A Role for β-Cell-Expressed G Protein-Coupled Receptor 119 in Glycemic Control by Enhancing Glucose-Dependent Insulin Release

Abstract

Pancreatic ␤-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 ␤-cell mass. These effects are mediated via stimulation of cAMP through ␤-cell GLP-1 receptors. We report that the G␣ s -coupled receptor GPR119 is largely restricted to insulin-producing ␤-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. (Endocrinology

G-protein coupled receptors mediating long chain fatty acid signalling in the pancreatic beta-cell

“…The conclusion that mature β-cells may not express GPR119 is contentious and is at variance with the results of a study which employed in situ hybridisation to demonstrate the presence of mRNA encoding GPR119 in both α-and β-cells of the rat [99]. These workers also developed their own antibody to GPR119 and used this to confirm the co-localisation of GPR119 with insulin in normal rat and mouse islets.…”

“…In order to evaluate this idea more fully, the distribution of GPR119 expression was examined in mammalian tissues by a number of authors and it was rapidly established that both the endocrine pancreas and certain cells of the GI tract express the receptor [87][88][89][90][91][92]. It is also possible that GPR119 may be expressed in some brain regions [93].…”

“…The authors concluded that the reported expression of GPR119 mRNA in various clonal islet β-cells (which include NIT-1 [95] & HIT-T15 [96] in addition to MIN6) may be representative of an immature phenotype. This proposal requires further confirmation but it is interesting to note that GPR119 is reportedly absent from the rat β-cell line RINm5F [97;98] consistent with the possibility that GPR119 is not universally present in mammalian β-cells.…”

“…Ectopic expression of GPR119 in various easily transfected cell lines has yielded unanimous support for the view that activation of the receptor is associated with a rise in cAMP levels [101][102][103][104]. Moeover, exposure of cultured β-cells to GPR119 ligands also elicits a rise in cAMP; as does treatment of the intestinal Lcell line, GLUTag [105].…”

“…In an attempt to move forward the development of pharmacological ligands targeted to GPR119, a number of groups have reported the synthesis of small molecules which can serve as agonists of this receptor [114][115][116]. These have largely been developed on the basis of their ability to elicit a response in cells transfected to express GPR119 but, encouragingly, several have also been shown to display activity in vivo.…”