Arginase-II Promotes Tumor Necrosis Factor- Release From Pancreatic Acinar Cells Causing -Cell Apoptosis in Aging

作者：Xiong Yuyan; Yepuri Gautham; Necetin Sevil; Montani Jean Pierre; Ming Xiu Fen^*; Yang Zhihong^*

来源：Diabetes, 2017, 66(6): 1636-1649.

DOI：10.2337/db16-1190

Aging is associated with glucose intolerance. Arginase-II (Arg-II), the type-II L-arginine-ureahydrolase, is highly expressed in pancreas. However, its role in regulation of pancreatic -cell function is not known. Here we show that female (not male) mice deficient in Arg-II (Arg-II-/-) are protected from age-associated glucose intolerance and reveal greater glucose induced-insulin release, larger islet size and -cell mass, and more proliferative and less apoptotic -cells compared with the age-matched wild-type (WT) controls. Moreover, Arg-II is mainly expressed in acinar cells and is upregulated with aging, which enhances p38 mitogen-activated protein kinase (p38 MAPK) activation and release of tumor necrosis factor- (TNF-). Accordingly, conditioned medium of isolated acinar cells from old WT (not Arg-II-/-) mice contains higher TNF- levels than the young mice and stimulates -cell apoptosis and dysfunction, which are prevented by a neutralizing anti-TNF- antibody. In acinar cells, our study demonstrates an age-associated Arg-II upregulation, which promotes TNF- release through p38 MAPK leading to -cell apoptosis, insufficient insulin secretion, and glucose intolerance in female rather than male mice.

• 出版日期2017-6-1