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p16Ink4a-induced senescence of pancreatic beta cells enhances insulin secretion

2016; Nature Portfolio; Volume: 22; Issue: 4 Linguagem: Inglês

10.1038/nm.4054

1546-170X

Aharon Helman, Agnes Klochendler, Narmen Azazmeh, Yael Gabai, E. Philip Horwitz, Shira Anzi, Avital Swisa, Reba Condiotti, Roy Z. Granit, Yuval Nevo, Yaakov Fixler, Dorin Shreibman, Amit Zamir, Sharona Tornovsky-Babeay, Chunhua Dai, Benjamin Gläser, Alvin C. Powers, A. M. James Shapiro, Mark A. Magnuson, Yuval Dor, Ittai Ben‐Porath,

Diabetes and associated disorders

Cellular senescence is thought to contribute to age-associated deterioration of tissue physiology. The senescence effector p16(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(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(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(Ink4a) activity. We found that islets from human adults contain p16(Ink4a)-expressing senescent beta cells and that senescence induced by p16(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(Ink4a) and cellular senescence in promoting insulin secretion by beta cells and in regulating normal functional tissue maturation with age.