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

Abstract

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.

Transcriptomic profiles of skeletal muscle tissue following an euglycemic-hyperinsulinemic clamp in insulin-resistant obese subjects

“…Metabolic pathway analyses indicate generally changes in pro-inflammatory, transcriptional, and G protein-coupled receptor (GPCR) signaling pathways. Previous studies have examined the rapid changes in the gene expression levels in skeletal muscle during euglycemichyperinsulinemic clamp conditions in healthy subjects (Coletta et al 2008;Rome et al 2003;Wu et al 2007). These studies demonstrate changes in gene expression levels of genes related mainly to transcription factors, intermediary and energy metabolisms, immune response, and intracellular signaling in healthy volunteers (Coletta et al 2008;Rome et al 2003;Wu et al 2007).…”

“…Previous studies have examined the rapid changes in the gene expression levels in skeletal muscle during euglycemichyperinsulinemic clamp conditions in healthy subjects (Coletta et al 2008;Rome et al 2003;Wu et al 2007). These studies demonstrate changes in gene expression levels of genes related mainly to transcription factors, intermediary and energy metabolisms, immune response, and intracellular signaling in healthy volunteers (Coletta et al 2008;Rome et al 2003;Wu et al 2007). Additionally, a study demonstrated that the beginning of insulin stimulation changes are usually apparent in the expression of early response transcription factors together with early signaling molecules, chemokines, and receptors followed afterward by secreted growth factors and proteases, Fig.…”

“…Previously Wu et al (2007) demonstrated that the effects of a euglycemic-hyperinsulinemic clamp were noted on all stages including transcription, mRNA processing, translation, post-translational protein modification, and protein degradation. In sum, these results suggest that key inflammatory and transcriptional pathways should be targeted in the development of nutritional as well as pharmaceutical therapies to decrease the risk of progression to type 2 diabetes for obese insulin-resistant subjects.…”

Session 2: Personalised nutrition Transcriptomic signatures that have identified key features of metabolic syndrome

“…1). In a similar approach to pathway analysis gene ontology classifications are routinely (21) Skeletal muscle T2DM -Das & Rao (38) Peripheral blood leucocytes Obesity; T2DM -MacLaren et al (39) Subcutaneous and omental adipose Obesity; insulin resistance -Henegar et al (22) Subcutaneous adipose Obesity -Gó mez-Ambrosi et al (40) Omental adipose Obesity -Von Eyben et al (41) Intra-abdominal and subcutaneous adipose Obesity -Linder et al (42) Visceral and subcutaneous adipose Obesity -Morello et al (43) Lymphoblasts Hyperlipidaemia Wu et al (44) Skeletal muscle Hyperinsulinaemia -Meugnier et al (33) Vastuslateralis muscle; Subcutaneous adipose Hyperglycaemia -Kabir et al (36) Subcutaneous adipose T2DM n-3 PUFA Kallio et al (34) Subcutaneous adipose Metabolic syndrome High-GI CHO v. low-GI CHO Sparks et al (28) Skeletal muscle -High-fat diet CHO, carbohydrate; GI, glycaemic index.…”

Study on distribution of Pro12Ala SNP of PPAR gamma 2 gene in randomly sampled diabetic population from Guwahati city

“…3,4 Several genes have been found to be related to type 2 diabetes like TCF7L2, PPARg2, KCNJ11, CAPN10, TNFa, RRAD, IGFBP5, INSIG1 and NGFI-B, out of which PPARg2 has the most significant role to play. 5,6 Peroxisome proliferated activated receptor gamma 2 (PPARg2) is a transcription factor that belongs to the same family of nuclear receptors like steroid and thyroid hormone receptors, 7 and is expressed predominantly in adipose tissues. Its action is triggered by certain fatty acids, prostanoids, and anti-diabetic agents like thiazolidinediones.…”