Regulation of Endogenous (Male) Rodent GLP-1 Secretion and Human Islet Insulin Secretion by Antagonism of Somatostatin Receptor 5.

Incretin and insulin responses to nutrient loads are suppressed in persons with diabetes, resulting in decreased glycemic control. Agents including sulfonylureas and dipeptidyl peptidase-4 inhibitors (DPP4i) partially reverse these effects and provide therapeutic benefit; however, their modes of action limit efficacy. Because somatostatin has been shown to suppress insulin and glucagonlike peptide-1 (GLP-1) secretion through the Gi-coupled receptor 5 isoform in vitro, antagonism of may improve glycemic control via intervention in both pathways. Here, we show that a potent and selective duanyu1942R5 antagonist reverses the blunting effects of duanyu1942 on insulin secretion from isolated human islets, and demonstrate that duanyu1942R5 antagonism affords increased levels of systemic GLP-1 in vivo. Knocking out Sstr5 in mice provided a similar increase in systemic GLP-1 levels, which were not increased further by treatment with the antagonist. Treatment of mice with the duanyu1942R5 antagonist in combination with a DPP4i resulted in increases in systemic GLP-1 levels that were more than additive and resulted in greater glycemic control compared with either agent alone. In isolated human islets, the duanyu1942R5 antagonist completely reversed the inhibitory effect of exogenous on insulin secretion. Taken together, these data suggest that duanyu1942R5 antagonism should increase circulating GLP-1 levels and stimulate insulin secretion (directly and via GLP-1) in humans, improving glycemic control in patients with diabetes.

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