Activation of the AMP-activated Protein Kinase by the Anti-diabetic Drug Metformin in Vivo ROLE OF MITOCHONDRIAL REACTIVE NITROGEN SPECIES

摘要: Metformin, one of the most commonly used drugs for treatment type II diabetes, was recently found to exert its therapeutic effects, at least in part, by activating AMP-activated protein kinase (AMPK). However, site action, as well mechanism activate AMPK, remains elusive. Here we report how metformin activates AMPK. In cultured bovine aortic endothelial cells, dose-dependently activated AMPK parallel with increased detection reactive nitrogen species (RNS). Further, either depletion mitochondria or adenoviral overexpression superoxide dismutases, inhibition nitric-oxide synthase, abolished metformin-enhanced phosphorylations and activities implicating that activation might be mediated mitochondria-derived RNS. Furthermore, administration metformin, which 3-nitrotyrosine staining hearts C57BL6, resulted aorta C57BL6 mice but not those synthase (eNOS) knockout had no effect on staining. Because eNOS expressed normal levels AMPK-α 5-aminoimidazole-4-carboxamide riboside, an agonist, these data indicate RNS generated is required vivo. addition, significantly co-immunoprecipitation upstream kinase, LKB1, administered Using pharmacological genetic inhibitors, c-Src PI3K enhanced metformin. We conclude RNS, c-Src/PI3K pathway generate a metabolite other molecule inside cell promote LKB1 complex.