The hydrolase DDAH2 enhances pancreatic insulin secretion by transcriptional regulation of secretagogin through a Sirt1-dependent mechanism in mice

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.-Hasegawa, K, Wakino, S., Kimoto, M, Minakuchi, H., Fujimura, K., Hosoya, K., Komatsu, M., Kaneko, Y., Kanda, T., Tokuyama, H., Hayashi, K., Itoh, H. The hydrolase DDAH2 enhances pancreatic insulin secretion by transcriptional regulation of secretagogin through a Sirt1-dependent mechanism in mice.