A role for beta-cell-expressed G protein-coupled receptor 119 in glycemic control by enhancing glucose-dependent insulin release.
Pancreatic beta-cell dysfunction is a hallmark event in the pathogenesis of type 2 diabetes. Injectable peptide agonists of the glucagon-like peptide 1 (GLP-1) receptor have shown significant promise as antidiabetic agents by virtue of their ability to amplify glucose-dependent insulin release and preserve pancreatic beta-cell mass. These effects are mediated via stimulation of cAMP through beta-cell GLP-1 receptors. We report that the Galpha(s)-coupled receptor GPR119 is largely restricted to insulin-producing beta-cells of pancreatic islets. Additionally, we show here that GPR119 functions as a glucose-dependent insulinotropic receptor. Unlike receptors for GLP-1 and other peptides that mediate enhanced glucose-dependent insulin release, GPR119 was suitable for the development of potent, orally active, small-molecule agonists. The GPR119-specific agonist AR231453 significantly increased cAMP accumulation and insulin release in both HIT-T15 cells and rodent islets. In both cases, loss of GPR119 rendered AR231453 inactive. AR231453 also enhanced glucose-dependent insulin release in vivo and improved oral glucose tolerance in wild-type mice but not in GPR119-deficient mice. Diabetic KK/A(y) mice were also highly responsive to AR231453. Orally active GPR119 agonists may offer significant promise as novel antihyperglycemic agents acting in a glucose-dependent fashion.
Chu
Zhi-Liang
ZL
Arena Pharmaceuticals, 6166 Nancy Ridge Drive, San Diego, CA 92121, USA.
Jones
Robert M
RM
He
Hongmei
H
Carroll
Chris
C
Gutierrez
Veronica
V
Lucman
Annette
A
Moloney
Molly
M
Gao
Hui
H
Mondala
Helen
H
Bagnol
Didier
D
Unett
David
D
Liang
Yin
Y
Demarest
Keith
K
Semple
Graeme
G
Behan
Dominic P
DP
Leonard
James
J
D000818:Animals; D001786:Blood Glucose / Q000502:physiology*; D002478:Cells, Cultured; D003920:Diabetes Mellitus / Q000235:genetics / Q000473:pathology; D005260:Female; D005947:Glucose / Q000494:pharmacology*; D005951:Glucose Tolerance Test; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008954:Models, Biological; D010069:Oxadiazoles / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011924:Rats, Zucker; D043562:Receptors, G-Protein-Coupled / Q000819:agonists / Q000235:genetics / Q000502:physiology*
C521085:AR 231453; D001786:Blood Glucose; C516207:Gpr119 protein, mouse; D007328:Insulin; D010069:Oxadiazoles; D011743:Pyrimidines; D043562:Receptors, G-Protein-Coupled; D005947:Glucose