title: β-Cell Inactivation ofGpr119Unmasks 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 inGpr119-/-mice and in newly generatedGpr119βcell-/-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 inGpr119βcell-/-mice on RC and high-fat diets. Moreover, islets fromGpr119-/-andGpr119βcell-/-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 andGpr119βcell-/-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.affiliation: Lunenfeld-Tanenbaum Research Institute, Department of Medicine, Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Brandon L
authors.initials: BL
authors.lastname: Panaro
authors.affiliation: Lunenfeld-Tanenbaum Research Institute, Department of Medicine, Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Grace B
authors.initials: GB
authors.lastname: Flock
authors.affiliation: Lunenfeld-Tanenbaum Research Institute, Department of Medicine, Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Jonathan E
authors.initials: JE
authors.lastname: Campbell
authors.affiliation: Lunenfeld-Tanenbaum Research Institute, Department of Medicine, Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Jacqueline L
authors.initials: JL
authors.lastname: Beaudry
authors.affiliation: Lunenfeld-Tanenbaum Research Institute, Department of Medicine, Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Xiemin
authors.initials: X
authors.lastname: Cao
authors.affiliation: Lunenfeld-Tanenbaum Research Institute, Department of Medicine, Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada drucker@lunenfeld.ca.
authors.forename: Daniel J
authors.identifier: 0000-0001-6688-8127
authors.initials: DJ
authors.lastname: Drucker
mesh_terms: D054392:Adipokines / Q000378:metabolism; D000818:Animals; D017209:Apoptosis; D001786:Blood Glucose / Q000378:metabolism*; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism*; D059305:Diet, High-Fat; D020869:Gene Expression Profiling; D005934:Glucagon / Q000378:metabolism; D052216:Glucagon-Like Peptide 1 / Q000187:drug effects / Q000378:metabolism*; D005947:Glucose / Q000378:metabolism; D005951:Glucose Tolerance Test; D054795:Incretins / Q000378:metabolism; D007328:Insulin / Q000378:metabolism; D007333:Insulin Resistance; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000378:metabolism*; D008297:Male; D018345:Mice, Knockout; D010069:Oxadiazoles / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D043562:Receptors, G-Protein-Coupled / Q000819:agonists / Q000235:genetics*
chemical_list: C521085:AR 231453; D054392:Adipokines; D001786:Blood Glucose; C516207:Gpr119 protein, mouse; D054795:Incretins; D007328:Insulin; D010069:Oxadiazoles; D011743:Pyrimidines; D043562:Receptors, G-Protein-Coupled; D052216:Glucagon-Like Peptide 1; D005934:Glucagon; D005947:Glucose