Monoacylglycerol as a Metabolic Coupling Factor in Glucose-Stimulated Insulin Secretion

Abstract

In the present study we demonstrate that the obliterated GSIS due to lipolysis inhibition incells can be restored by providing exogenous MAG. In the -cells MAG levels increase significantly in the presence of high glucose concentration and specific inhibition of the major MAG hydrolase, abhydrolase-6 (ABHD6), in -cells and islets with WWL70 leads to accumulation of MAG with concomitant increase in insulin secretion. Lipidomics analysis v indicated that the major MAG species that is elevated by high glucose as well as WWL70addition is 1-stearoylglycerol (1-SG). Exogenously added 1-SG and also 1-palmitoylglycerol(1-PG) strongly enhanced GSIS and this augmentation is not dependent on the generation of FFA by these MAGs. This indicates that MAG is a potential candidate for being the lipid signal for GSIS amplification. Further evidence for this was provided by the observation that overexpression of the MAG hydrolase ABHD6 in INS832/13 cells, resulted in decreased insulin secretion, probably owing to the lowered MAG level inside the -cells.Pharmacological studies using AMG9810, a specific antagonist of transient receptor potential vanilloid-1 (TRPV1) receptor that binds MAG, revealed that a blockade of TRPV1 strongly attenuated the MAG-augmented insulin secretion. Since MAG is a potential activator of TRPV1, it is likely that MAG binds on the inner surface of the cell membrane to TRPV1, which in turn triggers rapid influx of Ca 2+ thereby promoting insulin granule exocytosis. Thus, AMG9810 was found to lower Ca 2+ influx into dispersed rat islet cells that was induced by high glucose and also WWL70.These results collectively suggest that MAG is the potential mediator of the lipid amplification of glucose-stimulated insulin secretion. Our results also indicate that pharmacological intervening at the ABHD6 hydrolysis step enhances insulin secretion; this enzyme protein can be a promising thrapeutic target for the development of anti-diabetic drugs that promote insulin secretion.

Classical endocannabinoid‐like compounds and their regulation by nutrients

“…The full hydrolysis is accomplished by the combined action of adipose triacylglycerol lipase (ATGL), hormone sensitive lipase (HSL), and monoacylglycerol lipase (MAGL), and to our knowledge there are no reports of triacylglycerol derived monoacylglycerol signaling in adipose tissue. However, in the intestine and pancreas, there is emerging evidence that nonendocannabinoid 2‐MAGs may be involved in metabolic homeostasis .…”

“…In cell types with sparse triacylglycerol storage like those of the brain, 2‐MAGs are intermediates of phospholipid turnover, and consequently they have the potential to exert signaling functions of their own or interfere with the signaling of structurally related compounds like the endocannabinoid, 2‐AG. The signaling properties of 2‐AG in nervous tissue is widely studied, but only recently focus has been aimed at the signaling properties of other 2‐monacylglycerols and their potential roles in various tissues . In brain tissue the main pool of 2‐AG probably originates from hydrolysis of membrane associated phosphoinositides by action of phospholipase C (PLC) and membrane associated diacylglycerol lipases (DAGLα and β) .…”