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. 2003 Jul 8;100(14):8466-71.
doi: 10.1073/pnas.1032913100. Epub 2003 Jun 27.

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

Mary Elizabeth Patti  1 , 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
Affiliations

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

Mary Elizabeth Patti et al. Proc Natl Acad Sci U S A. .

Abstract

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 PPAR gamma coactivator 1-alpha and-beta (PGC1-alpha/PPARGC1 and PGC1-beta/PERC), coactivators of NRF-1 and PPAR gamma-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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Figures

Fig. 1.
Fig. 1.
(A) Expression of many oxidative metabolism genes is reduced in FH+ insulin-resistant nondiabetic and type 2 DM subjects. Hierarchical clustering was performed (genespring, algorithm similar to that of Eisen et al. (51) by using glycolysis, tricarboxylic acid cycle, and electron transport gene groups (genmapp). Genes known to be regulated by NRF transcription in humans or rodents are indicated by an asterisk. Colors represent gene expression values in individual subject expression changes relative to the mean (normalized to 1 for each gene), with red and green representing decreases or increases in expression, respectively by >50%. (B) Expression of genes regulated by NRF transcription is decreased in FH+ and DM2. The gene tree was created by compiling a list of NRF-regulated genes (52) as in A.
Fig. 2.
Fig. 2.
Decreases in transcription factor NRF-1 and coactivator PGC1 expression contribute to reductions in oxidative gene expression. (A) Expression of NRF-1 (quantitative PCR), is decreased in DM (*, P = 0.01 vs. FH- controls). (B) PGC1α expression (PCR) is reduced in prediabetic FH+ (34% reduction, P = 0.001 vs. FH-) and DM (36% decrease, P = 0.0009 vs. FH-). (C) PGC1β expression (PCR) is reduced in prediabetic FH+ (45% reduction, P = 0.045 vs. FH-) and DM (46% decrease, P = 0.01 vs. FH-).
Fig. 3.
Fig. 3.
Representative metabolic and expression correlates. (A) PGC1α expression correlates with that of pyruvate dehydrogenase (PDHA) (r = 0.81, P < 0.0001). (B) The complex III subunit UQCRH correlates inversely with BMI (r = -0.70, P = 0.0002).
Fig. 4.
Fig. 4.
Proposed contribution of PGC1 and NRF-1 to expression and metabolic phenotype of insulin resistance and type 2 DM.
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