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Ralph DeFronzo is a distinguished diabetes researcher and clinician whose groundbreaking work on insulin resistance has reshaped the understanding and treatment of type 2 diabetes. In this episode, Ralph shares insights from his five decades of research, including his pivotal role in bringing metformin to the U.S. and developing SGLT2 inhibitors. Ralph explores the impacts of insulin resistance on specific organs, the pharmacologic interventions available, and the gold-standard euglycemic clamp method for measuring insulin resistance. This episode is a masterclass in the pathophysiology and treatment of type 2 diabetes, featuring an in-depth discussion of GLP-1 receptor agonists, metformin, and a lesser-known class of drugs that opened Peter’s eyes to new possibilities in diabetes care.

We discuss:

• Metabolic disease as a foundational driver of chronic illness [4:00];
• Defining insulin resistance: effects on glucose, fat, and protein metabolism, and how it varies between healthy, obese, and diabetic individuals [8:15];
• The historical significance of the development of the euglycemic clamp technique for measuring insulin resistance [11:45];
• How insulin affects different tissues: liver, muscle, and fat cells [15:00];
• The different ways insulin resistance manifests in various tissues: Alzheimer’s disease, cardiovascular disease, and more [25:00];
• The dangers of hyperinsulinemia, and the importance of keeping insulin levels within a physiological range [29:00];
• The challenges of identifying the genetic basis of insulin resistance and type 2 diabetes [37:00];
• The “ominous octet”—a more comprehensive model of type 2 diabetes than the traditional triumvirate [45:45];
• The kidneys’ unexpected role in worsening diabetes, and how SGLT2 inhibitors were developed to treat diabetes [55:45];
• How insulin resistance in the brain and neurocircuitry dysfunction contribute to overeating and metabolic disease [1:04:15];
• Lipotoxicity: how overeating fuels insulin resistance and mitochondrial dysfunction [1:07:30];
• Pioglitazone: an underappreciated and misunderstood treatment for insulin resistance [1:10:15];
• Metformin: debunking the misconception that it is an insulin sensitizer and explaining its true mechanism of action [1:19:15];
• Treating diabetes with triple therapy vs. the ADA approach: a better path for diabetes management [1:24:00];
• GLP-1 agonists, the Qatar study, and rethinking diabetes treatment [1:31:30];
• Using a hyperglycemic clamp to look for genes that cause diabetes [1:45:15];
• The superiority of measuring C-peptide instead of insulin to assess beta-cell function [1:46:45];
• How GLP-1-induced weight loss affects muscle mass, the benefits and risks of myostatin inhibitors, and the need for better methods of evaluating functional outcomes of increased muscle mass [1:51:30];
• The growing crisis of childhood obesity and challenges in treating it [2:02:15];
• The environmental and neurological factors driving the obesity epidemic [2:07:30];
• The role of genetics, insulin signaling defects, and lipotoxicity in insulin resistance and diabetes treatment challenges [2:11:00];
• The oral glucose tolerance test (OGTT): detecting early insulin resistance and beta cell dysfunction [2:18:30]; and
• More.

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In this “Ask Me Anything” (AMA) episode, Peter tackles a diverse set of listener-submitted questions, covering a wide range of health and performance topics. He dives into assessing cardiovascular health, discussing key biomarkers and risk factors, and breaks down various fasting approaches, including time-restricted eating and prolonged fasting. The conversation also explores the impact of alcohol on health and disease risk, fundamental principles of nutrition, and optimal protein intake. Additionally, he examines the pros and cons of ketogenic and low-carb diets, strategies for building effective exercise routines, and the role of wearables in tracking health metrics. The episode concludes with insights on emotional health, making this a well-rounded discussion packed with practical takeaways for anyone looking to optimize their well-being.

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We discuss:

• Episode format: overview of common health topics based on listener questions [1:30];
• How to accurately assess your cardiovascular health [3:00];
• The impact of fasting, time-restricted eating, and dietary restriction on metabolic health [9:00];
• Alcohol: health risks of consumption, limitations of research, and how to weigh the risks against social and personal enjoyment [13:45];
• Principles of a well-balanced diet: macronutrients, micronutrients, protein, energy balance, and more [23:45];
• The benefits and drawbacks of ketogenic diets: impact on satiety, metabolic health, athletic performance, lipid levels, and more [29:15];
• Protein: best sources for muscle growth, total intake, PDCAAS scoring system, and getting adequate amounts on plant-based diets [36:15];
• Creating an effective fitness routine that fits into a busy schedule [41:45];
• The role of rest and recovery in a workout routine [46:00];
• How to track fitness progress beyond just weight on a scale [48:30];
• The best low-impact exercises for individuals with joint issues [52:00];
• Wearables: insight vs. compliance, and how to use them effectively [54:45];
• How to evaluate the risks and benefits of medical interventions: procedural risks, complication rates, and asking informed questions [59:00];
• Sleep: impact on metabolic and cognitive health, and tips for improving sleep quality [1:03:45];
• How to identify and address emotional health challenges [1:08:30]; and
• More.

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Mike Israetel is a sports physiologist, competitive bodybuilder, and co-founder of Renaissance Periodization, where he coaches athletes and professionals in diet and weight training. In this episode, Mike shares his journey from powerlifting to academia, breaking down the core principles of resistance training, including exercise selection, volume, intensity, and frequency. He debunks common misconceptions about strength training, explains how to structure an effective program for beginners and advanced lifters, and provides candid insights into his experience with anabolic steroids, discussing their effects on muscle growth, performance, and health risks. This conversation offers a deep dive into the science of building muscle, the realities of bodybuilding at the highest levels, and explores the potential of AI-driven breakthroughs to advance human performance and longevity.

We discuss:

• Mike’s academic journey, and early experiences in powerlifting, personal training, and sports physiology [3:30];
• Mike’s transition from powerlifting to bodybuilding, and his scientific and artistic approach to sculpting muscle and optimizing aesthetics [9:15];
• The value of strength training, time efficiency, and how it differs from endurance training [14:45];
• Neurological fatigue in strength training: balancing recovery and pushing the limits [26:15];
• The relationship between training intensity and volume, why muscle growth is not linear, and how different approaches affect results [35:00];
• Sustainable and effective approaches to maximizing muscle growth: training close to failure while minimizing fatigue [40:00];
• An efficient and effective resistance training program for beginners with limited time [49:00];
• Advice for finding a good trainer [1:06:30];
• Troubleshooting training plateaus: optimizing exercise selection, intensity, and recovery for muscle growth [1:13:30];
• The impact of genetics, age, and lifestyle on muscle growth [1:27:45];
• The importance of nutrition, protein intake, and consistency in both training and diet for muscle growth [1:31:00];
• The use of anabolic steroids to boost muscle growth: doses, drug combinations, and side effects [1:35:45];
• Long-term impact of steroid use: muscle retention, genetics and individual variability, and impact after discontinuation [1:52:15];
• Trade-offs of long-term usage of supraphysiologic doses of testosterone: health, performance, and Mike’s future plans [2:00:45];
• The potential for AI-driven medical breakthroughs to reverse aging and disease [2:07:30];
• The role of AI in accelerating drug development, advancing human longevity, and overcoming biological limitations [2:19:45];
• The philosophical implications of simulated reality, the impact of robotics on human labor and economics, and the challenge of predicting the future [2:25:15];
• Would having kids change Mike’s philosophy around anabolic steroid use? [2:32:15];
• The role of GLP-1 agonists in bodybuilding and general weight management, and the moral and philosophical debates surrounding their use [2:35:45]; and
• More.

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Tom Dayspring is a world-renowned expert in clinical lipidology and a previous guest on The Drive. In this episode, Tom explores the foundations of atherosclerosis and why atherosclerotic cardiovascular disease (ASCVD) is the leading cause of death worldwide for both men and women. He examines how the disease develops from a pathological perspective and discusses key risk factors, including often-overlooked contributors such as insulin resistance and chronic kidney disease. He breaks down the complexities of cholesterol and lipoproteins—including LDL, VLDL, IDL, and HDL—with an in-depth discussion on the critical role of apolipoprotein B (apoB) in the development of atherosclerosis. Additionally, he covers the importance of testing various biomarkers, the impact of nutrition on lipid levels, and the vital role of cholesterol in brain health, including how cholesterol is synthesized and managed in the brain, how it differs from cholesterol regulation in the rest of the body, and how pharmacological interventions can influence brain cholesterol metabolism.

We discuss:

• Defining atherosclerotic cardiovascular disease (ASCVD): development, risks, and physiological impact [2:45];
• The pathogenesis of ASCVD: the silent development over decades, and the importance of early detection for prevention of adverse outcomes [10:45];
• Risk factors versus risk markers for ASCVD, and how insulin resistance and chronic kidney disease contribute to atherosclerosis [17:30];
• How hyperinsulinemia elevates cardiovascular risk [24:00];
• How apoB-containing lipoproteins contribute to atherosclerosis, and why measuring apoB is a superior indicator of cardiovascular risk compared to LDL cholesterol [29:45];
• The challenges of detecting early-stage atherosclerosis before calcification appears [46:15];
• Lp(a): structure, genetic basis, and significant risks associated with elevated Lp(a) [55:30];
• How aging and lifestyle factors contribute to rising apoB and LDL cholesterol levels, and the lifestyle changes that can lower it [59:45];
• How elevated triglycerides, driven by insulin resistance, increase apoB particle concentration and promote atherosclerosis [1:08:00];
• How LDL particle size, remnant lipoproteins, Lp(a), and non-HDL cholesterol contribute to cardiovascular risk beyond apoB levels [1:21:45];
• The limitations of using HDL cholesterol as a marker for heart health [1:29:00];
• The critical role of cholesterol in brain function and how the brain manages its cholesterol supply [1:36:30];
• The impact of ApoE genotype on brain health and Alzheimer's disease risk [1:46:00];
• How the brain manages cholesterol through specialized pathways, and biomarkers to track cholesterol health of the brain [1:50:30];
• How statins might affect brain cholesterol synthesis and cognitive function, and alternative lipid-lowering strategies for high-risk individuals [1:57:30];
• Exciting advancements in therapeutics, diagnostics, and biomarkers coming in the next few years [2:09:30];
• Recent consensus statements on apoB and Lp(a) from the National Lipid Association (NLA) [2:12:30]; and
• More.

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In this special episode of The Drive, Peter introduces a brand-new roundtable format. Joined by three renowned experts in longevity science—Steven Austad, Richard Miller, and Matt Kaeberlein—the group explores the rapidly evolving field of geroscience. Together, they dive deep into topics like the relationship between healthspan and lifespan, evaluating interventions like rapamycin and senolytics, the role of epigenetic changes in aging, and whether GLP-1 receptor agonists hold geroprotective potential. They also tackle major challenges in funding and public acceptance of longevity research including how geroprotective interventions might be tested in humans. Packed with nuanced debate, humor, and groundbreaking insights, this episode is a must-listen for anyone fascinated by the science of aging.

We discuss:

• The recent rise in public interest in longevity, misconceptions, and the link between healthspan and lifespan [3:45];
• Redefining healthspan, the US healthcare paradox, and separating longevity science from commercial hype [12:30];
• The need to redirect medical research from disease-specific models to aging-focused approaches [21:30];
• Proactive healthcare: rethinking health, disease, and the role of aging [30:00];
• Biologic age versus chronologic age, and the limitations and potential of epigenetic clocks [35:00];
• The utility and drawbacks of the “hallmarks of aging” as a framework for research and funding [49:30];
• The role of epigenetic changes in aging and the challenges of proving causality [56:45];
• The translational challenges of moving aging research from preclinical studies to human applications [1:03:45];
• Distinguishing between a biomarker of aging and aging rate indicators [1:17:15];
• The difficulties of translating longevity research in mice to humans, and the difficulties of testing interventions in humans [1:21:15];
• Exercise, aging, and healthspan: does exercise slow aging? [1:35:45];
• Are GLP-1 receptor agonists geroprotective beyond caloric restriction effects? [1:41:00];
• The role of senescent cells in aging, challenges with reproducibility in studies, and differing views on the value of current research approaches [1:46:15];
• How funding challenges and leadership in NIH and other institutes impact the advancement of aging-related research [2:00:15];
• Metformin: geroprotective potential, mechanisms, and unanswered questions [2:02:30];
• Canagliflozin and rapamycin as geroprotective molecules: mechanisms, dosing strategies, and longevity potential [2:10:45];
• Resveratrol and NAD precursors—a lack of evidence for anti-aging effects [2:22:45];
• The potential of parabiosis and plasmapheresis to slow aging, the challenges in translating mouse studies to humans, and possible design for human studies [2:29:45]; and
• More.

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Olav Aleksander Bu is an internationally renowned sports scientist acclaimed for his coaching prowess with elite athletes spanning a diverse range of sports disciplines. In this episode, Olav returns to dive deeper into his groundbreaking work as an endurance coach, exercise scientist, engineer, and physiologist. The discussion explores his data-driven approach to coaching, unpacking key performance metrics like functional threshold power, VO2 max, and lactate threshold, while emphasizing the importance of consistent testing protocols. Olav shares insights on how training methodologies differ across sports, the impact of nutrition on endurance performance, and the evolving strategies for carbohydrate metabolism in fueling athletes for races. Olav concludes with a discussion on the use of artificial intelligence for optimizing training insights and performance.

We discuss:

• Olav’s unique, engineering-driven approach to endurance coaching [2:45];
• Definitions and applications of key performance metrics: FTP, power, anaerobic threshold, and lactate threshold [4:45];
• Lactate threshold: factors affecting lactate threshold, testing protocols, and how elite athletes' efficiency affects their performance and lactate profiles [14:15]
• VO2 max: definition, testing, factors affecting its accuracy, and methods for optimizing oxygen utilization in elite athletes [22:15];
• Testing VO2 max: common mistakes and key factors to consider—preparation, warm-up, timing, and more [34:00];
• VO2 max testing continued: measuring instruments, testing protocols, and advanced insights gained from elite athletes [41:45];
• The influence of supplements like beetroot concentrate and adaptogens on VO2 max and performance [49:45];
• How respiratory quotient (RQ) reflects metabolic shifts during exercise, the challenges in measuring and interpreting RQ in elite athletes, and the physiological adaptations needed for prolonged endurance events [53:30];
• Triathlon training: the challenge of maintaining elite performance across triathlon distances, metabolic efficiency, and swimming challenges [1:03:15];
• How reducing drag in swimming could revolutionize performance and the role of biofeedback tools in optimizing efficiency across various endurance sports [1:07:00];
• How endurance athletes prioritize effort regulation using RPE, heart rate, and power output, and the role of lactate in cardiac and athletic efficiency [1:20:00];
• Lactate’s role as a fuel, buffering methods to combat lactic acidosis, and the variability in athlete response to bicarbonate supplementation [1:25:45];
• The physiological mechanisms behind differences in performance between two elite athletes: lactate transport, cardiovascular efficiency, and compensatory systems [1:33:00];
• Comparing interventions like acetaminophen to enhance performance in high-heat conditions versus natural adaptations to heat [1:37:15];
• Advancements in nutrition science, changes in cyclist body composition, and the impact of fueling strategies on athletic performance and growth [1:39:30];
• Optimizing endurance performance with utilization of carbohydrates, and the potential role of ketones [1:48:00];
• Insights gained from elite performers in the 2020 and 2024 Olympics [1:58:30];
• The use of artificial intelligence to optimizing training insights and performance [2:06:30]; and
• More.

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Trenna Sutcliffe is a developmental behavioral pediatrician and the founder and medical director of the Sutcliffe Clinic in the San Francisco Bay Area, where she partners with families to provide care for children facing behavioral challenges, developmental differences, and school struggles. In this episode, Trenna shares her journey into developmental and behavioral pediatrics, including her pioneering work at Stanford and her expertise in autism, ADHD, and anxiety—the "three As." She explores the diagnostic processes, the overlap and comorbidities of these conditions, and the importance of personalized treatment plans that address both medical and environmental factors. Trenna offers valuable insights into the changing prevalence of autism, the impact of evolving diagnostic criteria, and the range of therapies and medications available to support children and their families. She also discusses the challenges in accessing care and the critical need for a holistic approach that bridges healthcare and education.

We discuss:

• Trenna’s passion for developmental-behavioral pediatrics (DBP), and the process of diagnosing anxiety, ADHD, and autism [3:15];
• Understanding anxiety and ADHD: assessing impairment and self-esteem and identifying anxiety and emotional well-being in young patients [9:45];
• The evolving diagnosis of autism: understanding the spectrum and individual needs [16:30];
• The dramatic rise in autism spectrum disorder (ASD): genetics, environment, expanded diagnostic criteria, and more [25:45];
• Exploring epigenetics and the potential multigenerational impact of environment exposures on susceptibility to certain disorders [37:15];
• The evolution of autism classifications, and the particular challenges for children with level 1 (mild) autism due to a lack of support [41:15];
• The broadening of the autism spectrum: benefits and risks of expanded diagnostic criteria and the need for future frameworks to focus on better outcomes [48:00];
• The overlap between ASD, ADHD, and anxiety [57:15];
• Understanding oppositional defiant disorder, and the importance of understanding the “why” behind a behavior when creating treatment plans [1:00:45];
• Defining developmental-behavioral pediatrics (DBP), and Trenna’s professional journey [1:07:00];
• Updated methods of ABA (applied behavioral analysis) therapy: evolution, controversies, challenges of scaling autism care, and the need for tailored interventions [1:13:45];
• Advice for parents trying to find and evaluate care for children with autism, ADHD, or anxiety [1:22:45];
• Tailored treatments for ADHD: balancing stimulant medications with behavioral training [1:28:30];
• The interplay between medication, behavioral therapy, and neuroplasticity in managing ADHD, and the potential to grow out of the need for medication [1:39:45];
• Using medication to treat anxiety and other symptoms in kids with autism without ADHD [1:44:45];
• FAQs about medicating children with ADHD: benefits, side effects, dosage, and more [1:46:30];
• The “superpowers” associated with level 1 autism [1:48:45];
• The next steps to increase support for children with ASD, anxiety, and ADHD [1:50:45]; and
• More.

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