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This version published online on July 20, 2006
Endocrinology, doi:10.1210/en.2006-0274
A more recent version of this article appeared on October 1, 2006
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Submitted on March 1, 2006
Accepted on July 7, 2006

Antidiabetic activity of a highly potent and selective non-peptide somatostatin receptor subtype-2 agonist

Mathias Z. Strowski*, Doreen E. Cashen, Elizabeth T. Birzin, Lihu Yang, Vandana Singh, Thomas M. Jacks, Krzysztof Nowak, Susan P. Rohrer, Arthur A. Patchett, Roy G. Smith, and James M. Schaeffer

Medizinische Klinik m. S. Hepatologie, Gastroenterologie, Endokrinologie und Stoffwechsel, Charité - Universitätsmedizin Berlin, Campus Virchow-Klinikum, 13353 Berlin, Germany Departments of Animal Pharmacology, Molecular Endocrinology and Metabolic Disorders, Atherosclerosis & Endocrinology, Medicinal Chemistry, Merck Research Laboratories, Rahway, New Jersey 07065, Huffington Center on Aging and Departments of Molecular and Cellular Biology and Medicine, Baylor College of Medicine, Houston, TX 77030-3498, USA, Department of Animal Physiology and Biochemistry, August Cieszkowski University of Agriculture, Poznan, Poland

* To whom correspondence should be addressed. 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. Here, we describe a novel approach to the treatment of type 2 diabetes using a highly sst2-selective, non-peptide 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 non-fasted 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 non-fasted 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 agents that suppress glucagon secretion offer a novel approach toward the development of orally bioavailable drugs for treatment of type 2 diabetes.
Key words: knock out • in vivo • in vitro • physiology • endocrine islets • pancreas




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