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We hypothesise that epigenetic mechanisms are involved in the regulation of <jats:italic>IRS2<\/jats:italic> in the liver of obese and type 2 diabetic individuals.<\/jats:p>\n<\/jats:sec><jats:sec>\n<jats:title>Methods<\/jats:title>\n<jats:p>DNA methylation of seven CpG sites was studied by bisulphite pyrosequencing and mRNA and microRNA (miRNA) expression was assessed by quantitative real-time PCR in liver biopsies of 50 obese non-diabetic and 31 obese type 2 diabetic participants, in a cross-sectional setting. Methylation-sensitive luciferase assays and electrophoretic mobility shift assays were performed. Furthermore, HepG2 cells were treated with insulin and high glucose concentrations to induce miRNA expression and <jats:italic>IRS2<\/jats:italic> downregulation.<\/jats:p>\n<\/jats:sec><jats:sec>\n<jats:title>Results<\/jats:title>\n<jats:p>We found a significant downregulation of <jats:italic>IRS2<\/jats:italic> expression in the liver of obese individuals with type 2 diabetes (0.84\u2009\u00b1\u20090.08-fold change; <jats:italic>p<\/jats:italic>\u2009=\u20090.0833; adjusted <jats:italic>p<\/jats:italic> value [<jats:italic>p<\/jats:italic><jats:sub>a<\/jats:sub>]\u2009=\u20090.0417; <jats:italic>n<\/jats:italic>\u2009=\u200931) in comparison with non-diabetic obese participants (<jats:italic>n<\/jats:italic>\u2009=\u200950). This downregulation correlated with hepatic <jats:italic>IRS2<\/jats:italic> DNA methylation at CpG5. Additionally, CpG6, which is located in intron 1 of <jats:italic>IRS2<\/jats:italic>, was hypomethylated in type 2 diabetes; this site spans the sterol regulatory element binding transcription factor 1 (SREBF1) recognition motif, which likely acts as transcriptional repressor. The adjacent polymorphism rs4547213 (G&gt;A) was significantly associated with DNA methylation at a specificity-protein-1 (SP1) binding site (CpG3). Moreover, DNA methylation of cg25924746, a CpG site located in the shore region of the <jats:italic>IRS2<\/jats:italic> promoter-associated CpG island, was increased in the liver of individuals with type 2 diabetes, as compared with those without diabetes. A second epigenetic mechanism, upregulation of hepatic miRNA hsa-let-7e-5p (let-7e-5p) in obese individuals with type 2 diabetes (<jats:italic>n<\/jats:italic>\u2009=\u200929) vs non-diabetic obese individuals (<jats:italic>n<\/jats:italic>\u2009=\u200949) (1.2\u2009\u00b1\u20090.08-fold change; <jats:italic>p<\/jats:italic>\u2009=\u20090.0332; <jats:italic>p<\/jats:italic><jats:sub>a<\/jats:sub>\u2009=\u20090.0450), is likely to act synergistically with altered <jats:italic>IRS2<\/jats:italic> DNA methylation to decrease <jats:italic>IRS2<\/jats:italic> expression. Mechanistic in vitro experiments demonstrated an acute upregulation of let-7e-5p expression and simultaneous <jats:italic>IRS2<\/jats:italic> downregulation in a liver (HepG2) cell line upon hyperinsulinaemic and hyperglycaemic conditions.<\/jats:p>\n<\/jats:sec><jats:sec>\n<jats:title>Conclusions\/interpretation<\/jats:title>\n<jats:p>Our study highlights a new multi-layered epigenetic network that could be involved in subtle dysregulation of <jats:italic>IRS2<\/jats:italic> in the liver of individuals with type 2 diabetes. This might lead to fine-tuning of <jats:italic>IRS2<\/jats:italic> expression and is likely to be supplementary to the already known factors regulating <jats:italic>IRS2<\/jats:italic> expression. Thereby, our findings could support the discovery of new diagnostic and therapeutic strategies for type 2 diabetes.<\/jats:p>\n\n<\/jats:sec>","DOI":"10.1007\/s00125-020-05212-6","type":"journal-article","created":{"date-parts":[[2020,7,24]],"date-time":"2020-07-24T05:03:54Z","timestamp":1595567034000},"page":"2182-2193","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":74,"title":["Multi-layered epigenetic regulation of IRS2 expression in the liver of obese individuals with type 2 diabetes"],"prefix":"10.1007","volume":"63","author":[{"given":"Christin","family":"Krause","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cathleen","family":"Gei\u00dfler","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heidi","family":"Tackenberg","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexander T.","family":"El Gammal","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefan","family":"Wolter","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joachim","family":"Spranger","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Oliver","family":"Mann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hendrik","family":"Lehnert","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7887-247X","authenticated-orcid":false,"given":"Henriette","family":"Kirchner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2020,7,24]]},"reference":[{"issue":"2","key":"5212_CR1","doi-asserted-by":"publisher","first-page":"95","DOI":"10.1016\/j.cmet.2007.12.009","volume":"7","author":"MS Brown","year":"2008","unstructured":"Brown MS, Goldstein JL (2008) Selective versus total insulin resistance: a pathogenic paradox. 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