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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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