Coordinated patterns of gene expression for substrate and energy metabolism in skeletal muscle of diabetic mice.
Metabolic abnormalities underlying diabetes are primarily the result of the lack of adequate insulin action and the associated changes in protein phosphorylation and gene expression. To define the full set of alterations in gene expression in skeletal muscle caused by diabetes and the loss of insulin action, we have used Affymetrix oligonucleotide microarrays and streptozotocin-diabetic mice. Of the genes studied, 235 were identified as changed in diabetes, with 129 genes up-regulated and 106 down-regulated. Analysis revealed a coordinated regulation at key steps in glucose and lipid metabolism, mitochondrial electron transport, transcriptional regulation, and protein trafficking. mRNAs for all of the enzymes of the fatty acid beta-oxidation pathway were increased, whereas those for GLUT4, hexokinase II, the E1 component of the pyruvate dehydrogenase complex, and subunits of all four complexes of the mitochondrial electron transport chain were all coordinately down-regulated. Only about half of the alterations in gene expression in diabetic mice could be corrected toward normal after 3 days of insulin treatment and euglycemia. These data point to as of yet undefined mechanisms for highly coordinated regulation of gene expression by insulin and potential new targets for therapy of diabetes mellitus.
Yechoor
Vijay K
VK
Joslin Diabetes Center and Department of Medicine, Harvard Medical School, One Joslin Place, Boston, MA 02215, USA.
Patti
Mary-Elizabeth
ME
Saccone
Robert
R
Kahn
C Ronald
CR
D000251:Adenosine Triphosphatases / Q000235:genetics; D000818:Animals; D001692:Biological Transport; D050260:Carbohydrate Metabolism; D002352:Carrier Proteins; D003546:Cysteine Endopeptidases / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000235:genetics*; D042967:Electron Transport Complex I; D042963:Electron Transport Complex II; D014450:Electron Transport Complex III / Q000235:genetics; D003576:Electron Transport Complex IV / Q000235:genetics; D004734:Energy Metabolism; D015870:Gene Expression; D020869:Gene Expression Profiling; D005959:Glucosidases; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins / Q000235:genetics; D051379:Mice; D025261:Mitochondrial Proton-Translocating ATPases; D009097:Multienzyme Complexes / Q000235:genetics / Q000378:metabolism; D018482:Muscle, Skeletal / Q000378:metabolism*; D000076250:Myristoylated Alanine-Rich C Kinase Substrate; D009247:NADH, NADPH Oxidoreductases / Q000235:genetics; D010088:Oxidoreductases / Q000235:genetics; D010750:Phosphoproteins / Q000235:genetics; D011347:Procollagen / Q000235:genetics; D046988:Proteasome Endopeptidase Complex; D013311:Streptozocin / Q000009:adverse effects; D013385:Succinate Dehydrogenase / Q000235:genetics
D002352:Carrier Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D009097:Multienzyme Complexes; D010750:Phosphoproteins; C512949:Prkcsh protein, mouse; D011347:Procollagen; D000076250:Myristoylated Alanine-Rich C Kinase Substrate; D013311:Streptozocin; D010088:Oxidoreductases; D042963:Electron Transport Complex II; D013385:Succinate Dehydrogenase; D009247:NADH, NADPH Oxidoreductases; D003576:Electron Transport Complex IV; D005959:Glucosidases; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex; D000251:Adenosine Triphosphatases; D025261:Mitochondrial Proton-Translocating ATPases; D042967:Electron Transport Complex I; D014450:Electron Transport Complex III; C020439:oligomycin sensitivity-conferring protein