The Novel, Potent and Orally Available GPR119 Agonist AS1790091 Enhances Insulin Secretion and Insulin Promoter Activity, Preserves B-Cell Function, Improves Insulin Resistance, and Reduces Body Weight Gain in Type 2 Diabetic Mice
Abstract Number: 1001-P
Authors: SHIGERU YOSHIDA, HIROTSUGU TANAKA, HIROYUKI OSHIMA, YASUHIRO YONETOKU, TAKAHIDE OHISHI, TETSUO MATSUI, MASAYUKI SHIBASAKI
Institutions: Tsukuba, Japan
Results: GPR119 is a Gs-coupled receptor expressed predominantly in pancreatic β-cells and enteroendocrine cells in the small intestine. Activation of the receptor leads to glucose-stimulated insulin secretion (GSIS) and incretin secretion via an increase in intracellular cAMP. Synthetic GPR119 agonists therefore represent a promising target in treating type 2 diabetes. In this study, we evaluated the therapeutic potential of AS1790091, a novel synthetic GPR119 agonist with an EC50 value of 0.5 µM for human GPR119. AS1790091 (0.1-10 µM) dose-dependently enhanced insulin secretion in the mouse pancreatic β-cell line MIN6B1 and transiently activated human insulin promoter transfected in the mouse pancreatic β-cell line NIT-1. The maximum efficacy for human insulin promoter activity occurred at doses of 10-30 µM, which was comparable to that of GLP-1 analog exendin-4 at 3 µM. Multiple once-daily dosing of AS1790091 (0.3-3 mg/kg, po) for 2 weeks in diabetic db/db mice significantly reduced blood glucose and increased plasma insulin levels at 1-3 mg/kg. Similarly, AS1790091 markedly improved pancreatic insulin contents that intend pancreatic preservative effects. In KK/Ay mice, a model of type 2 diabetes with hyperinsulinemia, multiple once-daily dosing of AS1790091 (0.3-3 mg/kg, po) for 1 week improved blood glucose and pancreatic insulin contents at 1-3 mg/kg, findings similar to those observed in db/db mice, particularly with regard to reduced plasma insulin levels. Further, AS1790091 induced a reduction in body weight at 3 mg/kg in both db/db and KK/Ay mice. We found that AS1790091 improved not only GSIS and preservation of pancreatic β-cells but also insulin resistance and body weight. Taken together, these findings suggest that GPR119 agonist will help research move on from the GLP-1 pathway as a new generation agent for type 2 diabetes with obesity.