Potentiation of Glucose-stimulated Insulin Secretion by the GPR40-PLC-TRPC Pathway in Pancreatic β-Cells (original) (raw)
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Endocrine journal, 2016
In pancreatic β-cells, glucose-induced closure of the ATP-sensitive K(+) (KATP) channel is an initial process triggering glucose-stimulated insulin secretion (GSIS). This KATP-channel dependent pathway has been believed to be a central mechanism for GSIS. However, since the resting membrane potential of cells is determined by the balance of the net result of current amplitudes in outward and inward directions, it must be taken into consideration that not only KATP channel inhibition but also inward current via the basal opening of non-selective cation channels (NSCCs) plays a crucial role in membrane potential regulation. The basal activity of NSCCs is essential to effectively evoke depolarization in concert with KATP channel closure that is dependent on glucose metabolism. The present study summarizes recent findings regarding the roles of NSCCs in GSIS and GTP-binding protein coupled receptor-(GPCR) operated potentiation of GSIS.
GPR40 Is Necessary but Not Sufficient for Fatty Acid Stimulation of Insulin Secretion In Vivo
Diabetes, 2007
Long-chain fatty acids amplify insulin secretion from the pancreatic β-cell. The G-protein–coupled receptor GPR40 is specifically expressed in β-cells and is activated by fatty acids; however, its role in acute regulation of insulin secretion in vivo remains unclear. To this aim, we generated GPR40 knockout (KO) mice and examined glucose homeostasis, insulin secretion in response to glucose and Intralipid in vivo, and insulin secretion in vitro after short- and long-term exposure to fatty acids. Our results show that GPR40 KO mice have essentially normal glucose tolerance and insulin secretion in response to glucose. Insulin secretion in response to Intralipid was reduced by ∼50%. In isolated islets, insulin secretion in response to glucose and other secretagogues was unaltered, but fatty acid potentiation of insulin release was markedly reduced. The Gαq/11 inhibitor YM-254890 dose-dependently reduced palmitate potentiation of glucose-induced insulin secretion. Islets from GPR40 KO ...
American Journal of Physiology-Endocrinology and Metabolism, 2005
It has long been thought that long-chain free fatty acids (FFAs) stimulate insulin secretion via mechanisms involving their metabolism in pancreatic β-cells. Recently, it was reported that FFAs function as endogenous ligands for GPR40, a G protein-coupled receptor, to amplify glucose-stimulated insulin secretion in an insulinoma cell line and rat islets. However, signal transduction mechanisms for GPR40 in β-cells are little known. The present study was aimed at elucidating GPR40-linked Ca2+signaling mechanisms in rat pancreatic β-cells. We employed oleic acid (OA), an FFA that has a high affinity for the rat GPR40, and examined its effect on cytosolic Ca2+concentration ([Ca2+]i) in single β-cells by fura 2 fluorescence imaging. OA at 1–10 μM concentration-dependently increased [Ca2+]iin the presence of 5.6, 8.3, and 11.2 mM, but not 2.8 mM, glucose. OA-induced [Ca2+]iincreases at 11.2 mM glucose were inhibited in β-cells transfected with small interfering RNA targeted to rat GPR40 ...
2019
It has been long known that hyperglycaemia-induced β-cell dysfunction precipitates type 2 diabetes (T2D) in insulin-resistant obesity, although the underlying mechanisms are still poorly defined. The few frequently used antidiabetic drugs on the market have still not satisfactorily demonstrated any long-lasting improvements of β-cell function and prevention of the disease. Islets synthesise and secrete numerous peptides, many of which having important impact on the regulation of metabolism, in particular blood glucose control. In paper I, we quantified mRNAs encoding all peptide ligands of islet G protein-coupled receptors (GPCRs) in isolated human and mouse islets. The study will allow accurate translation of mouse islet functional studies relevant for human physiology, which may pave the way to novel treatment of diabetes. In paper II, we show that ADGRG1 (GPR56) is the most abundant GPCR transcript in both human and mouse islets, and its expression in human islets strongly correl...