Monoacylglycerol as a metabolic coupling factor in glucose-stimulated insulin secretion

Insulin secretion by the pancreatic b-cell in response to post-prandial increase in blood glucose levels is an essential physiological process that is governed by cellular, nutritional and pathological factors. Other fuels including amino acids like leucine and glutamine and also fatty acids contribute to further augment insulin secretion. Failure to secrete adequate amount of insulin according to the changing demands of the body by b-cell is a key determinant of diabetes. The role played by the elevated Ca2+ influx and K+-ATP channels in insulin secretion is well known. Even though the precise mechanism of the lipid amplification of insulin secretion and the involved molecular signals are not clear, Glycerolipid/Free fatty acid (GL/FFA) cycle and its lipolytic segment have been recognized as essential components in the lipid amplification pathway of insulin secretion. Diacylglycerol produced by lipolysis was proposed as an important lipid amplification signal. However, hydrolysis of triglycerides and also of diacylglycerols is shown to be essential for glucose stimulated insulin secretion (GSIS), indicating a possible role for monoacylglycerol (MAG) in this process.   In the present study we demonstrate that the obliterated GSIS due to lipolysis inhibition in b-cells can be restored by providing exogenous MAG. In the b-cells MAG levels increase significantly in the presence of high glucose concentration and specific inhibition of the major MAG hydrolase, abhydrolase-6 (ABHD6), in b-cells and islets with WWL70 leads to accumulation of MAG with concomitant increase in insulin secretion. Lipidomics analysis indicated that the major MAG species that is elevated by high glucose as well as WWL70 addition 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 b-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 Ca2+ thereby promoting insulin granule exocytosis. Thus, AMG9810 was found to lower Ca2+ 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.

Keyphrases: MAG, ABHD6, TRPV1, Diabetes, Glucose-stimulated insulin secretion, Monoacylglycerol, ABHD6, TRPV1