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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 t