title: 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.
authors.affiliation: Molecular Nutrition Unit and Montreal Diabetes Research Center, CRCHUM, and Departments of Nutrition, Biochemistry and Molecular Medicine, Université de Montréal, Montréal H2X 0A9, Canada.
authors.forename: Shangang
authors.initials: S
authors.lastname: Zhao
authors.affiliation: Molecular Nutrition Unit and Montreal Diabetes Research Center, CRCHUM, and Departments of Nutrition, Biochemistry and Molecular Medicine, Université de Montréal, Montréal H2X 0A9, Canada.
authors.forename: Yves
authors.initials: Y
authors.lastname: Mugabo
authors.affiliation: Molecular Nutrition Unit and Montreal Diabetes Research Center, CRCHUM, and Departments of Nutrition, Biochemistry and Molecular Medicine, Université de Montréal, Montréal H2X 0A9, Canada.
authors.forename: Jose
authors.initials: J
authors.lastname: Iglesias
authors.affiliation: Department of Medicine, University of Toronto, Toronto, Ontario M5S 1A8, Canada.
authors.forename: Li
authors.initials: L
authors.lastname: Xie
authors.affiliation: Molecular Nutrition Unit and Montreal Diabetes Research Center, CRCHUM, and Departments of Nutrition, Biochemistry and Molecular Medicine, Université de Montréal, Montréal H2X 0A9, Canada.
authors.forename: Viviane
authors.initials: V
authors.lastname: Delghingaro-Augusto
authors.affiliation: Molecular Nutrition Unit and Montreal Diabetes Research Center, CRCHUM, and Departments of Nutrition, Biochemistry and Molecular Medicine, Université de Montréal, Montréal H2X 0A9, Canada.
authors.forename: Roxane
authors.initials: R
authors.lastname: Lussier
authors.affiliation: Molecular Nutrition Unit and Montreal Diabetes Research Center, CRCHUM, and Departments of Nutrition, Biochemistry and Molecular Medicine, Université de Montréal, Montréal H2X 0A9, Canada.
authors.forename: Marie-Line
authors.initials: ML
authors.lastname: Peyot
authors.affiliation: Molecular Nutrition Unit and Montreal Diabetes Research Center, CRCHUM, and Departments of Nutrition, Biochemistry and Molecular Medicine, Université de Montréal, Montréal H2X 0A9, Canada.
authors.forename: Erik
authors.initials: E
authors.lastname: Joly
authors.affiliation: Department of Pathology and Cell Biology, Université de Montréal, Montréal H2X 0A9, Canada.
authors.forename: Bouchra
authors.initials: B
authors.lastname: Taïb
authors.affiliation: Section on Lipid Sciences, Department of Pathology, Wake Forest University School of Medicine, Medical Center Boulevard, Winston-Salem, NC 27157, USA.
authors.forename: Matthew A
authors.initials: MA
authors.lastname: Davis
authors.affiliation: Section on Lipid Sciences, Department of Pathology, Wake Forest University School of Medicine, Medical Center Boulevard, Winston-Salem, NC 27157, USA.
authors.forename: J Mark
authors.initials: JM
authors.lastname: Brown
authors.affiliation: Organization and Dynamics of Biological Membranes, UMR 5246 ICBMS, CNRS-Université Claude Bernard Lyon 1, Bâtiment Raulin, 43, boulevard du 11 novembre 1918, 69622 Villeurbanne, Cedex, France.
authors.forename: Abdelkarim
authors.initials: A
authors.lastname: Abousalham
authors.affiliation: Department of Medicine, University of Toronto, Toronto, Ontario M5S 1A8, Canada.
authors.forename: Herbert
authors.initials: H
authors.lastname: Gaisano
authors.affiliation: Molecular Nutrition Unit and Montreal Diabetes Research Center, CRCHUM, and Departments of Nutrition, Biochemistry and Molecular Medicine, Université de Montréal, Montréal H2X 0A9, Canada. Electronic address: murthy.madiraju@crchum.qc.ca.
authors.forename: S R Murthy
authors.initials: SR
authors.lastname: Madiraju
authors.affiliation: Molecular Nutrition Unit and Montreal Diabetes Research Center, CRCHUM, and Departments of Nutrition, Biochemistry and Molecular Medicine, Université de Montréal, Montréal H2X 0A9, Canada. Electronic address: marc.prentki@umontreal.ca.
authors.forename: Marc
authors.initials: M
authors.lastname: Prentki
mesh_terms: D000818:Animals; D019440:Anti-Obesity Agents / Q000494:pharmacology; D001713:Biphenyl Compounds / Q000494:pharmacology; D002219:Carbamates / Q000494:pharmacology; D002478:Cells, Cultured; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005947:Glucose / Q000378:metabolism*; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells; D007783:Lactones / Q000494:pharmacology; D008049:Lipase / Q000037:antagonists & inhibitors; D050356:Lipid Metabolism; D008066:Lipolysis; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008994:Monoacylglycerol Lipases / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics; D050178:Monoglycerides / Q000096:biosynthesis / Q000378:metabolism* / Q000494:pharmacology; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D000077403:Orlistat; D011485:Protein Binding; D034622:RNA Interference; D034741:RNA, Small Interfering; D051381:Rats; D017208:Rats, Wistar; D043882:Receptors, Cannabinoid / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D019440:Anti-Obesity Agents; D001713:Biphenyl Compounds; D002219:Carbamates; D004791:Enzyme Inhibitors; D007328:Insulin; D007783:Lactones; D050178:Monoglycerides; C584421:N-methyl-N-((3-(4-pyridinyl)phenyl)methyl)-4'-(aminocarbonyl)(1,1'-biphenyl)-4-yl ester, carbamic acid; D009419:Nerve Tissue Proteins; D034741:RNA, Small Interfering; D043882:Receptors, Cannabinoid; C503321:Unc13a protein, mouse; D000077403:Orlistat; C527261:ABHD6 protein, mouse; D008994:Monoacylglycerol Lipases; D008049:Lipase; D005947:Glucose