GPR40 partial agonist MK-2305 lower fasting glucose in the Goto Kakizaki rat via suppression of endogenous glucose production

Abstract

GPR40 (FFA1) is a fatty acid receptor whose activation results in potent glucose lowering and insulinotropic effects in vivo. Several reports illustrate that GPR40 agonists exert glucose lowering in diabetic humans. To assess the mechanisms by which GPR40 partial agonists improve glucose homeostasis, we evaluated the effects of MK-2305, a potent and selective partial GPR40 agonist, in diabetic Goto Kakizaki rats. MK-2305 decreased fasting glucose after acute and chronic treatment. MK-2305-mediated changes in glucose were coupled with increases in plasma insulin during hyperglycemia and glucose challenges but not during fasting, when glucose was normalized. To determine the mechanism(s) mediating these changes in glucose metabolism, we measured the absolute contribution of precursors to glucose production in the presence or absence of MK-2305. MK-2305 treatment resulted in decreased endogenous glucose production (EGP) driven primarily through changes in gluconeogenesis from substrates entering at the TCA cycle. The decrease in EGP was not likely due to a direct effect on the liver, as isolated perfused liver studies showed no effect of MK-2305 ex vivo and GPR40 is not expressed in the liver. Taken together, our results suggest MK-2305 treatment increases glucose stimulated insulin secretion (GSIS), resulting in changes to hepatic substrate handling that improve glucose homeostasis in the diabetic state. Importantly, these data extend our understanding of the underlying mechanisms by which GPR40 partial agonists reduce hyperglycemia.

Combined deletion of free fatty-acid receptors 1 and 4 minimally impacts glucose homeostasis in mice

“…This possibility is consistent with the lower GIR observed during HGC in 28-30 weeks Gpr120/40KO mice, and is supported by the finding that Gpr120KO mice can develop insulin resistance [3]. However, glucagon secretion and glucagon sensitivity are elevated in Gpr120KO mice [27] and Gpr40 agonist treatment inhibits glucose production in Goto Kakizaki rat through changes in gluconeogenesis [56]. Hence, increased glycogenolysis and gluconeogenesis could also contribute to higher blood glucose levels in Gpr120/40KO mice.…”

Free fatty acid receptor 1 agonist, MR1704, lowers blood glucose levels in rats unresponsive to the sulfonylurea, glibenclamide

“…MR1704 reduced the plasma glucose excursion in rats unresponsive to glibenclamide treatment. Data from studies on GPR40/FFAR1 synthetic agonists (Chen et al, ; Lin et al, ; Miller et al, ; Tan et al, ; Tanaka et al, ; Tsujihata et al, , Ito et al, ) have demonstrated that activation of GPR40/FFAR1 can augment insulin secretion. GPR40/FFAR1 is a Gq family G‐protein coupled receptor (GPCR), activation of which promotes the phospholipase C‐mediated hydrolysis of phosphatidylinositol 4,5‐bisphosphate into diacylglycerol and inositol 1,4,5‐triphosphate.…”

Cell-Based In Vitro Assay Automation: Balancing Technology and Data Reproducibility/Predictability

“…GPR40 is from the class of GPCRs that signal through the Gq pathway. [20][21][22] Therefore, the highly robust Cisbio HTRF IP-1 Gq cell-based assay kit was employed that detects the accumulation of IP-1, a stable downstream metabolite of IP-3 induced by activation of a phospholipase C (PLC) cascade. 3,[23][24][25][26][27] According to the Cisbio IP-1 instructions, the kit allows direct characterization of all types of compounds acting on Gq-coupled receptors in either adherent or suspension cell assays.…”