What is it about?
Metformin, a medicine that has been used to treat millions of patients with type 2 diabetes, lowers blood glucose by suppressing liver glucose production. Recently it was claimed that metformin’s mechanism of action is due to a 30-50% inhibition of mitochondrial glycerol phosphate dehydrogenase (mGPD). For a number of reasons, we questioned whether a relatively weak inhibition of mGPD could be the mechanism of metformin’s action. mGPD is the rate limiting enzyme of the glycerol phosphate (GP) redox shuttle. The enzyme activity of mGPD in liver is the lowest of ten body tissues and metformin has beneficial effects in tissues where the activity of mGPD is much higher than liver, including the pancreatic insulin-producing beta cells, skeletal muscle and brown fat. Total body 100% knockout of mGPD in mice has no effect in liver where the action of the malate aspartate redox shuttle is redundant to and much more active than the GP shuttle. Knockout of mGPD does have adverse effects in tissues where mGPD is very high and where the malate aspartate shuttle is low or absent such as skeletal muscle and brown fat. Complete absence of the GP shuttle in the mGPD knockout mouse does not interfere with insulin secretion by the pancreatic beta cell because the malate aspartate redox shuttle is also active in the beta cell. Because of skepticism about metformin inhibiting mGPD, we used four different enzyme assay procedures to measure mGPD activity in liver and also in the beta cell that has a very high level of mGPD. Metformin in micromolar concentrations to millimolar concentrations 100-fold its therapeutic concentration did not inhibit mGPD in either tissue whatsoever (MacDonald, MJ et al, Metformin’s Therapeutic Action in the Treatment of Diabetes Does Not Involve Inhibition of Mitochondrial Glycerol Phosphate Dehydrogenase Diabetes. Diabetes. 2021 April 13:db201143. doi: 10.2337/db20-1143. Online ahead of print. PMID: 33849997).
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Why is it important?
It is fortunate that metformin does not inhibit mGPD. If metformin did inhibit mGPD, it would be harmful to tissues where mGPD is much higher than in liver and preclude its use as a diabetes medicine.
Perspectives
My laboratory has been studying mGPD and the malate aspartate shuttle and other metabolic shuttles in the pancreatic insulin cell since 1979. We have more than 30 manuscripts on these shuttles. Pathways that involve these shuttles are important for normal insulin secretion by the pancreatic insulin cell and the function of many other body tissues including skeletal muscle, brown fat ( a tissue that keeps the body warm) and sperm where mGPD is also very high. Inhibition of the glycerol phosphate shuttle by metformin, if it actually occurred, would make it impossible for metformin’s use as a diabetes medicine. It could also contribute to sterility in males.
Michael MacDonald
University of Wisconsin School of Medicine and Public Health
Read the Original
This page is a summary of: Metformin’s Therapeutic Efficacy in the Treatment of Diabetes Does Not Involve Inhibition of Mitochondrial Glycerol Phosphate Dehydrogenase, Diabetes, April 2021, American Diabetes Association,
DOI: 10.2337/db20-1143.
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