe kids [135:30] just been a little [135:32] and more exercise, right? And so it's [135:34] it's gratifying to hear that you're [135:36] doing these multi-pronged approaches and [135:39] um and that you do recommend exercise [135:42] including resistance training, right? [135:44] And it, you know, they do all these [135:46] studies that show diet and exercise [135:47] alone don't work because of the set [135:49] point. Like look ahead was a great [135:50] study, right? That was [135:51] >> that's running, right? It's like [135:52] treadmill [135:53] >> look ahead. Yeah, it was it was a lot of [135:54] that and it was a lot of um uh just [135:57] diet, heavy diet, too. And they found [135:59] they got like a 6% total weight loss or [136:02] something like that at 10 years and no [136:04] improvement in heart disease and stuff [136:05] like that, right? So there's other [136:06] studies that show it's hard to do it [136:08] alone just like the Biggest Loser [136:09] version and there's several other [136:10] versions of that where it's hard to do [136:11] it alone because you're not addressing [136:13] the countermeasures the bodies throw at [136:14] you, right? The body throws at you. But [136:16] that doesn't mean it's irrelevant, [136:17] right? So when you do a procedure like [136:19] say a gastric bypass surgery, right? Or [136:21] you go on a GLP1, you still got to fix [136:23] the fundamentals that got you in the [136:25] problem to begin with, right? You need [136:27] to start getting more fiber. You need [136:28] to, you know, have uh a better diet. You [136:31] know, try to avoid the insulin spikes. [136:33] Do what you can to treat those things. [136:35] You got to start moving. You got to [136:36] start exercising. Otherwise, it's going [136:38] to fail. The treatments will fail. The [136:40] endoscopic procedures, the surgeries, [136:41] the medicines will fail unless you [136:43] really address those underlying [136:44] problems. So, even though alone they [136:46] don't do it because the body has [136:48] adapted, they're still important to the [136:50] ultimate treatment. [136:51] So given where things are at now, the [136:54] treatments uh that you and colleagues [136:56] have have developed and when I say [136:58] colleagues, I mean people with in your [136:59] laboratory and clinic, but you know [137:01] clearly is like a international thing [137:04] going on trying to solve these issues. [137:06] Where are things headed next? You [137:08] mentioned AI. What's the potential role [137:10] of other technologies to improve um [137:13] health and outcomes? [137:15] >> Well, I think one uh thing that's very [137:17] exciting is is gene therapy, right? So, [137:20] we talked about GLP-1s and how it's mega [137:23] dosing, super physiologic. Um, it's not [137:26] nutrient responsive. [137:29] There's a new a company working on a new [137:31] approach which is a gene therapy and I [137:33] was involved in the very early work for [137:35] this. And basically what they're doing [137:37] is they've they've developed a a viral [137:40] vector, right, that has the gene for [137:42] GLP1 in it and they're using the [137:45] promoter for uh the beta cell insulin [137:48] gene, right? So basically when a a [137:52] patient would uh secrete insulin in a [137:55] nutrient responsive way, this [137:57] simultaneously be secretreting GLP-1. [138:00] These viral vectors are um they're [138:02] beautiful tool of of um biology where [138:06] you can put some genetic cargo into a [138:08] virus that doesn't cause any problems [138:10] but allows for stable expression of and [138:13] the production of certain proteins in a [138:14] cell. So how are you getting into the [138:16] pancreas? You injecting it through the [138:17] skin? No. So we actually using [138:20] endoscopic ultrasound. So you know that [138:22] same device we developed to actually you [138:24] know biopsy the pancreas. We're now [138:25] using something similar to actually [138:27] treat and you can you can ablate tumors [138:30] with energy as well. Uh people are using [138:32] electroporation to cause apoptosis. [138:34] They're using thermal means but you can [138:36] also inject something fineal injection [138:38] right. So and we're injecting the the [138:41] the viruses basically into the tail of [138:43] the pancreas. Now you wouldn't want to [138:45] just take this introvenously because [138:46] they end up in other tissue. Right? [138:47] We've done a lot of work to make sure [138:49] those things stay in the tail of the [138:50] pancreas too. Right? We've done a lot of [138:51] animal studies where we've injected it [138:53] and we make sure we use, you know, green [138:55] fluorescent protein. Make sure it [138:57] doesn't end up in areas it's not [138:58] supposed to be. Is this so we're getting [138:59] technical here, but is there a pancreas [139:01] specific promoter translation this would [139:04] allow even if some got out it could I [139:07] wouldn't get expressed elsewhere. Is [139:08] there a way to make it only expressed by [139:10] pancreatic eyelet? [139:11] >> Very very close. Yeah. But it still you [139:13] just don't want it getting anywhere else [139:15] anywhere. But it the only place it [139:16] becomes active is in the beta cells. [139:17] Doesn't become active in the alpha [139:19] cells, right? The pancreas, right? So [139:20] you're really just active in beta cells. [139:22] And and it again you you secrete insulin [139:25] into these little vesicles, right? And [139:27] so you're secreting GLP1 into those same [139:29] vesicles. So then when you have your [139:30] meal, the vesicles release GLP1 and [139:32] insulin together. [139:32] >> Oh, that's clever. [139:33] >> Nutrient. You're making the drug. I [139:35] mean, we were already making the drug, [139:37] but now you're making it an elevated [139:38] rate. [139:38] >> Not only that, you're not making it in [139:40] the L cells where it has to go all the [139:42] way up through, go to the liver, go [139:43] around, do its thing, right? you're [139:44] making it at the place where it's [139:46] needed, right at the pancreas. So, it [139:47] has an urine function, paracrine, you [139:49] know, and it can and it's it's much [139:51] faster. [139:52] >> How often are these cells turned over? [139:54] Because it it, you know, um if it were [139:56] brain, no problem because brain cells [139:58] don't turn over, but how often does [139:59] pancreas turn over? [140:00] >> Very important. Why you can't do it in [140:01] the bowel is because they're not [140:02] terminally differentiated, right? You're [140:04] turning over your whole bowel every 5 [140:05] days or whatever. [140:06] >> Pancreas terminate terminally [140:08] differentiated. So, they're not going to [140:10] be changing. So, it's a it's a permanent [140:12] the episomal DNA stays in there. doesn't [140:14] integrate into the host DNA stays next [140:16] to it and transcribe with it process. [140:19] >> But they're they're not going to, you [140:22] know, not going to have to turn over. [140:23] >> I feel like there's a here's another [140:25] theme emerging like we're hearing about [140:27] drugs that you can get one injection to [140:29] permanently lower your LDL. We're now [140:31] hearing about gene therapy to um chronic [140:34] chronically elevate GLP at exactly the [140:36] place and time that you want in order to [140:38] offset excess calorie consumption and [140:41] obesity. Is this what we're going to [140:43] see? Like instead of people taking [140:44] drugs, they're going to take a one-time [140:45] injection. [140:47] >> That's what I'm hoping, right? It's very [140:48] exciting. They actually just entered [140:49] clinical trials in uh I think the [140:51] Netherlands. So, it's very exciting. So, [140:53] we'll see how that goes. But it looks [140:55] like it'd be very promising, right? So, [140:56] one time GLP1 injection that could be [140:59] nice. Additionally, you could use it to [141:00] augment other therapies. You can use it [141:02] to augment the gastric procedure or the [141:04] small bowel procedures. It might be [141:05] another tool in your armamentarium. [141:08] It might be more use for diabetes than [141:10] it is for weight loss. We don't know, [141:12] right? So, uh it's so early right now, [141:14] but it's certainly very encouraging. [141:16] >> Really glad you're doing this work [141:18] because I'm aware of a few conditions, [141:20] but they're rare, fortunately, but [141:21] they're not exceedingly rare where [141:23] hyperphasia is an issue. Um Prader [141:25] Willie syndrome and other syndromes [141:27] where these kids just can't stop eating [141:30] because they lack of hypothamic signals [141:32] and I don't know my read is that the G [141:34] the traditional GLP drugs are are not [141:36] really working there. um this would be [141:38] amazing [141:39] >> and I mean in road models it's [141:41] phenomenal because we did these trials [141:43] where you randomize mice to get [141:44] saggotide high dose simaglletide much [141:47] higher than you get for a human and then [141:49] the trans gene right and both groups [141:51] lose weight trans gene lose a little [141:53] more then they stop losing so they don't [141:54] keep losing weight forever right which [141:56] is good and then you took the group [141:57] that's simagide and you randomize them [141:59] further to get nothing or to get the [142:00] trans gene they get the trans gene and [142:02] they go back right down to the same [142:04] settling point which is great and the [142:05] ones that were randomized to nothing put [142:07] all the way back gone. [142:08] >> Phenomenal, right? So, it seems to be [142:10] getting really good results from a [142:11] weight loss standpoint as well. I want [142:13] to take too much more of your time, but [142:15] if you're willing, we could just briefly [142:18] talk about you for a second. Um, we [142:20] won't go into deep layers. Uh, that's [142:22] not the purpose here, but you're an [142:23] interesting person. Um, whether uh you [142:27] realize it or not, I hope you do, [142:28] because it occurs to me that you you had [142:31] certain solutions in hand, but you [142:33] decided to make search for better [142:35] solutions. And so I'm just curious like [142:36] was that always you are you have you [142:38] always been a tool builder like in [142:40] medical school and residency or even [142:42] prior like high school? Are you are you [142:43] the person who like sees like okay like [142:45] the reason you have to keep I'm dating [142:47] myself here like like fix the antenna on [142:49] the TV is cuz actually the antenna [142:51] sucks. Let's let's do something to the [142:53] antenna. Were you that kid? [142:55] >> Yeah. My my mother would attest to that [142:57] unfortunately. I I took my motorcycle [142:59] apart in high school. Couldn't get it [143:00] back together. had to uh have it flatbed [143:03] away and fixed and I fixed uh I fixed [143:05] some parts in my car that ended up [143:07] bursting into flames. So I'm much better [143:09] at dealing with with patience than with [143:12] Could have been the other direction. [143:13] Right. [143:14] >> Exactly. So no I always I always would [143:17] tinker with things for sure and I needed [143:19] to do things with my hands. So that's [143:20] why in medical school I couldn't be kind [143:22] of a general internist. I think I needed [143:24] to I needed to solve problems with my [143:26] hands and I think that's fulfilling to [143:28] me is to I don't I don't like managing a [143:32] slow demise right and I felt like [143:34] internal medicine we were giving people [143:37] a reason to to continue with their [143:40] current life right and instead of [143:42] addressing problems like their blood [143:43] pressure is high well instead of finding [143:46] a way to really help them address that [143:48] is well take this medicine your LDL is [143:50] high instead of finding a way to address [143:51] it you give them a medicine and you see [143:53] what that gets us into these situations [143:55] where we treat HD we we treat a high LDL [143:58] APOB really effectively but we're not [144:00] and we reduce mortality from that [144:02] specific thing but we took our eye off [144:04] the ball and fatty liver is up and [144:06] diabetes is up and people are still [144:07] dying in greater numbers right so I feel [144:10] like we need to address the underlying [144:12] problem and that's very important but [144:14] aside from that I just like doing things [144:16] with my hands and I think that was a [144:18] large part why I was going to go into [144:19] cardiology or going to interventional [144:21] gastro [144:22] so grateful that you're a tinkerer. It's [144:24] a unique thing to find these qualities [144:26] and expertise woven into the same [144:28] person. The fact that you clearly have [144:30] immense compassion for your patients and [144:32] you're willing to come here and share [144:33] information publicly. You have many many [144:35] important roles in your daily life. Um [144:38] so the fact that you take the time out [144:39] of your uh schedule to um educate the [144:42] public is uh I and everyone listening [144:44] have immense gratitude for that and that [144:46] you're thinking about what could be done [144:48] better. That's like the ultimate quality [144:50] in my opinion of a of an excellent [144:51] physician or scientist or engineer. But [144:54] when it comes to physicians and the [144:56] general public, we need people who are [144:58] thinking about how things Yes, there are [145:01] some solutions for some people, but we [145:02] need to broaden the the treatments to [145:04] help many more people. So, I'm just very [145:06] grateful to you and and thanks for [145:07] coming here today and sharing this info. [145:09] >> Well, thanks so much for having me. Very [145:11] kind. It's definitely always a team [145:13] effort as you know, right? As as well as [145:14] anyone. Everything is a is a is a team [145:16] effort and I think innovation is never [145:18] the result of one person's you know [145:21] work. It's it's a it's a whole group and [145:22] I've been very fortunate to be [145:23] surrounded by a bunch of amazing people [145:25] that help help us move things forward. [145:27] So [145:27] >> well throughout today's discussion your [145:29] reflex to give proper attribution is [145:31] more a testament to what what you just [145:33] said. It's not lost on me when uh and [145:35] and nor the people listening people who [145:37] give credit where credit's due it it [145:38] says a lot about them. So thank you. uh [145:41] come back again maybe in a couple years [145:43] when you've solved everything or close [145:45] to it. Just joking. I'm sure you guys [145:46] are making uh tremendous strides, but [145:49] these things take time. Once again, [145:51] thank you very much. This was very very [145:53] informative and has enriched my thinking [145:55] a tremendous amount. I'm sure everyone [145:56] listening as well. [145:57] >> Thank you. [145:58] >> Thank you for joining me for today's [146:00] discussion with Dr. Chris Thompson. To [146:02] learn more about his work, please see [146:03] the links in the show notes caption. If [146:05] you're learning from and or enjoying [146:06] this podcast, please subscribe to our [146:08] YouTube channel. That's a terrific [146:10] zerocost way to support us. In addition, [146:12] please follow the podcast by clicking [146:14] the follow button on both Spotify and [146:16] Apple. 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