Coordinated reduction of genes of oxidative metabolism in humans with insulin resistance and diabetes: Potential role of PGC1 and NRF1.
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.
Patti
Mary Elizabeth
ME
Research Division, Joslin Diabetes Center, Boston, MA 02215, USA. mary.elizabeth.patti@joslin.harvard.edu
Butte
Atul J
AJ
Crunkhorn
Sarah
S
Cusi
Kenneth
K
Berria
Rachele
R
Kashyap
Sangeeta
S
Miyazaki
Yoshinori
Y
Kohane
Isaac
I
Costello
Maura
M
Saccone
Robert
R
Landaker
Edwin J
EJ
Goldfine
Allison B
AB
Mun
Edward
E
DeFronzo
Ralph
R
Finlayson
Jean
J
Kahn
C Ronald
CR
Mandarino
Lawrence J
LJ
D000328:Adult; D001706:Biopsy; D002952:Citric Acid Cycle / Q000235:genetics; D004268:DNA-Binding Proteins / Q000502:physiology*; D003920:Diabetes Mellitus / Q000235:genetics / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics*; D005260:Female; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D006019:Glycolysis / Q000235:genetics; D006801:Humans; D007333:Insulin Resistance / Q000235:genetics*; D015227:Lipid Peroxidation / Q000235:genetics; D008297:Male; D017058:Mexican Americans / Q000235:genetics; D008875:Middle Aged; D018482:Muscle, Skeletal / Q000378:metabolism / Q000473:pathology; D051265:NF-E2-Related Factor 1; D051266:Nuclear Respiratory Factor 1; D051264:Nuclear Respiratory Factors; D009765:Obesity; D020411:Oligonucleotide Array Sequence Analysis; D010085:Oxidative Phosphorylation; D011236:Prediabetic State / Q000235:genetics* / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000502:physiology; D015534:Trans-Activators / Q000502:physiology*; D014157:Transcription Factors / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D014158:Transcription, Genetic
D004268:DNA-Binding Proteins; D051265:NF-E2-Related Factor 1; C495633:NRF1 protein, human; D051266:Nuclear Respiratory Factor 1; D051264:Nuclear Respiratory Factors; D018160:Receptors, Cytoplasmic and Nuclear; D015534:Trans-Activators; D014157:Transcription Factors; C111264:peroxisome-proliferator-activated receptor-gamma coactivator-1