Coordinated reduction of genes of oxidative metabolism in humans with insulin resistance and diabetes: Potential role of PGC1 and NRF1

Mary Elizabeth Patti, Atul J. Butte, Sarah Crunkhorn, Kenneth Cusi, Rachele Berria, Sangeeta Kashyap, Yoshinori Miyazaki, Isaac Kohane, Maura Costello, Robert Saccone, Edwin J. Landaker, Allison B. Goldfine, Edward Mun, Ralph DeFronzo, Jean Finlayson, C. Ronald Kahn, Lawrence J. Mandarino

Research output: Contribution to journalArticle

1457 Scopus citations

Abstract

Type 2 diabetes mellitus (DM) is characterized by insulin resistance and pancreatic cell dysfunction. In high-risk subjects, the earliest detectable abnormality is insulin resistance in skeletal muscle. Impaired insulin-mediated signaling, gene expression, 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. Although NRF-1 expression is decreased only in diabetic subjects, expression of both PPARγ coactivator 1-α and-β (PGC1-α/PPARGC1 and PGC1-β/PERC), coactivators of NRF-1 and PPARγ-dependent transcription, is decreased in both diabetic subjects and family history-positive nondiabetic subjects. Decreased PGC1 expression may be responsible for decreased expression of NRF-dependent genes, leading to the metabolic disturbances characteristic of insulin resistance and DM.

Original languageEnglish (US)
Pages (from-to)8466-8471
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume100
Issue number14
DOIs
StatePublished - Jul 8 2003
Externally publishedYes

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    Patti, M. E., Butte, A. J., Crunkhorn, S., Cusi, K., Berria, R., Kashyap, S., Miyazaki, Y., Kohane, I., Costello, M., Saccone, R., Landaker, E. J., Goldfine, A. B., Mun, E., DeFronzo, R., Finlayson, J., Kahn, C. R., & Mandarino, L. J. (2003). Coordinated reduction of genes of oxidative metabolism in humans with insulin resistance and diabetes: Potential role of PGC1 and NRF1. Proceedings of the National Academy of Sciences of the United States of America, 100(14), 8466-8471. https://doi.org/10.1073/pnas.1032913100