Insulin Resistance: Molecular Mechanism

Insulin resistance in skeletal muscle is present in humans with type 2 diabetes (non-insulin dependent diabetes mellitus) and obesity and in rodents with these disorders. Malonyl CoA is a regulator of carnitine palmitoyl transferase l (CAP I), the enzyme that controls the transfer of long chain fatty acyl CoA into mitochondria, where it is oxidized. In rat skeletal muscle, the formation of malonyl CoA is regulated acutely (in minutes) by changes in the activity of acetyl CoA carboxylase (ACC), the enzyme that catalyzes malonyl CoA synthesis and is a source of its precursor, cytosolic acetyI CoA. Increase in cytosolic citrate leading to an increase in the concentration of malonyl CoA, occur when muscle is presented with insulin and glucose, or when it is made inactive by denervation. In contrast, exercise lowers the concentration of malonyl CoA by activating an AMP – activated protein kinase, which phosphorylates and inhibits ACC. A numbers of reports have linked sustained increases in the concentration of malonyl CoA in muscle to insulin resistance. In this paper, we review these reports, as well all the notion that changes in malonyl CoA contributed to the increases in long chain fatty acyl CoA (LCFA CoA), diacyglycerol and triglyceride contest and changes in protein kinase C activity, observed in insulin resistant muscle. It is our hypothesis that dysregulation of the malonyl CoA regulatory mechanism, if it leads to sustained increases in the concentration of malonyl CoA and cytosolic LCFA CoA, could pay a key role in the pathogenesis of insulin resistance in muscle.