title: The hydrolase DDAH2 enhances pancreatic insulin secretion by transcriptional regulation of secretagogin through a Sirt1-dependent mechanism in mice.
abstract: The role of dimethylarginine dimethylaminohydrolase 2 (DDAH2) in glucose metabolism is unknown. Here, we generated DDAH2 transgenic (Tg) mice. These mice had lower plasma glucose levels (60 min: 298±32 vs. 418±35 mg/dl; 120 min: 205±15 vs. 284±20 mg/dl) and higher insulin levels (15 min: 2.1±0.2 vs. 1.5±0.1 ng/ml; 30 min: 1.8±0.1 vs. 1.5±0.1 ng/ml) during intraperitoneal glucose tolerance tests when fed a high-fat diet (HFD) compared with HFD-fed wild-type (WT) mice. Glucose-stimulated insulin secretion (GSIS) was increased in Tg islets by 33%. Pancreatic asymmetrical dimethylarginine, nitric oxide, and oxidative stress levels were not correlated with improvements in insulin secretion in Tg mice. Secretagogin, an insulin vesicle docking protein, was up-regulated by 2.7-fold in Tg mice and in pancreatic MIN-6 cells overexpressing DDAH2. GSIS in MIN-6 cells was dependent on DDAH2-induced secretagogin expression. Pancreatic Sirt1, DDAH2, and secretagogin were down-regulated in HFD-fed WT mice by 70, 75, and 85%, respectively. Overexpression of Sirt1 overexpression by 3.9-fold increased DDAH2 and secretagogin expression in MIN-6 cells by 3.2- and 2.5-fold, respectively. DDAH2 overexpression improved GSIS in pancreas-specific Sirt1-deficient mice. In summary, the Sirt1/DDAH2/secretagogin pathway is a novel regulator of GSIS.
authors: Department of Internal Medicine, School of Medicine, Keio University, Tokyo, Japan.
authors: Kazuhiro
authors: K
authors: Hasegawa
authors: Shu
authors: S
authors: Wakino
authors: Masumi
authors: M
authors: Kimoto
authors: Hitoshi
authors: H
authors: Minakuchi
authors: Keiko
authors: K
authors: Fujimura
authors: Koji
authors: K
authors: Hosoya
authors: Motoaki
authors: M
authors: Komatsu
authors: Yuka
authors: Y
authors: Kaneko
authors: Takeshi
authors: T
authors: Kanda
authors: Hirobumi
authors: H
authors: Tokuyama
authors: Koichi
authors: K
authors: Hayashi
authors: Hiroshi
authors: H
authors: Itoh
mesh_terms: D000581:Amidohydrolases / Q000235:genetics / Q000502:physiology*; D000818:Animals; D001786:Blood Glucose / Q000502:physiology; D002135:Calcium-Binding Proteins / Q000235:genetics*; D002460:Cell Line; D005260:Female; D007328:Insulin / Q000378:metabolism*; D007333:Insulin Resistance / Q000235:genetics / Q000502:physiology; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000378:metabolism / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D010179:Pancreas / Q000378:metabolism / Q000502:physiology*; D064046:Secretagogins; D015398:Signal Transduction / Q000502:physiology; D056564:Sirtuin 1 / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D015854:Up-Regulation / Q000502:physiology*
chemical_list: D001786:Blood Glucose; D002135:Calcium-Binding Proteins; D007328:Insulin; D064046:Secretagogins; D000581:Amidohydrolases; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1; C059999:dimethylargininase
keywords: glucose tolerance; glucose-stimulated insulin secretion; knockout; overexpression; β cells