Microarray Profiling of Human Skeletal Muscle Reveals That Insulin Regulates ∼800 Genes during a Hyperinsulinemic Clamp

Insulin action in target tissues involved precise regulation of gene expression. To define the set of insulin-regulated genes in human skeletal muscle, we analyzed the global changes in mRNA levels during a 3-h hyperinsulinemic euglycemic clamp in vastus lateralis muscle of six healthy subjects. Using 29,308 cDNA element microarrays, we found that the mRNA expression of 762 genes, including 353 expressed sequence tags, was significantly modified during insulin infusion. 478 were up-regulated and 284 down-regulated. Most of the genes with known function are novel targets of insulin. They are involved in the transcriptional and translational regulation (29%), intermediary and energy metabolisms (14%), intracellular signaling (12%), and cytoskeleton and vesicle traffic (9%). Other categories consisted of genes coding for receptors, carriers, and transporters (8%), components of the ubiquitin/proteasome pathways (7%) and elements of the immune response (5.5%). These results thus define a transcriptional signature of insulin action in human skeletal muscle. They will help to better define the mechanisms involved in the reduction of insulin effectiveness in pathologies such as type 2 diabetes mellitus, a disease characterized by defective regulation of gene expression in response to insulin. Insulin action in target tissues involved precise regulation of gene expression. To define the set of insulin-regulated genes in human skeletal muscle, we analyzed the global changes in mRNA levels during a 3-h hyperinsulinemic euglycemic clamp in vastus lateralis muscle of six healthy subjects. Using 29,308 cDNA element microarrays, we found that the mRNA expression of 762 genes, including 353 expressed sequence tags, was significantly modified during insulin infusion. 478 were up-regulated and 284 down-regulated. Most of the genes with known function are novel targets of insulin. They are involved in the transcriptional and translational regulation (29%), intermediary and energy metabolisms (14%), intracellular signaling (12%), and cytoskeleton and vesicle traffic (9%). Other categories consisted of genes coding for receptors, carriers, and transporters (8%), components of the ubiquitin/proteasome pathways (7%) and elements of the immune response (5.5%). These results thus define a transcriptional signature of insulin action in human skeletal muscle. They will help to better define the mechanisms involved in the reduction of insulin effectiveness in pathologies such as type 2 diabetes mellitus, a disease characterized by defective regulation of gene expression in response to insulin. expressed sequence tag reverse transcription cAMP-response element-binding protein (CREB)-binding protein solubleN-ethylmaleimide factor attachment protein receptor insulin receptor substrate Insulin is an anabolic hormone that exerts a wide spectrum of effects and modulates a variety of biological processes and metabolic pathways such as glucose and lipid metabolism, protein synthesis and degradation, cell growth and differentiation, and DNA synthesis. To perform these actions insulin modifies the activity and the subcellular location of key regulatory enzymes and proteins, often by affecting their phosphorylation state (1Cheatham B. Kahn C.R. Endocr. Rev. 1995; 16: 117-142Crossref PubMed Google Scholar). Furthermore, insulin also controls the amount of numerous proteins, in part by acting at the level of mRNA translation and mainly at the level of their gene expression (2O'Brien R.M. Granner D.K. Physiol. Rev. 1996; 76: 1109-1161Crossref PubMed Scopus (438) Google Scholar). Over the past 15 years, the regulation of gene expression by insulin has been recognized as a major effect of the hormone, and about 150 insulin-regulated genes have been reported (2O'Brien R.M. Granner D.K. Physiol. Rev. 1996; 76: 1109-1161Crossref PubMed Scopus (438) Google Scholar). However, the identification of insulin-regulated genes has been mostly performed in cell culture experiments and using animal models (2O'Brien R.M. Granner D.K. Physiol. Rev. 1996; 76: 1109-1161Crossref PubMed Scopus (438) Google Scholar). Little is known about the transcriptional changes induced in vivo by insulin in human tissues, particularly in skeletal muscle, the main site of insulin-dependent glucose disposal and the major site of insulin resistance in type 2 diabetes mellitus. Although it has been demonstrated that insulin can modulate the mRNA levels of some important genes in human skeletal muscle, such as hexokinase II, Glut4, p85α phosphatidylinositol 3-kinase, or lipoprotein lipase (3Pendergrass M. Koval J. Vogt C. Yki-Jarvinen H. Iozzo P. Pipek R. Ardehali H. Printz R. Granner D. DeFronzo R.A. Mandarino L.J. Diabetes. 1998; 47: 387-394Crossref PubMed Scopus (99) Google Scholar, 4Andersen P.H. Lund S. Vestergaard H. Junker S. Kahn B.B. Pedersen O. J. Clin. Endocrinol. Metab. 1993; 77: 27-32Crossref PubMed Scopus (58) Google Scholar, 5Laville M. Auboeuf D. Khalfallah Y. Vega N. Riou J.P. Vidal H. J. Clin. Invest. 1996; 98: 43-49Crossref PubMed Scopus (128) Google Scholar), most of these studies were focused on a small number of selected genes involved in glucose and lipid metabolism (5Laville M. Auboeuf D. Khalfallah Y. Vega N. Riou J.P. Vidal H. J. Clin. Invest. 1996; 98: 43-49Crossref PubMed Scopus (128) Google Scholar, 6Ducluzeau P.H. Perretti N. Laville M. Andreelli F. Vega N. Riou J.P. Vidal H. Diabetes. 2001; 50: 1134-1142Crossref PubMed Scopus (226) Google Scholar) and did not give a global view of insulin action on gene expression. It is likely that insulin coordinates a complex program of transcriptional changes in target tissues, which represents the molecular basis of its action. Hence, the characterization of this global pattern of modifications in skeletal muscle is an important step for a better understanding of the mechanism of action of insulin and of its defects in situations of insulin resistance. The development of microarray technology offers powerful tools for characterizing such large scale changes in transcript levels. Recently, this methodology was applied to investigate the effects of intensive insulin treatment for 10 days on the mRNA profile in skeletal muscle of type 2 diabetic patients (7Sreekumar R. Halvatsiotis P. Schimke J.C. Nair K.S. Diabetes. 2002; 51: 1913-1920Crossref PubMed Scopus (227) Google Scholar). Using Affymetrix oligonucleotide microarrays allowing the analysis of 6800 mRNAs, the expression of about 100 genes was found to be modified during insulin therapy (7Sreekumar R. Halvatsiotis P. Schimke J.C. Nair K.S. Diabetes. 2002; 51: 1913-1920Crossref PubMed Scopus (227) Google Scholar). With a similar methodology, it was also demonstrated that 3 days of insulin treatment induced changes in the abundance of about 100 mRNAs in streptozotocin diabetic mice, suggesting a coordinated regulation of gene expression by insulin in skeletal muscle (8Yechoor V.K. Patti M.E Saccone R. Kahn C.R. Proc. Natl. Acad. Sci. U. S. A. 2002; 99: 10587-10592Crossref PubMed Scopus (139) Google Scholar). However, it was difficult to conclude on the direct role of insulin on gene expression in these two studies because the observed modifications could be the consequences of the metabolic changes that occurred during the treatment with insulin. To determine the global transcriptional modifications directly produced by insulin in human skeletal muscle, we used cDNA microarrays (9Clement K. Viguerie N. Diehn M. Alizadeh A. Barbe P. Thalamas C. Storey J.D. Brown P.O. Barsh G.S. Langin D. Genome Res. 2002; 12: 281-291Crossref PubMed Scopus (141) Google Scholar) to analyze the changes in the mRNA levels of 29,308 genes and expressed sequence tags (ESTs)1 induced by 3 h of euglycemic hyperinsulinemic clamp in the vastus lateralis muscle of healthy lean subjects. It is well accepted that the hyperinsulinemic clamp method allows the individual effect of insulin to be studied, and the short duration of the insulin infusion was chosen to limit possible secondary effects due to metabolic modifications. Rapid changes in the mRNA levels of candidate genes have been previously reported in human skeletal muscle during similar euglycemic hyperinsulinemic clamp conditions (5Laville M. Auboeuf D. Khalfallah Y. Vega N. Riou J.P. Vidal H. J. Clin. Invest. 1996; 98: 43-49Crossref PubMed Scopus (128) Google Scholar, 6Ducluzeau P.H. Perretti N. Laville M. Andreelli F. Vega N. Riou J.P. Vidal H. Diabetes. 2001; 50: 1134-1142Crossref PubMed Scopus (226) Google Scholar). We report here that insulin directly modulates the mRNA levels of about 800 genes in human muscle. Most of them are novel targets of the hormone and belong to functional classes that can account for most of the biological and metabolic effects of insulin in human skeletal muscle. Twelve lean healthy Caucasian volunteers (4 men and 9 women) with a mean (±S.E.) age of 32 ± 4 years and a body mass index of 22.2 ± 0.6 kg/m2 participated in the study. None had a familial or personal history of diabetes, obesity, dyslipidemia, or hypertension, and they were not taking medication except for oral They were on their the and was in of the and possible of the study. The was by the of studies were performed in the state an The volunteers were to a 3-h euglycemic hyperinsulinemic clamp with an insulin infusion of 2 as previously (5Laville M. Auboeuf D. Khalfallah Y. Vega N. Riou J.P. Vidal H. J. Clin. Invest. 1996; 98: 43-49Crossref PubMed Scopus (128) Google Scholar). of the vastus lateralis muscle was with a and 3 h of insulin infusion (5Laville M. Auboeuf D. Khalfallah Y. Vega N. Riou J.P. Vidal H. J. Clin. Invest. 1996; 98: 43-49Crossref PubMed Scopus (128) Google Scholar). muscle of ± 4 were in and at were in and was with the method (5Laville M. Auboeuf D. Khalfallah Y. Vega N. Riou J.P. Vidal H. J. Clin. Invest. 1996; 98: 43-49Crossref PubMed Scopus (128) Google Scholar). and were using an The mean of was ± 2 of muscle and was not for the and the 4 women) were using the in to for to the cDNA the of reverse transcription of of with a a sequence transcription of the DNA with to of mRNA 16: Scopus Google Scholar). has been and it has been demonstrated that it not the abundance of individual mRNAs an 16: Scopus Google Scholar, A. Brown Res. 2001; Scopus Google Scholar). of and conditions of of the six were with 3 or during a reverse transcription using the cDNA They were at to the cDNA microarray to the by the The cDNA microarrays consisted of on with 29,308 The six were with a microarray and the were analyzed using 3 were the scale factor was applied to and and with an the were not for The of the was for To the results the were in to have a mean of and a of by using the program Brown P.O. D. Proc. Natl. Acad. Sci. U. S. A. 1998; PubMed Scopus Google Scholar). with on the six were selected for this were with changes in mRNA levels in response to insulin were using the of R. Proc. Natl. Acad. Sci. U. S. A. 2001; 98: PubMed Scopus Google Scholar), a for expressed genes a of genes and an of the which represents the of genes that could be by (9Clement K. Viguerie N. Diehn M. Alizadeh A. Barbe P. Thalamas C. Storey J.D. Brown P.O. Barsh G.S. Langin D. Genome Res. 2002; 12: 281-291Crossref PubMed Scopus (141) Google Scholar, R. Proc. Natl. Acad. Sci. U. S. A. 2001; 98: PubMed Scopus Google Scholar). were of in the of 100 of using and The was performed using a in a of of a of the and 15 of the DNA with 3 and the and reverse The of the is in a analysis was performed to the of the a was with six of target cDNA in the The analysis was performed using the of the used for mRNA by in a To investigate the effect of insulin on gene healthy lean volunteers were to a 3-h euglycemic hyperinsulinemic clamp to insulin (5Laville M. Auboeuf D. Khalfallah Y. Vega N. Riou J.P. Vidal H. J. Clin. Invest. 1996; 98: 43-49Crossref PubMed Scopus (128) Google Scholar, 6Ducluzeau P.H. Perretti N. Laville M. Andreelli F. Vega N. Riou J.P. Vidal H. Diabetes. 2001; 50: 1134-1142Crossref PubMed Scopus (226) Google Scholar). ± 3 in the state to ± during the of the ± to ± 4 The was at ± The of glucose infusion to during the of the clamp was ± 0.6 a effect of insulin on body glucose disposal (5Laville M. Auboeuf D. Khalfallah Y. Vega N. Riou J.P. Vidal H. J. Clin. Invest. 1996; 98: 43-49Crossref PubMed Scopus (128) Google Scholar, 6Ducluzeau P.H. Perretti N. Laville M. Andreelli F. Vega N. Riou J.P. Vidal H. Diabetes. 2001; 50: 1134-1142Crossref PubMed Scopus (226) Google Scholar). as by ± insulin infusion to ± at the of the clamp the glucose disposal was ± 0.6 during the of insulin infusion. muscle were and at the of the hyperinsulinemic and was the cDNA microarray experiments were performed with the men and 4 women) of the involved in the study. and their metabolic during the clamp did not the of the not The cDNA microarrays used in the analysis of the changes in mRNA levels of 29,308 genes and The (9Clement K. Viguerie N. Diehn M. Alizadeh A. Barbe P. Thalamas C. Storey J.D. Brown P.O. Barsh G.S. Langin D. Genome Res. 2002; 12: 281-291Crossref PubMed Scopus (141) Google Scholar, R. Proc. Natl. Acad. Sci. U. S. A. 2001; 98: PubMed Scopus Google Scholar) was performed on for which were in the six With an of we found that were by insulin. in the this selected for which the in the on the six that the genes were by insulin in the in the six subjects. of of some on the the to 762 genes is in the these 762 genes, 478 were and 284 were during the 3 h of the hyperinsulinemic that the of the up-regulated genes a in mRNA as by the mean on of the or the genes, a or in expression To the of the microarray experiments and the the changes in mRNA levels of 9 genes were using in of the of the 3-h hyperinsulinemic These genes wide in their response to insulin on the microarray to and belong to the 3 main functional categories that were to the insulin-regulated genes of the in II, the changes by the microarray for genes except The of the receptor observed by microarray was not by However, it be that the mRNA level of was to the limit of the of microarray results with ± using ± using ± using ± using ± ± using ± using ± using ± using changes in mRNA levels of 10 selected genes were by using a on subjects. are the ± experiments were performed on six using using in a The changes in mRNA levels of 10 selected genes were by using a on subjects. are the ± experiments were performed on six subjects. We that the used in the microarray did not genes with expression in muscle. Using the for and at and the of the human skeletal muscle transcriptional profile R. C. R. C. Y. F. U. D. N. C. Genome Res. PubMed Scopus Google Scholar, S. K. Genome Res. Google Scholar, S. F. C. Genome Res. PubMed Scopus Google Scholar), we found that 32 of the 762 insulin-regulated genes have been reported to be expressed in the muscle in tissues, with to the genes as expressed in skeletal muscle R. C. R. C. Y. F. U. D. N. C. Genome Res. PubMed Scopus Google S. F. C. Genome Res. PubMed Scopus Google Scholar). about 150 genes, mostly with had been found to be expressed in the skeletal muscle. that the used in the did not genes to their mRNA expression levels to analyze the effect of insulin on the global muscle However, because the analysis was performed in it could not be that regulation of gene expression in cell in muscle have to the the 762 genes that a regulation during the hyperinsulinemic have a known location in the the gene was found on due to the that participated in the and the to the genes that did not give a in the six of the location that the insulin-regulated genes are the and the number of genes on is to the of the genes on and 10 on It could be that and are characterized by the of or None of these has been reported to be with insulin resistance or type 2 diabetes in However, of these have been to and R. B. C. Sci. 2002; PubMed Scopus Google Scholar). and PubMed were used to the genes functional categories the for a of the genes and their the 762 genes found to be by 353 and to or a expression during the clamp and a suggesting that a number of insulin-regulated genes will the of the the genes with known the to genes coding for involved in the transcriptional and translational regulation (29%), intermediary and energy metabolisms (14%), or in intracellular signaling Other functional categories consisted of genes involved in cytoskeleton and vesicle traffic receptors, carriers, and transporters (8%), components of the ubiquitin/proteasome pathways and the immune response (5.5%). genes did not to of these major 2 are of these main metabolic and functional pathways with of the number of and The functional are in of the effects of insulin on gene expression in skeletal muscle. The main functional categories of the mRNAs are The number of up-regulated genes is with and the number of genes is with of the most biological effects of insulin is its on the of mainly an of gene transcription and a of mRNA translation (2O'Brien R.M. Granner D.K. Physiol. Rev. 1996; 76: 1109-1161Crossref PubMed Scopus (438) Google Scholar). It not that the of the genes found to be during an insulin infusion for transcription as transcription factor transcription factor transcription and for involved in and translation and and translation 2 and translation factor the mRNA expression of proteins, including 4 of the is induced during the hyperinsulinemic Insulin also the expression of genes coding for proteins, or enzymes involved in to the of protein synthesis that protein and a number of modifications. skeletal muscle, insulin the of and and their metabolic The of glucose and is by are mostly used for protein synthesis. 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The that insulin infusion for 3 h during a hyperinsulinemic euglycemic clamp results in changes in the mRNA levels of about 800 genes in human skeletal muscle. of them are with The could be functional categories that can most of the biological and metabolic effects of insulin. The microarray were by the mRNA levels of a of genes using some of these genes, such as hexokinase and p85α phosphatidylinositol 3-kinase, have been previously reported to be by insulin in the of the target genes of insulin that was previously mostly on the basis of experiments with animal the as an important of insulin action in human muscle. is to insulin the coordinated regulation of these target The mechanism of action of insulin on gene expression in skeletal muscle is The identification of insulin response elements in the of of genes will help the of the transcription the effect of insulin on genes because that defects in and in insulin-regulated gene expression be involved in the of insulin resistance and type 2 diabetes (2O'Brien R.M. Granner D.K. Physiol. Rev. 1996; 76: 1109-1161Crossref PubMed Scopus (438) Google Scholar, 6Ducluzeau P.H. Perretti N. Laville M. Andreelli F. Vega N. Riou J.P. Vidal H. Diabetes. 2001; 50: 1134-1142Crossref PubMed Scopus (226) Google Scholar), of the 800 genes in the are novel in pathologies with insulin