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.