p16Ink4a-induced senescence of pancreatic beta cells enhances insulin secretion

A Helman, A Klochendler, N Azazmeh, Y Gabai… - Nature medicine, 2016 - nature.com
A Helman, A Klochendler, N Azazmeh, Y Gabai, E Horwitz, S Anzi, A Swisa, R Condiotti…
Nature medicine, 2016nature.com
Cellular senescence is thought to contribute to age-associated deterioration of tissue
physiology. The senescence effector p16Ink4a 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 p16Ink4a 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 …
Abstract
Cellular senescence is thought to contribute to age-associated deterioration of tissue physiology. The senescence effector p16Ink4a 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 p16Ink4a 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 p16Ink4a 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 p16Ink4a activity. We found that islets from human adults contain p16Ink4a-expressing senescent beta cells and that senescence induced by p16Ink4a 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 p16Ink4a and cellular senescence in promoting insulin secretion by beta cells and in regulating normal functional tissue maturation with age.
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