REACTIVE OXYGEN SPECIES (ROS), MITOCHONDRIAL DYSFUNCTION AND T2D (PROT 1)

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Type 2 diabetes mellitus (T2DM) is an insulin resistant state characterized by hyperglycemia, elevated plasma FFA levels, and excessive lipid accumulation in insulin target tissues (muscle and live) and in beta cells. Elevated plasma FFA/intracellular lipid content exerts deleterious effects on muscle insulin sensitivity and beta cell function and this has been referred to a "lipotoxicity". We and others have demonstrated decreased expression of multiple mitochondrial genes involved in oxidative phosphorylation and the Krebs cycle in skeletal muscle from T2DM and genetically predisposed, insulin resistant mitochondrial gene expression observed in T2DM. We postulate that there is a self perpetuating negative feedback cycle whereby a mitochondrial defect (genetic or acquired) leads to impaired FACoA oxidation and increased generation of ROS. The resultant increases in cyctosolic FACoA and ROS, through activation of inflammatory pathways (NF-kB, p38 MAPK, JNK), causes serine phosphorylation of key elements of the insulin signaling cascade causing insulin resistance. "Glucotoxicity" also has been implicated in the development of muscle insulin resistance and progressive beta cell failure in T2DM. In humans a chronic physiologic increase in plasma glucose or glucosamine causes insulin resistance in muscle and, in rodents, glucosamine infusion impairs mitochondrial gene expression, inhibits oxidative phosphorylation, and reduces basal energy expenditure. We postulate that chronic glucose overload of cells, like chronic lipid overload, leads to increased ROS generation and activation of inflammatory pathways that inhibit insulin signaling. In the present study we shall examine: (1) the role of mitochondrial dysfunction, increased generation of ROS/RNS, and oxidative stress-activation of inflammatory pathways in the development of impaired muscle insulin signaling and insulin resistance in lean and obese type 2 diabetic individuals, in the normal-glucose-tolerant insulin-resistant offspring of two diabetic parents, and in obese normal-glucose-tolerant individuals; (2) the effect of chronic (3 day) infusion of lipid alone (to double plasma FFA), glucosamine (and glucose) alone, and glucosamine (and glucose) plus lipid on muscle mitochondrial function, generation of ROS/RNS, stress-activated inflammatory pathways, insulin signaling and insulin sensitivity in healthy subjects; (3) whether treatment with a PPAR-y agonist (pioglitazone) or an antioxidant (alpha lipoic acid) can amerliorate mitochondrial dysfunction, reduce the generation of ROS/RNS, inhibit stress-activated inflammatory pathways, improve insulin signaling, reverse insulin resistance, and enhance beta cell function in T2DM patients and in normal glucose-tolerant, insulin resistant offspring.