α/β-Hydrolase Domain-6-Accessible Monoacylglycerol Controls Glucose-Stimulated Insulin Secretion

Abstract

Glucose metabolism in pancreatic β cells stimulates insulin granule exocytosis, and this process requires generation of a lipid signal. However, the signals involved in lipid amplification of glucose-stimulated insulin secretion (GSIS) are unknown. Here we show that in β cells, glucose stimulates production of lipolysis-derived long-chain saturated monoacylglycerols, which further increase upon inhibition of the membrane-bound monoacylglycerol lipase α/β-Hydrolase Domain-6 (ABHD6). ABHD6 expression in β cells is inversely proportional to GSIS. Exogenous monoacylglycerols stimulate β cell insulin secretion and restore GSIS suppressed by the pan-lipase inhibitor orlistat. Whole-body and β-cell-specific ABHD6-KO mice exhibit enhanced GSIS, and their islets show elevated monoacylglycerol production and insulin secretion in response to glucose. Inhibition of ABHD6 in diabetic mice restores GSIS and improves glucose tolerance. Monoacylglycerol binds and activates the vesicle priming protein Munc13-1, thereby inducing insulin exocytosis. We propose saturated monoacylglycerol as a signal for GSIS and ABHD6 as a negative modulator of insulin secretion.

Chronic Exposure to Excess Nutrients Left-shifts the Concentration Dependence of Glucose-stimulated Insulin Secretion in Pancreatic β-Cells

“…Another likely lipid candidate is monoacylglycerol. We have recently shown that monoacylglycerol stimulates basal insulin secretion, and Zhao et al have shown that it binds the exocytotic protein Munc13-1 (32,56). Another possibility is that a change in the lipid composition of the plasma membrane may alter the Ca 2ϩ threshold needed for GSIS and thus shift the dose-response curve.…”

Identification of a mammalian glycerol-3-phosphate phosphatase: Role in metabolism and signaling in pancreatic β-cells and hepatocytes

“…After transfection using Lipofectamine, INS832/13 cells were cultured for 48 h in 96-well, 12-well, or 6-well plates. siRNAs against G3PP and two scrambled siRNAs were introduced into INS832/13 cells by RNAiMAX (40). Transfected cells were used for Western blotting and measurements of insulin secretion, caspase activity, glycerol and FFA release, O 2 consumption, and fatty acid oxidation and esterification.…”

Isocitrate-to-SENP1 signaling amplifies insulin secretion and rescues dysfunctional β cells

“…These include a glycerolipid/ free fatty acid cycle (15), which generates monoacylglycerol as a coupling factor (16); a phosphoenolpyruvate and mitochondrial GTP-dependent pathway (17,18); and so-called "pyruvate cycles" (19)(20)(21), which export reducing equivalents from the mitochondria to the cytosol. The mitochondrial export of citrate and isocitrate and subsequent engagement of isocitrate with the cytosolic NADP + -dependent isocitrate dehydrogenase (IDH1, hereafter referred to as ICDc) has been shown to regulate insulin secretion (22,23), but the metabolites generated by this pathway that engage with the Insulin secretion from β cells of the pancreatic islets of Langerhans controls metabolic homeostasis and is impaired in individuals with type 2 diabetes (T2D).…”