Arginase-II promotes tumor necrosis Factor-α release from pancreatic acinar cells causing β-cell apoptosis in aging

Xiong, Yuyan; Yepuri, Gautham; Necetin, Sevil; Montani, Jean-Pierre; Ming, Xiu-Fen; Yang, Zhihong

doi:10.2337/db16-1190

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Arginase-II promotes tumor necrosis Factor-α release from pancreatic acinar cells causing β-cell apoptosis in aging

Xiong, Yuyan Cardiovascular and Aging Research, Department of Medicine, Division of Physiology, University of Fribourg, Switzerland - Kidney Control of Homeostasis, Swiss National Centre of Competence in Research, Zurich, Switzerland
Yepuri, Gautham Cardiovascular and Aging Research, Department of Medicine, Division of Physiology, University of Fribourg, Switzerland
Necetin, Sevil Cardiovascular and Aging Research, Department of Medicine, Division of Physiology, University of Fribourg, Switzerland
Montani, Jean-Pierre Cardiovascular and Aging Research, Department of Medicine, Division of Physiology, University of Fribourg, Switzerland - Kidney Control of Homeostasis, Swiss National Centre of Competence in Research, Zurich, Switzerland
Ming, Xiu-Fen Cardiovascular and Aging Research, Department of Medicine, Division of Physiology, University of Fribourg, Switzerland - Kidney Control of Homeostasis, Swiss National Centre of Competence in Research, Zurich, Switzerland
Yang, Zhihong Cardiovascular and Aging Research, Department of Medicine, Division of Physiology, University of Fribourg, Switzerland - Kidney Control of Homeostasis, Swiss National Centre of Competence in Research, Zurich, Switzerland

01.06.2017

Published in:

Diabetes. - 2017, vol. 66, no. 6, p. 1636–1649

English 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 β-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 β-cell mass, and more proliferative and less apoptotic β-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-α (TNF-α). Accordingly, conditioned medium of isolated acinar cells from old WT (not Arg-II−/−) mice contains higher TNF-α levels than the young mice and stimulates β-cell apoptosis and dysfunction, which are prevented by a neutralizing anti–TNF-α antibody. In acinar cells, our study demonstrates an age-associated Arg-II upregulation, which promotes TNF-α release through p38 MAPK leading to β-cell apoptosis, insufficient insulin secretion, and glucose intolerance in female rather than male mice.

Faculty

Faculté des sciences et de médecine

Department

Département de Médecine

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