| Target Validation Information | |||||
|---|---|---|---|---|---|
| Target ID | T93788 | ||||
| Target Name | Glucose-dependent insulinotropic receptor | ||||
| Target Type | Clinical Trial |
||||
| Drug Potency against Target | APD668 | Drug Info | EC50 = 2.51 nM | [552050] | |
| Action against Disease Model | APD668 | APD668 increases adenylate cyclase activation in HEK293 cells transfected with h uMan GPR119 (but not in non-transfected cells) in a concentration-dependent manner with an EC50 of 23 nM. It also enhanced insulin release from both rat and h uMan isolated pancreatic islets in a glucose-dependent manner. in Zucker Diabetic Fatty (ZDF) rats. APD668 significantly reduced blood glucose and glycated hemoglobin (HbA1c) levels over eight weeks of treatment (QD), with no desensitization of the acute drug response over this period at 30 mg/kg po | [531413] | Drug Info | |
| The Effect of Target Knockout, Knockdown or Genetic Variations | We examined the importance of endogenous incretin receptors for control of glucose homeostasis through analysis of Glp1r(-/-), Gipr(-/-), and double incretin receptor knockout (DIRKO) mice fed a high-fat (HF) diet. DIRKO mice failed to upregulate levels of plasma insulin, pancreatic insulin mRNA transcripts, and insulin content following several months of HF feeding. Both single incretin receptor knockout and DIRKO mice exhibited resistance to diet-induced obesity, preservation of insulin sensitivity, and increased energy expenditure associated with increased locomotor activity. Moreover, plasma levels of plasminogen activator inhibitor-1 and resistin failed to increase significantly in DIRKO mice after HF feeding, and the GIP receptor agonist [D-Ala(2)]GIP, but not the GLP-1 receptor agonist exendin-4, increased the levels of plasma resistin in studies of both acute and chronic administration. These findings extend our understanding of how endogenous incretin circuits regulate glucose homeostasis independent of the beta cell via control of adipokine secretion and energy expenditure. | [531413] | |||
| References | |||||
| Ref 531413 | Bioorg Med Chem Lett. 2011 May 15;21(10):3134-41. Epub 2011 Mar 13.Discovery of fused bicyclic agonists of the orphan G-protein coupled receptor GPR119 with in vivo activity in rodent models of glucose control. | ||||
| Ref 552050 | GPR119 agonists: a promising new approach for the treatment of type 2 diabetes and related metabolic disorders. Curr Opin Drug Discov Devel. 2009 Jul;12(4):519-32. | ||||
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