Insulin Action, Insulin Resistance, and Their Link to Histone Acetylation
Posttranslational covalent histone modifications, usually referred as epigenetic changes, including acetylation, methylation and phosphorylation; and DNA methylation on cytosines are main mechanism of regulation of chromatin structure and transcription.
Insulin, the main anabolic hormone, exerts pleiotropic actions by acting on insulin-sensitive tissues. In addition to the control of metabolism, insulin extensively modulates gene expression. The relevance of insulin-dependent gene regulation has been confirmed by the observation that in insulin resistance and T2DM, insulin-regulated gene expression is impaired.
In this chapter, we provide an overview of the current knowledge on the link between the hormonal action of insulin, via its intracellular signaling pathways, and the influence of these pathways on epigenetic modifications that act as central regulators of insulin-dependent gene transcription. We specifically focus on the link between insulin signaling and transcriptional control via histone acetylation. The occurrence of alterations of proper acetylation patterns within the context of insulin resistance and type 2 diabetes mellitus (T2DM) will also be discussed. Reversing these alterations might provide novel therapeutic options against insulin resistance and/or T2DM.
KeywordsHistone acetylation Insulin signaling Insulin resistance Histones Histone posttranslational modifications Histone deacetylases Histone acetyltransferases Type 2 diabetes mellitus GLUT4, PI 3-kinase
List of Abbreviations
Type 2 diabetes mellitus
- Agardh E, Lundstig A, Perfilyev A, Volkov P, Freiburghaus T, Lindholm E, Ronn T, Agardh CD, Ling C (2015) Genome-wide analysis of DNA methylation in subjects with type 1 diabetes identifies epigenetic modifications associated with proliferative diabetic retinopathy. BMC Med 13:182CrossRefPubMedPubMedCentralGoogle Scholar
- Bouzakri K, Roques M, Gual P, Espinosa S, Guebre-Egziabher F, Riou JP, Laville M, Le Marchand-Brustel Y, Tanti JF, Vidal H (2003) Reduced activation of phosphatidylinositol-3 kinase and increased serine 636 phosphorylation of insulin receptor substrate-1 in primary culture of skeletal muscle cells from patients with type 2 diabetes. Diabetes 52:1319–1325CrossRefPubMedGoogle Scholar
- Cho H, Mu J, Kim JK, Thorvaldsen JL, Chu Q, Crenshaw EB, 3rd, Kaestner KH, Bartolomei MS, Shulman GI, and Birnbaum MJ (2001). Insulin resistance and a diabetes mellitus-like syndrome in mice lacking the protein kinase Akt2 (PKB beta). Science 292, 1728–1731Google Scholar
- Dayeh T, Volkov P, Salo S, Hall E, Nilsson E, Olsson AH, Kirkpatrick CL, Wollheim CB, Eliasson L, Ronn T et al (2014) Genome-wide DNA methylation analysis of human pancreatic islets from type 2 diabetic and non-diabetic donors identifies candidate genes that influence insulin secretion. PLoS Genet 10:e1004160CrossRefPubMedPubMedCentralGoogle Scholar
- Draznin B (2006) Molecular mechanisms of insulin resistance: serine phosphorylation of insulin receptor substrate-1 and increased expression of p85Â: the two sides of a coin. Diabetes 55(8):2392–2397Google Scholar
- Duong DT, Waltner-Law ME, Sears R, Sealy L, Granner DK (2002) Insulin inhibits hepatocellular glucose production by utilizing liver-enriched transcriptional inhibitory protein to disrupt the association of CREB-binding protein and RNA polymerase II with the phosphoenolpyruvate carboxykinase gene promoter. J Biol Chem 277:32234–32242CrossRefPubMedGoogle Scholar
- Huang Y, Gao S, Chen J, Albrecht E, Zhao R, Yang X (2016) Maternal butyrate supplementation induces insulin resistance associated with enhanced intramuscular fat deposition in the offspring. Oncotarget 8:13073–13084Google Scholar
- Marzluff WF Jr, McCarty KS (1970) Two classes of histone acetylation in developing mouse mammary gland. J Biol Chem 245, 5635–5642Google Scholar
- Muka T, Nano J, Voortman T, Braun KV, Ligthart S, Stranges S, Bramer WM, Troup J, Chowdhury R, Dehghan A et al (2016) The role of global and regional DNA methylation and histone modifications in glycemic traits and type 2 diabetes: a systematic review. Nutr Metab Cardiovasc Dis 26:553–566CrossRefPubMedGoogle Scholar
- Pederson TM, Kramer DL, Rondinone CM (2001) Serine/Threonine phosphorylation of IRS-1 triggers its degradation: possible regulation by tyrosine phosphorylation. Diabetes 50(1):24–31Google Scholar
- Rome S, Clement K, Rabasa-Lhoret R, Loizon E, Poitou C, Barsh GS, Riou JP, Laville M, Vidal H (2003) Microarray profiling of human skeletal muscle reveals that insulin regulates approximately 800 genes during a hyperinsulinemic clamp. J Biol Chem 278:18063–18068. Epub 12003 Mar 18005CrossRefPubMedGoogle Scholar
- Rome S, Meugnier E, Lecomte V, Berbe V, Besson J, Cerutti C, Pesenti S, Granjon A, Disse E, Clement K et al (2009) Microarray analysis of genes with impaired insulin regulation in the skeletal muscle of type 2 diabetic patients indicates the involvement of basic helix-loop-helix domain-containing, class B, 2 protein (BHLHB2). Diabetologia 52:1899–1912CrossRefPubMedGoogle Scholar
- Sathishkumar C, Prabu P, Balakumar M, Lenin R, Prabhu D, Anjana RM, Mohan V, Balasubramanyam M (2016) Augmentation of histone deacetylase 3 (HDAC3) epigenetic signature at the interface of proinflammation and insulin resistance in patients with type 2 diabetes. Clin Epigenetics 8:125CrossRefPubMedPubMedCentralGoogle Scholar
- Wojtala M, Pirola L, Balcerczyk A (2017) Modulation of the vascular endothelium functioning by dietary components, the role of epigenetics. Biofactors: https://doi.org/10.1002/biof.1306
- Zeggini E, Scott LJ, Saxena R, Voight BF, Marchini JL, Hu T, de Bakker PI, Abecasis GR, Almgren P, Andersen G et al (2008) Meta-analysis of genome-wide association data and large-scale replication identifies additional susceptibility loci for type 2 diabetes. Nat Genet 40:638–645CrossRefPubMedPubMedCentralGoogle Scholar
- Zerzaihi O, Chriett S, Vidal H, Pirola L (2014) Insulin-dependent transcriptional control in L6 rat myotubes is associated with modulation of histone acetylation and accumulation of the histone variant H2A.Z in the proximity of the transcriptional start site. Biochem Cell Biol 92:61–67CrossRefPubMedGoogle Scholar