Tissue-specific overexpression of lipoprotein lipase causes tissue-specific insulin resistance

Insulin resistance in skeletal muscle and liver may play a primary role in the development of type 2 diabetes mellitus, and the mechanism by which ins ulin resistance occurs may be related to alterations in fat metabolism. Tra nsgenic mice with muscle- and liver-specific overexpression of lipoprotein lipase were studied during a 2-h hyperinsulinemic-euglycemic clamp to deter mine the effect of tissue-specific increase in fat on insulin action and si gnaling. Muscle-lipoprotein lipase mice had a 3-fold increase in muscle tri glyceride content and were insulin resistant because of decreases in insuli n-stimulated glucose uptake in skeletal muscle and insulin activation of in sulin receptor substrate-l-associated phosphatidylinositol 3-kinase activit y. In contrast, liver-lipoprotein lipase mice had a 2-fold increase in live r triglyceride content and were insulin resistant because of impaired abili ty of insulin to suppress endogenous glucose production associated with def ects in insulin activation of insulin receptor substrate-2-associated phosp hatidylinositol 3-kinase activity. These defects in insulin action and sign aling were associated with increases in intracellular fatty acid-derived me tabolites (i.e.. diacylglycerol, fatty acyl CoA, ceramides). Our findings s uggest a direct and causative relationship between the accumulation of intr acellular fatty acid-derived metabolites and insulin resistance mediated vi a alterations in the insulin signaling pathway, independent of circulating adipocyte-derived hormones.