If Metformin Inhibited the Mitochondrial Glycerol Phosphate Dehydrogenase It Might Not Benefit Diabetes

Abstract

The mitochondrial glycerol phosphate dehydrogenase is the rate-limiting enzyme of the glycerol phosphate shuttle. It was recently claimed that metformin, a first line drug used worldwide for the treatment of type 2 diabetes, works by inhibiting the mitochondrial glycerol phosphate dehydrogenase 30-50% thus suppressing hepatic gluconeogenesis. This enzyme is 30-60 fold higher in the pancreatic islet than in liver. If metformin actually inhibited the enzyme, why would it not inhibit insulin secretion and exacerbate diabetes? Total body knockout of the mitochondrial glycerol phosphate dehydrogenase does not inhibit insulin secretion because insulin cells and liver cells possess the malate aspartate shuttle that is redundant to the action of the glycerol phosphate shuttle. In view of these and other apparent inconsistencies we reassessed the idea that metformin inhibited the mitochondrial glycerol phosphate dehydrogenase. We measured the enzymes activity in whole cell homogenates and mitochondria of insulin cells and liver cells using four different enzyme assays and were unable to show that metformin directly inhibits the enzyme. We conclude that metformin does not actually inhibit the enzyme. If it did, it might not be efficacious as a diabetes medicine.