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#337 - Insulin resistance masterclass: The full body impact of metabolic dysfunction and prevention, diagnosis, and treatment | Ralph DeFronzo, M.D.

The Peter Attia Drive

Release Date: 02/24/2025

Lower back pain: causes, treatment, and prevention of lower back injuries and pain | Stuart McGill, Ph.D. (#287 rebroadcast) show art Lower back pain: causes, treatment, and prevention of lower back injuries and pain | Stuart McGill, Ph.D. (#287 rebroadcast)

The Peter Attia Drive

Stuart McGill is a distinguished professor emeritus at the University of Waterloo and the chief scientific officer at Backfitpro where he specializes in evaluating complex cases of lower back pain from across the globe. In this episode, Stuart engages in a deep exploration of lower back pain, starting with the anatomy of the lower back, the workings of the spine, the pathophysiology of back pain, and areas of vulnerability. He challenges the concept of nonspecific back pain, emphasizing the importance of finding a causal relationship between injury and pain. Stuart highlights compelling...

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#362 ‒ Understanding anxiety: defining, assessing, and treating health anxiety, OCD, and the spectrum of anxiety disorders | Josh Spitalnick, Ph.D., A.B.P.P. show art #362 ‒ Understanding anxiety: defining, assessing, and treating health anxiety, OCD, and the spectrum of anxiety disorders | Josh Spitalnick, Ph.D., A.B.P.P.

The Peter Attia Drive

Josh Spitalnick is a clinical and research psychologist with expertise in treating a variety of anxiety conditions with cognitive-behavioral therapy (CBT) and other evidence-based approaches. In this episode, Josh unpacks the four layers of anxiety—psychological, emotional, cognitive, and behavioral—highlighting why avoidance is the key feature that transforms ordinary worry into disorder. He explains why he continues to treat OCD and PTSD as anxiety conditions despite their DSM-5 reclassification, and he draws important distinctions between worries versus worrying and thoughts versus...

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#361 - AMA #74: Sugar and sugar substitutes: weight control, metabolic effects, and health trade-offs show art #361 - AMA #74: Sugar and sugar substitutes: weight control, metabolic effects, and health trade-offs

The Peter Attia Drive

In this “Ask Me Anything” (AMA) episode, Peter explains how to evaluate sugar and its substitutes in the context of health. Peter explores the role of sweeteners in three common use-cases – beverages, protein supplements, and sweet treats – and breaks down how our evolutionary craving for sweetness now clashes with today’s food environment. He examines whether sugar is uniquely fattening, the hormonal effects of sugar consumption, and the significance of timing in sugar intake. The episode compares natural versus refined sugars, sugar in beverages versus in solid foods, and the...

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#360 ‒ How to change your habits: why they form and how to build or break them | Charles Duhigg, M.B.A show art #360 ‒ How to change your habits: why they form and how to build or break them | Charles Duhigg, M.B.A

The Peter Attia Drive

Charles Duhigg is a Pulitzer Prize-winning journalist and best-selling author known for distilling complex neuroscience and psychology into practical strategies for behavior change, performance, and decision-making. In this episode, Charles explores the neuroscience behind habit formation, including how cue-routine-reward loops drive nearly half of our daily actions and why positive reinforcement is far more effective than punishment. He explains how institutions like the military and Alcoholics Anonymous engineer environments to change behavior at scale, as well as discussing the limits of...

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#359 ‒ How metabolic and immune system dysfunction drive the aging process, the role of NAD, promising interventions, aging clocks, and more | Eric Verdin, M.D. show art #359 ‒ How metabolic and immune system dysfunction drive the aging process, the role of NAD, promising interventions, aging clocks, and more | Eric Verdin, M.D.

The Peter Attia Drive

Eric Verdin is a physician-scientist and the CEO of the Buck Institute for Research on Aging whose career has centered on understanding how epigenetics, metabolism, and the immune system influence the aging process. In this episode, Eric traces his scientific journey from studying viruses and histone deacetylases (HDACs) to leading aging research at the Buck Institute, offering insights into how aging impairs immune and nervous system function—including thymic shrinkage, chronic inflammation, and reduced vaccine response—and how these changes impact lifespan. He explores the metabolic...

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#358 ‒ Peter’s takeaways on navigating HRT, rejuvenating the face, understanding the biology of aging, optimizing fertility, and learning to live well from the dying | Quarterly Podcast Summary #6 show art #358 ‒ Peter’s takeaways on navigating HRT, rejuvenating the face, understanding the biology of aging, optimizing fertility, and learning to live well from the dying | Quarterly Podcast Summary #6

The Peter Attia Drive

In this quarterly podcast summary (QPS) episode, Peter summarizes his biggest takeaways from the last three months of guest interviews on the podcast. Peter shares key insights from his discussions with Paul Turek and Paula Amato on male and female fertility; Rachel Rubin on menopause and hormone replacement therapy; Brian Kennedy on the biology of aging; Tanuj Nakra and Suzan Obagi on facial aging and skin rejuvenation; and BJ Miller and Bridget Sumser on lessons we can learn from the dying about how to live. Peter highlights the most important insights from each episode and any behavioral...

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#357 ‒ A new era of longevity science: models of aging, human trials of rapamycin, biological clocks, promising compounds, and lifestyle interventions | Brian Kennedy, Ph.D. show art #357 ‒ A new era of longevity science: models of aging, human trials of rapamycin, biological clocks, promising compounds, and lifestyle interventions | Brian Kennedy, Ph.D.

The Peter Attia Drive

Brian Kennedy is a renowned biologist, leader in aging research, and director of the Center for Healthy Longevity at the National University of Singapore. In this episode, Brian shares insights from ongoing human aging studies, including clinical trials of rapamycin and how dosing strategies, timing, and exercise may influence outcomes. He presents two key models of aging—one as a linear accumulation of biological decline and the other as an exponential rise in mortality risk—and explains why traditional models of aging fall short. He also explains why most current aging biomarkers lack...

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#356 - AMA #73: Preserving brain health, optimizing exercise programming, improving body composition, and more show art #356 - AMA #73: Preserving brain health, optimizing exercise programming, improving body composition, and more

The Peter Attia Drive

In this “Ask Me Anything” (AMA) episode, Peter addresses frequently requested topics, including brain health, exercise programming, and body composition. He explores the factors that influence dementia risk—including metabolic health, fitness, sleep, hearing, cholesterol levels, and more. He explains how to implement zone 2 training and VO₂ max intervals for cardiovascular fitness and also covers how to combine cardio modalities, how to stay in zone 2, and special considerations for women. Peter highlights the benefits of light movement after meals and offers strength training tips...

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Navigating bone health: early life influences and advanced strategies for improvement and injury prevention (#214 rebroadcast) show art Navigating bone health: early life influences and advanced strategies for improvement and injury prevention (#214 rebroadcast)

The Peter Attia Drive

In this episode from July 2022, Peter dives deep into the topic of bone health and explains why this is an important topic for everyone, from children to the elderly. He begins with an overview of bone mineral density, how it’s measured, how it changes over the course of life, and the variability between sexes largely due to changes in estrogen levels. From there he provides insights into ways that one can improve bone health, from exercise to nutrition supplements to drugs. Additionally, Peter discusses what happens when one may be forced to be sedentary (e.g., bedrest) and how you can...

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#355 – Skincare strategies, the science of facial aging, and cosmetic-intervention guidance | Tanuj Nakra, M.D. & Suzan Obagi, M.D. show art #355 – Skincare strategies, the science of facial aging, and cosmetic-intervention guidance | Tanuj Nakra, M.D. & Suzan Obagi, M.D.

The Peter Attia Drive

Tanuj Nakra and Suzan Obagi, two leading experts in aesthetic medicine, join Peter to explore the science of facial aging and skin health as well as the responsibilities physicians face in the world of cosmetic procedures. In this episode, they examine the biological and hormonal drivers of facial aging, the evolutionary and psychological foundations of attractiveness, and the impact of modern media on beauty standards. They discuss the rise in cosmetic procedures among adolescents and the ethical responsibilities of physicians in these cases. The conversation then shifts to a practical,...

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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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