induced senescence of pancreatic beta cells enhances insulin secretion

Cellular senescence is thought to contribute to age-associated deterioration of tissue physiology. The senescence Effector [p16.sup.Ink4a] is expressed in pancreatic beta cells during aging and limits their proliferative potential; however, its effects on beta cell function are poorly characterized. We found that beta cell-specific activation of [p16.sup.Ink4a] in transgenic mice enhances glucose-stimulated insulin secretion (GSIS). In mice with diabetes, this leads to improved glucose homeostasis, providing an unexpected functional benefit. Expression of [p16.sup.Ink4a] in beta cells induces hallmarks of senescence--including cell enlargement, and greater glucose uptake and mitochondrial activity--which promote increased insulin secretion. GSIS increases during the normal aging of mice and is driven by elevated [p16.sup.Ink4a] activity. We found that islets from human adults contain [p16.sup.Ink4a]-expressing senescent beta cells and that senescence induced by [p16.sup.Ink4a] in a human beta cell line increases insulin secretion in a manner dependent, in part, on the activity of the mechanistic target of rapamycin (mTOR) and the peroxisome proliferator-activated receptor (PPAR)-γ proteins. Our findings reveal a novel role for [p16.sup.Ink4a] and cellular senescence in promoting insulin secretion by beta cells and in regulating normal functional tissue maturation with age.