期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 100, 期 14, 页码 8466-8471出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1032913100
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资金
- NCRR NIH HHS [RR-01346, M01 RR001346] Funding Source: Medline
- NHGRI NIH HHS [P01HG01323] Funding Source: Medline
- NHLBI NIH HHS [U01 HL066582, HL066582] Funding Source: Medline
- NIDDK NIH HHS [DK02526, DK06087, K12 DK063696, DK063696, R56 DK024092, R01 DK024092, DK47936, R01 DK047936, U24 DK058739, DK24092, R01 DK060837] Funding Source: Medline
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, 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 PPARgamma coactivator 1-alpha and-beta (PGC1-alpha/PPARGC1 and PGC1-beta/PERC), coactivators of NRF-1 and PPARgamma-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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