title: Arginase-II Promotes Tumor Necrosis Factor-α Release From Pancreatic Acinar Cells Causing β-Cell Apoptosis in Aging.
abstract: Aging is associated with glucose intolerance. Arginase-II (Arg-II), the type-IIL-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.
authors.affiliation: Cardiovascular and Aging Research, Department of Medicine, Division of Physiology, University of Fribourg, Fribourg, Switzerland.|Kidney Control of Homeostasis, Swiss National Centre of Competence in Research, Zurich, Switzerland.
authors.forename: Yuyan
authors.initials: Y
authors.lastname: Xiong
authors.affiliation: Cardiovascular and Aging Research, Department of Medicine, Division of Physiology, University of Fribourg, Fribourg, Switzerland.
authors.forename: Gautham
authors.initials: G
authors.lastname: Yepuri
authors.affiliation: Cardiovascular and Aging Research, Department of Medicine, Division of Physiology, University of Fribourg, Fribourg, Switzerland.
authors.forename: Sevil
authors.initials: S
authors.lastname: Necetin
authors.affiliation: Cardiovascular and Aging Research, Department of Medicine, Division of Physiology, University of Fribourg, Fribourg, Switzerland.|Kidney Control of Homeostasis, Swiss National Centre of Competence in Research, Zurich, Switzerland.
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Montani
authors.affiliation: Cardiovascular and Aging Research, Department of Medicine, Division of Physiology, University of Fribourg, Fribourg, Switzerland xiu-fen.ming@unifr.ch zhihong.yang@unifr.ch.|Kidney Control of Homeostasis, Swiss National Centre of Competence in Research, Zurich, Switzerland.
authors.forename: Xiu-Fen
authors.initials: XF
authors.lastname: Ming
authors.affiliation: Cardiovascular and Aging Research, Department of Medicine, Division of Physiology, University of Fribourg, Fribourg, Switzerland xiu-fen.ming@unifr.ch zhihong.yang@unifr.ch.|Kidney Control of Homeostasis, Swiss National Centre of Competence in Research, Zurich, Switzerland.
authors.forename: Zhihong
authors.initials: Z
authors.lastname: Yang
mesh_terms: D061354:Acinar Cells / Q000378:metabolism*; D000375:Aging / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000235:genetics*; D001119:Arginase / Q000235:genetics*; D016207:Cytokines / Q000235:genetics; D018149:Glucose Intolerance / Q000235:genetics* / Q000378:metabolism; D005951:Glucose Tolerance Test; D015151:Immunoblotting; D020287:In Situ Nick-End Labeling; D050417:Insulin-Secreting Cells / Q000378:metabolism* / Q000473:pathology; D007515:Islets of Langerhans / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D009929:Organ Size; D010179:Pancreas / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D016207:Cytokines; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D048051:p38 Mitogen-Activated Protein Kinases; C481673:Arg2 protein, mouse; D001119:Arginase