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

Highlights

• Subpopulations of pancreatic β cells differ and change proportions with aging

• Markers of β cell age show heterogeneity both within islets and between islets

• IGF1R-expressing β cells are senescent and have dysfunctional insulin secretion

• Insulin resistance accelerated expression of p16^Ink4a and aging markers in β cells

Summary

We hypothesized that the known heterogeneity of pancreatic β cells was due to subpopulations of β 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 β cells, including IGF1R. In β cells IGF1R expression correlated with age, dysfunction, and expression of known age markers p16^ink4a, p53BP1, and senescence-associated β-galactosidase. The new markers showed striking heterogeneity both within and between islets in both mouse 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 β cells. These novel findings about β 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.