TY - JOUR
T1 - Coordinated reduction of genes of oxidative metabolism in humans with insulin resistance and diabetes
T2 - Potential role of PGC1 and NRF1
AU - Patti, Mary Elizabeth
AU - Butte, Atul J.
AU - Crunkhorn, Sarah
AU - Cusi, Kenneth
AU - Berria, Rachele
AU - Kashyap, Sangeeta
AU - Miyazaki, Yoshinori
AU - Kohane, Isaac
AU - Costello, Maura
AU - Saccone, Robert
AU - Landaker, Edwin J.
AU - Goldfine, Allison B.
AU - Mun, Edward
AU - DeFronzo, Ralph
AU - Finlayson, Jean
AU - Kahn, C. Ronald
AU - Mandarino, Lawrence J.
PY - 2003/7/8
Y1 - 2003/7/8
N2 - 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.
AB - 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.
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U2 - 10.1073/pnas.1032913100
DO - 10.1073/pnas.1032913100
M3 - Article
C2 - 12832613
AN - SCOPUS:0037477855
SN - 0027-8424
VL - 100
SP - 8466
EP - 8471
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 14
ER -