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Characterization of Somatostatin Receptor Subtype-Specific Regulation of Insulin and Glucagon Secretion: An in Vitro Study on Isolated Human Pancreatic Islets

Medizinische Klinik mit Schwerpunkt Hepatologie (V.S., S.Z., S.M., B.W., U.P., M.Z.S.), Gastroenterologie & Interdisziplinäres Stoffwechsel-Centrum: Endokrinologie und Diabetes mellitus, Charité—Universitätsmedizin Berlin, Campus Virchow Klinikum, 13353 Berlin, Germany; and Third Medical Department and Policlinic (M.D.B., H.J., R.G.B.), University Hospital, Justus-Liebig University, Rodthohl 6, 35932 Giessen, Germany

Address all correspondence and requests for reprints to: Mathias Z. Strowski, M.D., Medizinische Klinik m. S. Hepatologie und Gastroenterologie & Interdisziplinäres Stoffwechsel-Centrum: Endokrinologie, Diabetes und Stoffwechsel, Charité—Universitätsmedizin Berlin, Campus Virchow Klinikum, Augustenburger Platz 1, 13353 Berlin, Germany. E-mail: mathias.strowski{at}charite.de.

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 20 mM 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, 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 insulin and glucagon secretion from human pancreas.

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				V. Singh, C. Grotzinger, K. W. Nowak, S. Zacharias, E. Goncz, G. Pless, I. M. Sauer, I. Eichhorn, B. Pfeiffer-Guglielmi, B. Hamprecht, et al. Somatostatin Receptor Subtype-2-Deficient Mice with Diet-Induced Obesity Have Hyperglycemia, Nonfasting Hyperglucagonemia, and Decreased Hepatic Glycogen Deposition Endocrinology, August 1, 2007; 148(8): 3887 - 3899. [Abstract] [Full Text] [PDF]