TY - JOUR
T1 - α/β-Hydrolase Domain-6-accessible monoacylglycerol controls glucose-stimulated insulin secretion
AU - Zhao, Shangang
AU - Mugabo, Yves
AU - Iglesias, Jose
AU - Xie, Li
AU - Delghingaro-Augusto, Viviane
AU - Lussier, Roxane
AU - Peyot, Marie Line
AU - Joly, Erik
AU - Taïb, Bouchra
AU - Davis, Matthew A.
AU - Brown, J. Mark
AU - Abousalham, Abdelkarim
AU - Gaisano, Herbert
AU - Madiraju, S. R.Murthy
AU - Prentki, Marc
N1 - Funding Information:
This work was supported by grants from the Canadian Institutes of Health Research (M.P. and S.R.M.M.). M.P. holds the Canada Research Chair in Diabetes and Metabolism. H.G. is supported by grants from the Canadian Institutes of Health Research. S.Z. was supported by studentships from Diabète Québec and the Montreal Diabetes Research Center. Y.M. was supported by studentships from the Fonds de Recherche Québec-Santé, the department of Nutrition of Université de Montréal, and Diabète Québec, and B.T. received a fellowship from Diabète Québec. We thank Robert Zimmermann, Christopher Nolan, Vincent Poitout, Robert Farese, Jr., and Stephanie Fulton for critical review of the manuscript. We thank Dr. Thierry Alquier for his advice for isolation of hypothalamic regions and Dr. Josep Rizo, University of Texas, for a gift of Munc13-1-C1-GST expression plasmid.
PY - 2014/6/3
Y1 - 2014/6/3
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84902270757&partnerID=8YFLogxK
U2 - 10.1016/j.cmet.2014.04.003
DO - 10.1016/j.cmet.2014.04.003
M3 - Article
C2 - 24814481
AN - SCOPUS:84902270757
SN - 1550-4131
VL - 19
SP - 993
EP - 1007
JO - Cell Metabolism
JF - Cell Metabolism
IS - 6
ER -
