AI Article Synopsis
- Somatostatin inhibits both glucagon and insulin secretion, but its effect on controlling hyperglycemia in type 2 diabetes is limited because it also suppresses insulin secretion.
- A new study introduces an sst(2)-selective, nonpeptide agonist (compound 1) that effectively reduces glucagon secretion from pancreatic islets, leading to lowered glucose levels without affecting insulin concentration.
- In animal models of type 2 diabetes, compound 1 demonstrated significant glucose-lowering effects, particularly in the fasting state, showcasing its potential as an innovative oral treatment option for managing the disease.
Article 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.
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| http://dx.doi.org/10.1210/en.2006-0274 | DOI Listing |
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