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

Abstract

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 (sst(1)-sst(5)) mediate the effects of somatostatin on a cellular level. Pancreatic A cells express sst(2), whereas B cells express sst(5). In this study, we describe a novel approach to the treatment of type 2 diabetes using a highly sst(2)-selective, nonpeptide agonist (compound 1). Compound 1 effectively inhibited glucagon secretion from pancreatic islets isolated from wild-type mice, whereas glucagon secretion from sst(2)-deficient islets was not suppressed. Compound 1 did not influence nonfasted insulin concentration. In sst(2)-deficient mice, compound 1 did not have any effects on glucagon or glucose levels, confirming its sst(2) 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 sst(2)-selective agonists that suppress glucagon secretion offer a novel approach toward the development of orally bioavailable drugs for treatment of type 2 diabetes.

Function and expression of somatostatin receptors of the endocrine pancreas

“…Using pancreatic islets isolated from mice with SSTR2-deletion (Zheng et al, 1997), SST and two different non-peptidal SSTR2-selective agonists were unable to inhibit glucagon secretion (Strowski et al, 2000;Strowski et al, 2006). These observations coupled with the inability of other SSTR-selective agonists to influence glucagon secretion (Berk et al, 1999;Rohrer et al, 1998;Rohrer and Schaeffer 2000) favours the glucagonostatic role of SSTR2 in mice.…”

“…For example the putative SSTR2-selective agonist NC 8-12, also binds to SSTR3 at nanomolar range and DC-25-100 to SSTR3 and SSTR4, as well as SSTR2 (Patel and Srikant 1994;. The role of SSTR2 in regulating glucagon secretion was confirmed using a highly selective nonpeptidal agonist for SSTR2 (Yang et al, 1998), which potently reduced non-fasting glucagon secretion in non-diabetic, diabetic (ob/ob, db/db) mice and in fasted dogs (Strowski et al, 2006). Noteworthy, this was accompanied by a fall of plasma glucose concentrations.…”

“…Recently, the role of SSTR2 in regulating glucagon secretion has been strengthened by the results of two separate in vivo studies utilizing lean and obese SSTR2-deficient mice (Strowski et al, 2006;Singh et al, 2007b). Specifically, the deterioration of glycemic control in SSTR2-deficient mice fed high-fat diet, suggests a potential novel therapeutic opportunity to alleviate hyperglycemia in diabetes.…”

Physiology of the pancreatic α-cell and glucagon secretion: role in glucose homeostasis and diabetes

“…Somatostatin analogues Because of the different expression of SSTR in the islet (Kumar et al 1999), several studies have explored the modulation of glucagon secretion by subtype-specific somatostatin analogues (Strowski et al 2006). It has been shown that SSTR2 is the subtype receptor predominantly expressed in rodent a-cells, and that SSTR2-deficient mice develop hyperglycaemia and non-fasting hyperglucagonaemia (Singh et al 2007).…”

“…It has been shown that SSTR2 is the subtype receptor predominantly expressed in rodent a-cells, and that SSTR2-deficient mice develop hyperglycaemia and non-fasting hyperglucagonaemia (Singh et al 2007). In mice, the use of a highly SSTR2-selective non-peptide agonist inhibited glucagon release without affecting insulin release (Strowski et al 2006). However, there is some overlapping in human islets between the different SSTR subtypes in a-and b-cells that limit, at present, the use of subtype-specific somatostatin analogues (Singh et al 2007).…”