The effect of insulin on expression of genes and biochemical pathways in human skeletal muscle

Department of Nutrition Sciences, University of Alabama at Birmingham, 1675 University Boulevard, Birmingham, AL 35294-3360, USA.
Endocrine (Impact Factor: 3.88). 03/2007; 31(1):5-17. DOI: 10.1007/s12020-007-0007-x
Source: PubMed


To study the insulin effects on gene expression in skeletal muscle, muscle biopsies were obtained from 20 insulin sensitive individuals before and after euglycemic hyperinsulinemic clamps. Using microarray analysis, we identified 779 insulin-responsive genes. Particularly noteworthy were effects on 70 transcription factors, and an extensive influence on genes involved in both protein synthesis and degradation. The genetic program in skeletal muscle also included effects on signal transduction, vesicular traffic and cytoskeletal function, and fuel metabolic pathways. Unexpected observations were the pervasive effects of insulin on genes involved in interacting pathways for polyamine and S-adenoslymethionine metabolism and genes involved in muscle development. We further confirmed that four insulin-responsive genes, RRAD, IGFBP5, INSIG1, and NGFI-B (NR4A1), were significantly up-regulated by insulin in cultured L6 skeletal muscle cells. Interestingly, insulin caused an accumulation of NGFI-B (NR4A1) protein in the nucleus where it functions as a transcription factor, without translocation to the cytoplasm to promote apoptosis. The role of NGFI-B (NR4A1) as a new potential mediator of insulin action highlights the need for greater understanding of nuclear transcription factors in insulin action.

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    • "The NR4A1 protein is fetal muscle specific and adult liver specific, and it acts as a nuclear transcription factor. A prior study of the effect of insulin on gene expression in skeletal muscle showed that NR4A1, IGFBP5 and INSIG2 mRNA levels were significantly up-regulated in cultured skeletal muscle cells (Wu et al. 2007). INSR and INSIG2 upregulation in H bulls is consistent with the role of NR4A1 as a potential mediator of insulin action and highlights the need for greater understanding of the role of nuclear transcription factors in bovine insulin pathways. "
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    ABSTRACT: This study examined liver transcriptomic profiles of cattle distinctly different in meat and milk production capacity. It was performed on bulls of two different genetic backgrounds: Herefords (H), a meat breed, and Holstein-Friesians (HF), a dairy breed. Using bovine long oligo-microarrays and qPCR, we identified 128 genes that are differentially expressed between the two breeds. In H bulls, we observed up-regulation of genes involved in fatty acid biosynthesis and lipid metabolism (CD36, CAT, HSD3B1, FABP1, ACAA1) and involved in insulin signaling (INSR, INSIG2, NR4A1) and down-regulation of genes involved in somatotropic axis signaling (IGF1, GHR, IGFBP3) as compared to HF. Transcriptome profiling of these two breeds allowed us to pinpoint the transcriptional differences between Holstein and Hereford bulls at hepatic level associated with changes in metabolism and postnatal growth.
    Animal Genetics 12/2013; 45(2). DOI:10.1111/age.12116 · 2.21 Impact Factor
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    • "As mentioned above, there was no replicable significant effect of NR4A3 genetic variability on insulin sensitivity in the two study populations, despite that both NR4A1 and NR4A3 expression is reduced in skeletal muscle of various diabetic animal models [11] and increased in L6 skeletal muscle cells and muscle biopsies upon insulin stimulation [31] or dietary restriction [32]. We also were not able to show a replicable association with BMI in our two study cohorts. "
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    ABSTRACT: Neuron-derived orphan receptor (Nor) 1, nuclear receptor (Nur) 77, and nuclear receptor-related protein (Nurr) 1 constitute the NR4A family of orphan nuclear receptors which were recently found to modulate hepatic glucose production, insulin signalling in adipocytes, and oxidative metabolism in skeletal muscle. In this study, we assessed whether common genetic variation within the NR4A3 locus, encoding Nor-1, contributes to the development of prediabetic phenotypes, such as glucose intolerance, insulin resistance, or beta-cell dysfunction. We genotyped 1495 non-diabetic subjects from Southern Germany for the five tagging single nucleotide polymorphisms (SNPs) rs7047636, rs1526267, rs2416879, rs12686676, and rs10819699 (minor allele frequencies >or= 0.05) covering 100% of genetic variation within the NR4A3 locus (with D' = 1.0, r2 >or= 0.9) and assessed their association with metabolic data derived from the fasting state, an oral glucose tolerance test (OGTT), and a hyperinsulinemic-euglycemic clamp (subgroup, N = 506). SNPs that revealed consistent associations with prediabetic phenotypes were subsequently genotyped in a second cohort (METSIM Study; Finland; N = 5265) for replication. All five SNPs were in Hardy-Weinberg equilibrium (p >or= 0.7, all). The minor alleles of three SNPs, i.e., rs1526267, rs12686676, and rs10819699, consistently tended to associate with higher insulin release as derived from plasma insulin at 30 min(OGTT), AUCC C-peptide-to-AUC Gluc ratio and the AUC Ins30-to-AUC Gluc30 ratio with rs12686676 reaching the level of significance (p <or= 0.03, all; additive model). The association of the SNP rs12686676 with insulin secretion was replicated in the METSIM cohort (p <or= 0.03, additive model). There was no consistent association with glucose tolerance or insulin resistance in both study cohorts. We conclude that common genetic variation within the NR4A3 locus determines insulin secretion. Thus, NR4A3 represents a novel candidate gene for beta-cell function which was not covered by the SNP arrays of recent genome-wide association studies for type 2 diabetes mellitus.
    BMC Medical Genetics 09/2009; 10(1):77. DOI:10.1186/1471-2350-10-77 · 2.08 Impact Factor
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    • "Thus, changes in the activity of mTOR signaling enzymes and eIF2B provides a possible explanation for the observed changes in the translational machinery before and after pioglitazone treatment. Moreover, recent microarray-based studies of gene expression in skeletal muscle of healthy humans have shown that the majority of the genes upregulated in response to acute insulin infusion codes for proteins involved in transcriptional and translational regulation including a number of ribosomal proteins [41], [45]. These reports lend support to the hypothesis that in the long term, insulin also increases the cellular content of ribosomes augmenting the capacity for protein synthesis. "
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    ABSTRACT: Insulin resistance is a common metabolic abnormality in women with PCOS and leads to an elevated risk of type 2 diabetes. Studies have shown that thiazolidinediones (TZDs) improve metabolic disturbances in PCOS patients. We hypothesized that the effect of TZDs in PCOS is, in part, mediated by changes in the transcriptional profile of muscle favoring insulin sensitivity. Using Affymetrix microarrays, we examined the effect of pioglitazone (30 mg/day for 16 weeks) on gene expression in skeletal muscle of 10 obese women with PCOS metabolically characterized by a euglycemic-hyperinsulinemic clamp. Moreover, we explored gene expression changes between these PCOS patients before treatment and 13 healthy women. Treatment with pioglitazone improved insulin-stimulated glucose metabolism and plasma adiponectin, and reduced fasting serum insulin (all P<0.05). Global pathway analysis using Gene Map Annotator and Pathway Profiler (GenMAPP 2.1) and Gene Set Enrichment Analysis (GSEA 2.0.1) revealed a significant upregulation of genes representing mitochondrial oxidative phosphorylation (OXPHOS), ribosomal proteins, mRNA processing reactome, translation factors, and proteasome degradation in PCOS after pioglitazone therapy. Quantitative real-time PCR suggested that upregulation of OXPHOS genes was mediated by an increase in PGC-1alpha expression (P<0.05). Pretreatment expression of genes representing OXPHOS and ribosomal proteins was down-regulated in PCOS patients compared to healthy women. These data indicate that pioglitazone therapy restores insulin sensitivity, in part, by a coordinated upregulation of genes involved in mitochondrial OXPHOS and ribosomal protein biosynthesis in muscle in PCOS. These transcriptional effects of pioglitazone may contribute to prevent the onset of type 2 diabetes in these women.
    PLoS ONE 06/2008; 3(6):e2466. DOI:10.1371/journal.pone.0002466 · 3.23 Impact Factor
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