American Diabetes Association
mGPD Paper Diabetes Online Appendix 5-21-21.pdf (284.18 kB)

Metformin’s Therapeutic Action in the Treatment of Diabetes Does Not Involve Inhibition of Mitochondrial Glycerol Phosphate Dehydrogenase

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Version 2 2021-06-25, 21:56
Version 1 2021-04-13, 18:36
posted on 2021-06-25, 21:56 authored by Michael J. MacDonald, Israr-ul H. Ansari, Melissa J. Longacre, Scott W. Stoker
Mitochondrial glycerol phosphate dehydrogenase (mGPD) is the rate-limiting enzyme of the glycerol phosphate redox shuttle. It was recently claimed that metformin, a first line drug used for the treatment of type 2 diabetes, inhibits liver mGPD 30-50% suppressing gluconeogenesis through a redox mechanism. Various factors cast doubt on this idea. Total body100% knockout of mGPD in mice has adverse effects in several tissues where mGPD is high, but has little or no effect in liver where mGPD is the lowest of ten tissues. Metformin has beneficial effects in humans in tissues with high levels of mGPD such as pancreatic beta cells where mGPD is much higher than in liver. Insulin secretion in mGPD knockout mouse beta cells is normal because, like liver, beta cells possess the malate aspartate redox shuttle that’s redox action is redundant to the glycerol phosphate shuttle. For these and other reasons we used four different enzyme assays to reassess whether metformin inhibited mGPD. Metformin did not inhibit mGPD in homogenates or mitochondria from insulin cells or liver cells. If metformin actually inhibited mGPD, adverse effects in tissues where the level of mGPD is much higher than in liver could prevent metformin’s use as a diabetes medicine.


This work was supported by the Nowlin Family Trust of the InFaith Community Foundation and the estate of the late Ramona Garde.


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