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

Abstract

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-/- 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 Gpr119βcell-/- mice on RC and high-fat diets. Moreover, islets from Gpr119-/- and Gpr119βcell-/- mice exhibited normal insulin responses to glucose and β-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 Gpr119βcell-/- mice. These findings demonstrate that β-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.

• Authors: Brandon L Panaro, Grace B Flock, Jonathan E Campbell, Jacqueline L Beaudry, Xiemin Cao, Daniel J Drucker
• Journal: Diabetes (Diabetes) Vol. 66 Issue 6 Pg. 1626-1635 (06 2017) ISSN: 1939-327X [Electronic] United States
• PMID: 28254842 (Publication Type: Journal Article)
• Copyright: © 2017 by the American Diabetes Association.

Chemical References

• AR 231453
• Adipokines
• Blood Glucose
• Gpr119 protein, mouse
• Incretins
• Insulin
• Oxadiazoles
• Pyrimidines
• Receptors, G-Protein-Coupled
• Glucagon-Like Peptide 1
• Glucagon
• Glucose

Topics

• Adipokines (metabolism)
• Animals
• Apoptosis
• Blood Glucose (metabolism)
• Diabetes Mellitus, Experimental (metabolism)
• Diet, High-Fat
• Gene Expression Profiling
• Glucagon (metabolism)
• Glucagon-Like Peptide 1 (drug effects, metabolism)
• Glucose (metabolism)
• Glucose Tolerance Test
• Incretins (metabolism)
• Insulin (metabolism)
• Insulin Resistance
• Insulin Secretion
• Insulin-Secreting Cells (metabolism)
• Male
• Mice, Knockout
• Oxadiazoles (pharmacology)
• Pyrimidines (pharmacology)
• Receptors, G-Protein-Coupled (agonists, genetics)