Inhibition of monoglyceride lipase by proton pump inhibitors: investigation using docking and in vitro experiments.

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 IC ₅₀ at 4.2 µM. 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.