Version 2 2021-06-25, 21:56Version 2 2021-06-25, 21:56
Version 1 2021-04-13, 18:36Version 1 2021-04-13, 18:36
figure
posted on 2021-06-25, 21:56authored byMichael 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.
Funding
This work was supported by the Nowlin Family Trust of the InFaith Community Foundation and the estate of the late Ramona Garde.