衰老
β细胞
生物
分泌物
内分泌学
葡萄糖稳态
内科学
胰岛素
细胞生物学
PI3K/AKT/mTOR通路
小岛
信号转导
胰岛素抵抗
医学
作者
Aharon Helman,Agnes Klochendler,Narmen Azazmeh,Yael Gabai,E. P. 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
出处
期刊:Nature Medicine
[Springer Nature]
日期:2016-03-07
卷期号:22 (4): 412-420
被引量:246
摘要
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.
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