In this wide-ranging conversation from 2010, Dr. Scott Connelly reframes metabolism through the lens of insulin and glucose homeostasis, arguing that insulin is the primary regulator of energy allocation, disease risk, and body composition. Drawing on cancer biology, epidemiology, and comparative physiology, he revisits the Warburg observation that malignant cells exhibit extreme “glucose avidity,” clarifying that while high glycolytic rates do not initiate cancer, they are driven by insulin-pathway signaling (notably AKT) and are a shared feature of transformed cells. Connelly emphasizes that glucose is both essential and toxic: the brain’s absolute dependence on glucose forces the body to tightly regulate blood sugar, using insulin to direct fuel toward oxidation or long-term storage—primarily fat.

Rejecting the simplistic “calories in, calories out” model, Connelly explains that humans are open, non-equilibrium systems in which insulin dynamically alters how efficiently energy is stored or dissipated. Dramatic changes in fat mass can occur without changes in caloric intake when insulin sensitivity shifts, as seen in diabetes, steroid use, fatty-acid ratios, and evolutionary adaptations. He distinguishes between metabolically healthy obesity and pathological insulin resistance, identifying dysregulated liver glucose production alongside insulin-sensitive fat storage as a key driver of cardiovascular disease. The practical takeaway is that in modern Western populations, controlling carbohydrate intake is the most powerful lever for health. His baseline prescription—heavy resistance training, high protein intake, restrained carbohydrates, and particular caution with fructose—targets insulin first, with improvements in body composition and disease risk following downstream.