Type 1 diabetes in the era of obesity: Pathophysiology and therapeutic implications

Type 1 diabetes is defined by immune-mediated beta-cell failure and dependence on exogenous insulin. That definition is correct, but it may not fully describe many people seen in current clinical practice. Overweight and obesity are now common in type 1 diabetes, leading to variable combinations of high insulin requirement, hypertension, dyslipidemia, metabolic syndrome, metabolic dysfunction-associated steatotic liver disease (MASLD), and increased cardiovascular and renal risk. These features have been termed double diabetes, but that term is descriptive rather than mechanistic. The overlap between type 1 and type 2 diabetes features may reflect overweight or obesity, effects of intensive insulin therapy (with treatment-related hyperinsulinemia leading to disproportionate peripheral vs. hepatic insulin action), inherited or environmental factors leading to insulin resistance, glucagon dysregulation, ectopic fat, and inflammation. This review summarizes the epidemiology, pathophysiology, clinical consequences, and therapeutic implications of insulin-resistant type 1 diabetes, reviewing the established precedent of amylin replacement and potential treatments including incretin receptor agonists and next-generation amylin receptor agonists.