Ralph DeFronzo, a distinguished diabetes researcher, discusses his groundbreaking insights on insulin resistance and its effects on metabolic health. He delves into the impacts on organs like the liver and muscles, the revolutionary euglycemic clamp technique, and the emerging role of drugs such as SGLT2 inhibitors and GLP-1 receptor agonists. The conversation also touches on the alarming rise of type 2 diabetes in adolescents, addressing lifestyle and genetic factors. DeFronzo’s deep knowledge offers a masterclass on diagnosis, treatment, and the future of diabetes care.