Introduction: Pancreatic A- and B-cells express somatostatin receptors. 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: Characterization of 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- 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 20 mM L-arginine. Basal secretion of insulin and glucagon were measured at 2.8 or 3.3 mM D-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: 28 nM). 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 human insulin and glucagon secretion.