Control of gluconeogenesis by metformin: does redox trump energy charge?

Abstract

Metformin is the most widely prescribed drug to lower glucose in type II diabetics, yet its mechanism of action remains controversial. A new study reveals that metformin inhibits mitochondrial glycerol-3-phosphate dehydrogenase, triggering reduction of the cytosolic NADH/NAD(+) pool and impaired utilization of redox-dependent substrates for gluconeogenesis (Madiraju et al., 2014).

Figure

Metformin inhibits mitochondrial Glycerol-3-phosphate dehydrogenase (mGPD), raising cytosolic NADH and blocking incorporation of lactate into glucose. A) If mGPD functions predominantly in the glycerophosphate shuttle (red box), inhibition by metformin will be expected to slow the removal of NADH, leading to an increase in the cytosolic NADH/NAD⁺ ratio that feeds back on lactate dehydrogenase (LDH). B) If flux from glycerol to glucose is significant (blue box), inhibition of mGPD by metformin may lead to accumulation of glycerol-3-phosphate (G-3-P) such that oxidation to dihydroxyacetone phosphate (DHAP) by cGPD becomes favorable. Whereas mGPD catalyzes this reaction by donating electrons directly to the electron transport chain, cGPD would concomitantly produce NADH, increasing the cytosolic NADH/NAD⁺ ratio, which would feed back on LDH. Note that the glycerophosphate shuttle catalyzes the net transfer of electrons from NADH to ubiquinone (Q) in the electron transport chain with regeneration of the intermediate dihydroxyacetone phosphate (DHAP) and G-3-P pools. Reverse flux through cGPD would not be expected in the absence of an external source of G-3-P or oxidation of the cytosolic NADH pool.