Antidiabetic activity of a highly potent and selective nonpeptide somatostatin receptor subtype-2 agonist.
Endocrinology
; 147(10): 4664-73, 2006 Oct.
Article
in En
| MEDLINE
| ID: mdl-16857751
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.
Search on Google
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Receptors, Somatostatin
/
Hypoglycemic Agents
Type of study:
Prognostic_studies
Limits:
Animals
Language:
En
Journal:
Endocrinology
Year:
2006
Document type:
Article
Affiliation country:
Germany