To study the effects of GPR at the

To study the effects of GPR40 at the whole-animal level, GPR40 mice have been generated in two different genetic backgrounds [18], [19]. GPR40 mice from both backgrounds were apparently healthy with no overt signs of metabolic or other abnormalities. As expected, pancreatic islets taken from GPR40 mice of both backgrounds showed greatly reduced LCFA amplification of glucose-stimulated insulin secretion compared to their wild-type littermates. Here, however, the similarities ended. One group of investigators have reported little difference between islets taken from wild-type and KO mice in their ability to maintain insulin secretion after exposure to palmitate for 72h [19]. In contrast, a separate group reported that islets taken from the KO mice were apparently protected from the lipotoxic effects of 48-hour exposure to palmitate [18]. In addition, they also reported that GPR40 mice resisted the development of hyperinsulinemia, hepatic steatosis, hypertriglyceridemia, and glucose intolerance after being fed a high-fat diet for 8 weeks as compared to wild-type mice. Based on these results, they have postulated that GPR40 antagonists may represent a viable therapeutic strategy for treating diabetes. Given the contradiction in reported results, the viability of either GPR40 agonists or antagonists will likely be settled in the clinic. As will be shown in the next sections, the preponderance of GPR40 modulators reported to date are agonists and thus they are more likely to be the first tested in the clinic.
LONG CHAIN ALKYL ACID DERIVATIVES Several diphenylpyrimidine derivatives typified by [33] and [34] have been reported as GPR40 agonists. These compounds feature a long alkyl tether between the pyrimidine moiety and the carboxylic VKGILS-NH2 moiety. Compounds and were reported to display 101% and 104% activation, respectively, at 10μM compared to linoleic acid in a FLIPR assay using recombinant HEK293 cells expressing GPR40 receptors.
ACID ISOSTERES One of the original reports that identified fatty acids as ligands for GPR40 also reported that the thiazolidinedione-containing antidiabetic agent rosiglitazone is also a potent activator of GPR40 [9]. Several research groups have reported GPR40 agonists that feature related carboxylic acid isosteres. Structures – typify several series of thiazolidinedione, oxazolidinedione and oxadiazolidinedione derivatives that have been reported to activate GPR40 receptors [25], [35], [36].
CONCLUSION GPR40 is a G-protein couple receptor expressed primarily in the pancreas, but also found in the small intestine and brain. Within the pancreas, GPR40 mRNA levels suggest that GPR40 is expressed mainly in the islet β-cells. GPR40 is activated by fatty acids. Experiments with siRNA specific for GPR40 inhibits insulin secretion mediated by fatty acids in vitro. Furthermore, GPR40 agonists potentiate glucose-stimulated insulin secretion in MIN6 cells, a mouse pancreatic β-cell line, suggesting that GPR40 agonists can function as glucose-dependent insulin secretagogues. A GPR40 agonist has also been reported to lower glucose levels in a rat i.p. glucose tolerance test (ipGTT). Taken together, this data suggests that GPR40 may function as a lipid sensor that mediates insulin secretion from islet β-cells in a glucose-dependent manner and that GPR40 agonists will be useful in the treatment of Type II diabetes.
Introduction Type 2 diabetes mellitus (T2DM) is a metabolic disorder disease characterized by both defective insulin secretion and insulin action in maintaining glucose homeostasis [1]. T2DM often leads to multiple macrovascular and microvascular complications, including cardiovascular diseases, nephropathy, neuropathy and retinopathy [[2], [3], [4]]. The incidence of T2DM is increasing at an alarming rate. By 2017, the number of individuals affected worldwide was about 425 million and this figure may reach 629 million in 2045 [5]. This severe situation, along with the undesirable side effects caused by current hypoglycemic agents, such as high risk of hypoglycemia, body weight gain and gastric symptoms [[6], [7], [8]], stimulate urgent needs for novel drugs with improved safety and glycemic control.