| First Author | Helman A | Year | 2016 |
| Journal | Nat Med | Volume | 22 |
| Issue | 4 | Pages | 412-20 |
| PubMed ID | 26950362 | Mgi Jnum | J:234557 |
| Mgi Id | MGI:5790265 | Doi | 10.1038/nm.4054 |
| Citation | Helman A, et al. (2016) p16(Ink4a)-induced senescence of pancreatic beta cells enhances insulin secretion. Nat Med 22(4):412-20 |
| abstractText | 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)-gamma 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. |
