title: Inhibition of Monoacylglycerol Lipase Activity Decreases Glucose-Stimulated Insulin Secretion in INS-1 (832/13) Cells and Rat Islets.
abstract: Lipid signals derived from lipolysis and membrane phospholipids play an important role in glucose-stimulated insulin secretion (GSIS), though the exact secondary signals remain unclear. Previous reports have documented a stimulatory role of exogenously added mono-acyl-glycerol (MAG) on insulin secretion from cultured β-cells and islets. In this report we have determined effects of increasing intracellular MAG in the β-cell by inhibiting mono-acyl-glycerol lipase (MGL) activity, which catalyzes the final step in triacylglycerol breakdown, namely the hydrolysis of MAG to glycerol and free fatty acid (FA). To determine the role of MGL in GSIS, we used three different pharmacological agents (JZL184, MJN110 and URB602). All three inhibited GSIS and depolarization-induced insulin secretion in INS-1 (832/13). JZL184 significantly inhibited both GSIS and depolarization-induced insulin secretion in rat islets. JZL184 significantly decreased lipolysis and increased both mono- and diacyglycerol species in INS-1 cells. Analysis of the kinetics of GSIS showed that inhibition was greater during the sustained phase of secretion. A similar pattern was observed in the response of Ca2+ to glucose and depolarization but to a lesser degree suggesting that altered Ca2+ handling alone could not explain the reduction in insulin secretion. In addition, a significant reduction in long chain-CoA (LC-CoA) was observed in INS-1 cells at both basal and stimulatory glucose following inhibition of MGL. Our data implicate an important role for MGL in insulin secretion.
authors: Department of Medicine, Obesity Research Center, Boston University School of Medicine, Boston, Massachusetts, United States of America.
authors: Charles A
authors: CA
authors: Berdan
authors: Department of Medicine, Obesity Research Center, Boston University School of Medicine, Boston, Massachusetts, United States of America.
authors: Karel A
authors: KA
authors: Erion
authors: Department of Medicine, Obesity Research Center, Boston University School of Medicine, Boston, Massachusetts, United States of America.
authors: Nathan E
authors: NE
authors: Burritt
authors: Department of Medicine, Obesity Research Center, Boston University School of Medicine, Boston, Massachusetts, United States of America.
authors: Barbara E
authors: BE
authors: Corkey
authors: Department of Medicine, Obesity Research Center, Boston University School of Medicine, Boston, Massachusetts, United States of America.
authors: Jude T
authors: JT
authors: Deeney
mesh_terms: D000818:Animals; D052117:Benzodioxoles / Q000737:chemistry; D001713:Biphenyl Compounds / Q000737:chemistry; D002118:Calcium / Q000737:chemistry / Q000378:metabolism; D002219:Carbamates / Q000737:chemistry; D002460:Cell Line; D005227:Fatty Acids / Q000737:chemistry; D005230:Fatty Acids, Nonesterified / Q000378:metabolism; D005947:Glucose / Q000378:metabolism*; D005990:Glycerol / Q000737:chemistry / Q000378:metabolism; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000166:cytology; D007515:Islets of Langerhans / Q000166:cytology; D007700:Kinetics; D008055:Lipids / Q000737:chemistry; D008066:Lipolysis; D008297:Male; D008994:Monoacylglycerol Lipases / Q000037:antagonists & inhibitors*; D010743:Phospholipids / Q000737:chemistry / Q000378:metabolism; D010880:Piperidines / Q000737:chemistry; D051381:Rats; D017207:Rats, Sprague-Dawley; D013388:Succinimides / Q000737:chemistry
chemical_list: D052117:Benzodioxoles; D001713:Biphenyl Compounds; D002219:Carbamates; D005227:Fatty Acids; D005230:Fatty Acids, Nonesterified; D007328:Insulin; C534333:JZL 184; D008055:Lipids; C587715:MJN110; D010743:Phospholipids; D010880:Piperidines; D013388:Succinimides; C501835:URB602; D008994:Monoacylglycerol Lipases; D005947:Glucose; D005990:Glycerol; D002118:Calcium