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Somatostatin Receptor Subtype 5 Regulates Insulin Secretion and Glucose Homeostasis

Departments of Molecular Endocrinology (M.Z.S., Z.L., D.S., B.B.Z.), Atherosclerosis & Endocrinology (J.M.S., H.A.W.), Metabolic Disorders (H.Y.C., M.E.T.), Ion Channels (M.K.), Comparative Medicine (S.G.-T., J.K.F.), Merck Research Laboratories, Rahway, New Jersey 07065; and Department of Biology (A.D.B.), Seton Hall University, South Orange, New Jersey 07079

Address all correspondence and requests for reprints to: Dr. Hilary A. Wilkinson, Department of Atherosclerosis & Endocrinology, Merck Research Laboratories, RY80Y-305, Rahway, New Jersey 07065. E-mail: hilary_wilkinson{at}merck.com; or Dr. Mathias Z. Strowski, Medizinische Klinik M. S. Hepatologie und Gastroenterologie, Charitè, Campus Virchow-Klinikum, Humboldt University, 13353 Berlin, Germany. E-mail: mathias.strowski{at}charite.de.

Somatostatin (SRIF) regulates pancreatic insulin and glucagon secretion. In the present study we describe the generation of SRIF receptor subtype 5 knockout (sst₅ KO) mice to examine the role of SRIF receptor subtypes (sst) in regulating insulin secretion and glucose homeostasis. Mice deficient in sst₅ were viable, fertile, appeared healthy, and displayed no obvious phenotypic abnormalities. Pancreatic islets isolated from sst₅ KO mice displayed increased total insulin content as compared with islets obtained from wild-type (WT) mice. Somatostatin-28 (SRIF-28) and the sst₅/sst₁-selective agonist compound 5/1 potently inhibited glucose-stimulated insulin secretion from WT islets. SRIF-28 inhibited insulin secretion from sst₅ KO islets with 16-fold less potency while the maximal effect of compound 5/1 was markedly diminished when compared with its effects in WT islets. sst₅ KO mice exhibited decreased blood glucose and plasma insulin levels and increased leptin and glucagon concentrations compared with WT mice. Furthermore, sst₅ KO mice displayed decreased susceptibility to high fat diet-induced insulin resistance. The results of these studies suggest sst₅ mediates SRIF inhibition of pancreatic insulin secretion and contributes to the regulation of glucose homeostasis and insulin sensitivity. Our findings suggest a potential beneficial role of sst₅ antagonists for alleviating metabolic abnormalities associated with obesity and insulin resistance.

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