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?-Cell Inactivation of Gpr119 Unmasks Incretin Dependence of GPR119-Mediated Glucoregulation.

ABSTRACT: GPR119 was originally identified as an orphan ?-cell receptor; however, subsequent studies demonstrated that GPR119 also regulates ?-cell function indirectly through incretin hormone secretion. We assessed the importance of GPR119 for ?-cell function in Gpr119^-/- mice and in newly generated Gpr119^?cell-/- mice. Gpr119^-/- mice displayed normal body weight and glucose tolerance on a regular chow (RC) diet. After high-fat feeding, Gpr119^-/- mice exhibited reduced fat mass, decreased levels of circulating adipokines, improved insulin sensitivity, and better glucose tolerance. Unexpectedly, oral and intraperitoneal glucose tolerance and the insulin response to glycemic challenge were not perturbed in Gpr119^?cell-/- mice on RC and high-fat diets. Moreover, islets from Gpr119^-/- and Gpr119^?cell-/- mice exhibited normal insulin responses to glucose and ?-cell secretagogues. Furthermore, the selective GPR119 agonist AR231453 failed to directly enhance insulin secretion from perifused islets. In contrast, AR231453 increased plasma glucagon-like peptide 1 (GLP-1) and insulin levels and improved glucose tolerance in wild-type and Gpr119^?cell-/- mice. These findings demonstrate that ?-cell GPR119 expression is dispensable for the physiological control of insulin secretion and the pharmacological response to GPR119 agonism, findings that may inform the lack of robust efficacy in clinical programs assessing GPR119 agonists for the therapy of type 2 diabetes.

SUBMITTER: Panaro BL

PROVIDER: S-EPMC5860191 | biostudies-literature | 2017 Jun

REPOSITORIES: biostudies-literature

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β-Cell Inactivation of Gpr119 Unmasks Incretin Dependence of GPR119-Mediated Glucoregulation.

Panaro Brandon L BL Flock Grace B GB Campbell Jonathan E JE Beaudry Jacqueline L JL Cao Xiemin X Drucker Daniel J DJ

Diabetes 20170302 6

GPR119 was originally identified as an orphan β-cell receptor; however, subsequent studies demonstrated that GPR119 also regulates β-cell function indirectly through incretin hormone secretion. We assessed the importance of GPR119 for β-cell function in Gpr119-/- mice and in newly generated Gpr119βcell-/- mice. Gpr119-/- mice displayed normal body weight and glucose tolerance on a regular chow (RC) diet. After high-fat feeding, Gpr119< ...[more]

PMID: 28254842

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Project description:AIMS/HYPOTHESIS:Abnormal cannabidiol (Abn-CBD) and AS-1269574 are potent selective agonists for GPR55 and GPR119, respectively. The present study evaluated the actions and ability of these small-molecule agonists to counteract experimental diabetes in mice. METHODS:Diabetes was induced in NIH Swiss mice by five consecutive daily intraperitoneal injections of 40 mg/(kg body weight) streptozotocin. Diabetic mice received daily oral administration of Abn-CBD or AS-1269574 (0.1 μmol/kg) or saline vehicle (0.9% wt/vol. NaCl) over 28 days. Body weight, food intake, fluid intake, plasma glucose, insulin, glucose tolerance, insulin release, lipid profile and pancreatic morphology were examined. Mechanism of action of agonists was assessed in acute studies using incretin-receptor-knockout mice. RESULTS:Abn-CBD and AS-1269574 decreased plasma glucose (20-26%, p < 0.05) and increased circulating insulin (47-48%, p < 0.05) by 10-28 days, compared with saline-treated diabetic controls. Food intake and polydipsia were reduced by both agonists (21-23%, p < 0.05 and 33-35%, p < 0.01, respectively). After 28 days of treatment, plasma glucagon concentrations were reduced (p < 0.01) and glucose tolerance was enhanced by 19-44% by Abn-CBD (p < 0.05 or p < 0.001) and AS-1269574 (p < 0.05 to p < 0.001). Plasma insulin responses were improved (p < 0.01) and insulin resistance was decreased (p < 0.05 or p < 0.01) in both Abn-CBD- and AS-1269574-treated groups. Triacylglycerols were decreased by 19% with Abn-CBD (p < 0.05) and 32% with AS-1269574 (p < 0.01) while total cholesterol was reduced by 17% (p < 0.01) and 15% (p < 0.05), respectively. Both agonists enhanced beta cell proliferation (p < 0.001) although islet area was unchanged. Acute studies in Gipr- and Glp1r-knockout mice revealed an important role for the glucagon-like peptide 1 (GLP-1) receptor in the actions of both agonists, with the glucose-lowering effects of Abn-CBD also partly mediated through the glucose-dependent insulinotropic peptide (GIP) receptor. CONCLUSIONS/INTERPRETATION:These data highlight the potential for fatty acid G-protein-coupled receptor-based therapies as novel insulinotropic and glucose-lowering agents acting partly through the activation of incretin receptors.

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?-Cell Inactivation of Gpr119 Unmasks Incretin Dependence of GPR119-Mediated Glucoregulation.

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β-Cell Inactivation of <i>Gpr119</i> Unmasks Incretin Dependence of GPR119-Mediated Glucoregulation.

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