P 106 - Targeting of O2●-/NO ratio as a strategy to improve energy metabolism in diabetes

Abstract

Redox homeostasis disturbance, mainly caused by increased O 2 •– level and/or decreased NO bioavailability, represents an important contributing factor in the (ethio)pathology of diabetes. We examined whether targeting of O 2 •– /NO ratio by two redox-modulating compounds, L-arginine (substrate for NO synthases) and Mn(II) pentaazamacrocyclic mimics of SOD, could improve diabetic state and associated impairment of energy metabolism. Multiple beneficial effects of L-arginine and SOD mimics in alloxan-induced diabetes were observed. First of all, acting directly on pancreas, L-arginine and SOD mimic induce β-cells regeneration. In skeletal muscle, those treatments restore diabetes-induced impairment in mitochondrial energy metabolism (OXPHOS) and glucose transport (GLUT4) by targeting AMPKα signaling. Similarly, SOD mimic improves energy metabolism in hippocampus of diabetic rats. L-arginine and SOD mimic stabilize diabetes-induced redox disbalance in diabetic skin acting on NO producing (NOS) and O 2 •– /H 2 O 2 removing (MnSOD and GPx) systems. The data suggest that fine settings of O 2 •– /NO ratio by L-arginine and SOD mimic could have beneficial implications for several pathological hallmarks of diabetes: impaired insulin synthesis and sensitivity as well as accompanying metabolic complications and speak in favor of therapeutic potential of these redox-active agents in diabetic conditions.