E-CBIL-28 - Transcription profiling of skeletal muscle from diabetic or non-diabetic Mexican Americans with or without a family history of diabetes
Released on 28 June 2007, last updated on 6 December 2011
Type 2 diabetes mellitus (DM) is characterized by insulin resistance and pancreatic beta-cell dysfunction. In high-risk subjects, the earliest detectable abnormality is insulin resistance in skeletal muscle. Impaired insulin-mediated signaling, gene expression, and glycogen synthesis, and accumulation of intramyocellular triglycerides have all been linked with insulin resistance, but no specific defect responsible for insulin resistance and DM has been identified in humans. To identify genes potentially important in the pathogenesis of DM, we analyzed gene expression in skeletal muscle from healthy metabolically characterized nondiabetic (family history negative and positive for DM) and diabetic Mexican-American subjects. We demonstrate that insulin resistance and DM associate with reduced expression of multiple nuclear respiratory factor-1 (NRF-1)-dependent genes encoding key enzymes in oxidative metabolism and mitochondrial function. While NRF-1 expression is decreased only in diabetic subjects, expression of both PPARg coactivator 1-alpha and -beta (PGC1-a/PPARGC1, and PGC1-b/PERC), coactivators of NRF-1 and PPARg-dependent transcription, is decreased in both diabetic subjects and family history positive nondiabetic subjects. Decreased PGC1 expression may be responsible for decreased expression of NRFdependent genes, leading to the metabolic disturbances characteristic of insulin resistance and DM.
transcription profiling by array, disease state, family history
Coordinated reduction of genes of oxidative metabolism in humans with insulin resistance and diabetes: Potential role of PGC1 and NRF1. Patti Mary Elizabeth, Butte Atul J, Crunkhorn Sarah, Cusi Kenneth, Berria Rachele, Kashyap Sangeeta, Miyazaki Yoshinori, Kohane Isaac, Costello Maura, Saccone Robert, Landaker Edwin J, Goldfine Allison B, Mun Edward, DeFronzo Ralph, Finlayson Jean, Kahn C Ronald, Mandarino Lawrence J.