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Antidiabetic Activity of a Highly Potent and Selective Nonpeptide Somatostatin Receptor Subtype-2 Agonist

Medizinische Klinik m. S. Hepatologie, Gastroenterologie, Endokrinologie und Stoffwechsel (M.Z.S., V.S.), Charité-Universitätsmedizin Berlin, Campus Virchow-Klinikum, 13353 Berlin, Germany; Departments of Animal Pharmacology (D.E.C., T.M.J.), Molecular Endocrinology and Metabolic Disorders, Atherosclerosis and Endocrinology (E.T.B, S.P.R., J.M.S.), and Medicinal Chemistry (L.Y., A.A.P.), Merck Research Laboratories, Rahway, New Jersey 07065; Huffington Center on Aging and Departments of Molecular and Cellular Biology and Medicine (R.G.S.), Baylor College of Medicine, Houston, Texas 77030; and Department of Animal Physiology and Biochemistry (K.W.N.), August Cieszkowski University of Agriculture, 60-637 Poznan, Poland

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

Somatostatin inhibits both glucagon and insulin secretion. Glucagon significantly contributes to hyperglycemia in type 2 diabetes. Despite its function in the inhibition of glucagon secretion, somatostatin fails to reduce hyperglycemia in type 2 diabetes, due to a parallel suppression of insulin secretion. Five pharmacologically distinct somatostatin receptor subtypes (sst₁–sst₅) mediate the effects of somatostatin on a cellular level. Pancreatic A cells express sst₂, whereas B cells express sst₅. In this study, we describe a novel approach to the treatment of type 2 diabetes using a highly sst₂-selective, nonpeptide agonist (compound 1). Compound 1 effectively inhibited glucagon secretion from pancreatic islets isolated from wild-type mice, whereas glucagon secretion from sst₂-deficient islets was not suppressed. Compound 1 did not influence nonfasted insulin concentration. In sst₂-deficient mice, compound 1 did not have any effects on glucagon or glucose levels, confirming its sst₂ selectivity. In animal models of type 2 diabetes in the nonfasted state, circulating glucagon and glucose levels were decreased after treatment with compound 1. In the fasting state, compound 1 lowered blood glucose by approximately 25%. In summary, small-molecule sst₂-selective agonists that suppress glucagon secretion offer a novel approach toward the development of orally bioavailable drugs for treatment of type 2 diabetes.

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