Characterization of somatostatin receptor subtype-specific regulation of insulin and glucagon secretion:: An in vitro study on isolated human pancreatic islets

Introduction: Pancreatic A- and B-cells express somatostatin receptors ( SSTRs). Five pharmacologically distinct SSTR subtypes are known ( SSTR1-SSTR5). In rodents, SSTR2 inhibits glucagon secretion, whereas SSTR5 suppresses the release of insulin. Human pancreatic A- and B-cells express SSTR1-3 and SSTR5; however, their contribution to the regulation of glucagon and insulin secretion is not well known. Aim of the Study: The goal of this study was to characterize the role of individual SSTR subtypes in regulating human glucagon and insulin secretion in vitro. Methods: Human pancreatic islets were isolated from healthy donors and incubated with somatostatin, SSTR1-3-selective and SSTR5-selective agonists, or an SSTR2-selective antagonist ( DC-41-33). Stimulation of insulin secretion was induced by glucose ( 10, 20 mM) alone or in combination with 10 nM exendin-4 or 10 mM L-arginine. Glucagon secretion was induced by 20mM L-arginine. Basal secretion of insulin and glucagon was measured at 2.8 or 3.3 mM glucose. Results: SSTR1-, SSTR2-, and SSTR5-selective agonists inhibited insulin secretion with the following order of potency: SSTR2 ( EC50, 0.08 nM) > SSTR5 ( EC50, 5.3 nM) > SSTR1 ( EC50, 35 nM). Glucagon secretion was inhibited by SSTR- selective agonists with the following order of potency: SSTR2 ( EC50, 0.05 nM) > SSTR1 ( EC50, 1.8 nM) > SSTR5 ( EC50, 28nM). DC-41-33 dose-dependently reversed the effects of the SSTR2- selective agonist on insulin and glucagon secretion. Conclusion: Our study demonstrates that SSTR2- agonist is the most potent inhibitor of insulin and glucagon secretion from isolated human pancreatic islets. Furthermore, we identify SSTR1- and SSTR5-selective agonists as additional inhibitors of insulin and glucagon secretion from human pancreas.