Journal
PHARMACOLOGICAL REPORTS
Volume 72, Issue 2, Pages 435-442Publisher
SPRINGER HEIDELBERG
DOI: 10.1007/s43440-019-00013-0
Keywords
Monoglyceride lipase; Proton pump inhibitors; Docking; Insulin resistance; Diabetes mellitus
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Funding
- Hamdi-Mango Center for Scientific Research at the University of Jordan
- Deanship of Scientific Research at the University of Jordan
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Background Currently, there is overwhelming evidence linking elevated plasma free fatty acids with insulin resistance and inflammation. Monoglyceride lipase (MGL) plays a crucial metabolic role in lipolysis by mediating the release of fatty acids. Therefore, inhibiting MGL should be a promising pharmacological approach for treating type 2 diabetes and inflammatory disorders. Proton pump inhibitors (PPIs) have been reported to improve glycemic control in type 2 diabetes albeit via largely unknown mechanism. Methods The anti-MGL bioactivities of three PPIs, namely, lansoprazole, rabeprazole, and pantoprazole, were investigated using docking experiments and in vitro bioassay. Results The three PPIs inhibited MGL in low micromolar range with rabeprazole exhibiting the best IC50 at 4.2 mu M. Docking experiments showed several binding interactions anchoring PPIs within MGL catalytic site. Conclusion Our study provides evidence for a new mechanism by which PPIs improve insulin sensitivity independent of serum gastrin. The three PPIs effectively inhibit MGL and, therefore, serve as promising leads for the development of new clinical MGL inhibitors.
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