β Cell Aging Markers Have Heterogeneous Distribution and Are Induced by Insulin Resistance

We hypothesized that the known heterogeneity of pancreatic beta cells was due to subpopulations of beta cells at different stages of their life cycle with different functional capacities and that further changes occur with metabolic stress and aging. We identified new markers of aging in beta cells, including IGF1R. In beta cells IGF1R expression correlated with age, dysfunction, and expression of known age markers p16(ink4a), p53BP1, and senescence-associated beta-galactosidase. The new markers showed striking heterogeneity both within and between islets in bothmouse and human pancreas. Acute induction of insulin resistance with an insulin receptor antagonist or chronic ER stress resulted in increased expression of aging markers, providing insight into how metabolic stress might accelerate dysfunction and decline of beta cells. These novel findings about beta cell and islet heterogeneity, and how they change with age, open up an entirely new set of questions about the pathogenesis of type 2 diabetes.