Antidiabetic activity of a highly potent and selective nonpeptide somatostatin receptor subtype-2 agonist.
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.
Strowski
Mathias Z
MZ
Medizinische Klinik m. S. Hepatologie, Gastroenterologie, Endokrinologie und Stoffwechsel, Charité-Universitätsmedizin Berlin, Campus Virchow-Klinikum, Augustenburger Platz 1, 13353 Berlin, Germany. mathias.strowski@charite.de
Cashen
Doreen E
DE
Birzin
Elizabeth T
ET
Yang
Lihu
L
Singh
Vandana
V
Jacks
Thomas M
TM
Nowak
Krzysztof W
KW
Rohrer
Susan P
SP
Patchett
Arthur A
AA
Smith
Roy G
RG
Schaeffer
James M
JM
D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics / Q000378:metabolism; D004285:Dogs; D005934:Glucagon / Q000378:metabolism; D013006:Growth Hormone / Q000378:metabolism; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D066298:In Vitro Techniques; D007328:Insulin / Q000378:metabolism / Q000494:pharmacology; D007515:Islets of Langerhans / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008820:Mice, Obese; D051381:Rats; D017481:Receptors, Somatostatin / Q000819:agonists* / Q000235:genetics
D001786:Blood Glucose; D007004:Hypoglycemic Agents; D007328:Insulin; D017481:Receptors, Somatostatin; C106140:somatostatin receptor sst2A; D013006:Growth Hormone; D005934:Glucagon