Ralph DeFronzo is a distinguished diabetes researcher & clinician whose groundbreaking work on insulin resistance has reshaped the understanding & 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 US & developing SGLT2 inhibitors. Ralph explores the impacts of insulin resistance on specific organs, the pharmacologic interventions available, & the gold-standard euglycemic clamp method for measuring insulin resistance. This episode is a masterclass in the pathophysiology & treatment of type 2 diabetes, featuring an in-depth discussion of GLP-1 receptor agonists, metformin, & a lesser-known class of drugs that opened Peter’s eyes to new possibilities in diabetes care. View show notes here: https://bit.ly/3Xe8o2y Become a member to receive exclusive content: https://peterattiamd.com/subscribe/ Sign up to receive Peter's email newsletter: https://peterattiamd.com/newsletter/ 0:00:00-Intro 0:01:10-Metabolic disease as a foundational driver of chronic illness 0:05:59-Defining insulin resistance: effects on glucose, fat, & protein metabolism, & how it varies between healthy, obese, & diabetic individuals 0:09:59-The historical significance of the development of the euglycemic clamp technique for measuring insulin resistance 0:13:38-How insulin affects liver, muscle, & fat cells 0:24:40-Different ways insulin resistance manifests in various tissues: Alzheimer’s disease, cardiovascular disease 0:28:56-Dangers of hyperinsulinemia, & the importance of keeping insulin levels within a range 0:38:07-Challenges of identifying the genetic basis of insulin resistance & T2D 0:47:50-The “ominous octet”—a comprehensive model of type 2 diabetes 0:58:45-The kidneys’ unexpected role in worsening diabetes 1:08:35-How insulin resistance in the brain contribute to overeating & metabolic disease 1:12:15-Lipotoxicity: how overeating fuels insulin resistance & mitochondrial dysfunction 1:15:28-Pioglitazone: an underappreciated treatment for insulin resistance 1:26:07-Metformin: the misconception that it is an insulin sensitizer & its true mechanism of action 1:31:46-Treating diabetes with triple therapy vs. the ADA approach: a better path for diabetes management 1:40:12-GLP-1 agonists, the Qatar study, & rethinking diabetes treatment 1:56:11-Using a hyperglycemic clamp to look for genes that cause diabetes 1:57:59-Measuring C-peptide instead of insulin to assess beta-cell function 2:03:33-How GLP-1-induced weight loss affects muscle mass, the benefits & risks of myostatin inhibitors, & the need for better methods of evaluating functional outcomes of increased muscle mass 2:15:52-Growing crisis of childhood obesity & challenges in treating it 2:21:43-Environmental & neurological factors driving the obesity epidemic 2:25:39-Role of genetics, insulin signaling defects, & lipotoxicity in insulin resistance & diabetes treatment challenges 2:34:41-The oral glucose tolerance test (OGTT) -------- About: The Peter Attia Drive is a deep-dive podcast focusing on maximizing longevity, & all that goes into that from physical to cognitive to emotional health. With over 90 million episodes downloaded, it features topics including exercise, nutritional biochemistry, cardiovascular disease, Alzheimer’s disease, cancer, mental health, & much more. Peter Attia is the founder of Early Medical, a medical practice that applies the principles of Medicine 3.0 to patients with the goal of lengthening their lifespan & simultaneously improving their healthspan. Learn more: https://peterattiamd.com Connect with Peter on: Facebook: http://bit.ly/PeterAttiaMDFB Twitter: http://bit.ly/PeterAttiaMDTW Instagram: http://bit.ly/PeterAttiaMDIG Subscribe to The Drive: Apple Podcast: http://bit.ly/TheDriveApplePodcasts Overcast: http://bit.ly/TheDriveOvercast Spotify: http://bit.ly/TheDriveSpotify Google Podcasts: http://bit.ly/TheDriveGoogle Disclaimer: This podcast is for general informational purposes only and does not constitute the practice of medicine, nursing, or other professional healthcare services, including the giving of medical advice. No doctor-patient relationship is formed. The use of this information and the materials linked to this podcast is at the user's own risk. The content on this podcast is not intended to be a substitute for professional medical advice, diagnosis, or treatment. Users should not disregard or delay in obtaining medical advice for any medical condition they have, and they should seek the assistance of their healthcare professionals for any such conditions. I take conflicts of interest very seriously. For all of my disclosures and the companies I invest in or advise, please visit my website where I keep an up-to-date and active list of such companies. For a full list of our registered and unregistered trademarks, trade names, and service marks, please review our Terms of Use: https://peterattiamd.com/terms-of-use/