Activation of AMP-activated protein kinase reduces hyperglycemia-induced mitochondrial reactive oxygen species production and promotes mitochondrial biogenesis …

D Kukidome, T Nishikawa, K Sonoda, K Imoto… - Diabetes, 2006 - Am Diabetes Assoc
D Kukidome, T Nishikawa, K Sonoda, K Imoto, K Fujisawa, M Yano, H Motoshima, T Taguchi…
Diabetes, 2006Am Diabetes Assoc
We previously proposed that the production of hyperglycemia-induced mitochondrial
reactive oxygen species (mtROS) is a key event in the development of diabetes
complications. The association between the pathogenesis of diabetes and its complications
and mitochondrial biogenesis has been recently reported. Because metformin has been
reported to exert a possible additional benefit in preventing diabetes complications, we
investigated the effect of metformin and 5-aminoimidazole-4-carboxamide ribonucleoside …
We previously proposed that the production of hyperglycemia-induced mitochondrial reactive oxygen species (mtROS) is a key event in the development of diabetes complications. The association between the pathogenesis of diabetes and its complications and mitochondrial biogenesis has been recently reported. Because metformin has been reported to exert a possible additional benefit in preventing diabetes complications, we investigated the effect of metformin and 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR) on mtROS production and mitochondrial biogenesis in cultured human umbilical vein endothelial cells. Treatment with metformin and AICAR inhibited hyperglycemia-induced intracellular and mtROS production, stimulated AMP-activated protein kinase (AMPK) activity, and increased the expression of peroxisome proliferator–activated response-γ coactivator-1α (PGC-1α) and manganese superoxide dismutase (MnSOD) mRNAs. The dominant negative form of AMPKα1 diminished the effects of metformin and AICAR on these events, and an overexpression of PGC-1α completely blocked the hyperglycemia-induced mtROS production. In addition, metformin and AICAR increased the mRNA expression of nuclear respiratory factor-1 and mitochondrial DNA transcription factor A (mtTFA) and stimulated the mitochondrial proliferation. Dominant negative–AMPK also reduced the effects of metformin and AICAR on these observations. These results suggest that metformin normalizes hyperglycemia-induced mtROS production by induction of MnSOD and promotion of mitochondrial biogenesis through the activation of AMPK-PGC-1α pathway.
Am Diabetes Assoc