title: SIRT2 negatively regulates insulin resistance in C2C12 skeletal muscle cells.
abstract: SIRT2 is primarily a cytoplasmic protein deacetylase and is abundantly expressed in metabolically active tissues like adipocytes and brain. However, its role, if any, in regulating insulin signaling in skeletal muscle cells, is not known. We have examined the role of SIRT2 in insulin-mediated glucose disposal in normal and insulin resistant C2C12 skeletal muscle cells in vitro. SIRT2 was over expressed in insulin resistant skeletal muscle cells. Pharmacological inhibition of SIRT2 increased insulin-stimulated glucose uptake and improved phosphorylation of Akt and GSK3β in insulin resistant cells. Knockdown of endogenous SIRT2 and over expression of catalytically-inactive SIRT2 mutant under insulin-resistant condition showed similar amelioration of insulin sensitivity. Our results suggest that down-regulation of SIRT2 improved insulin sensitivity in skeletal muscle cells under insulin-resistant condition. Previously it has been reported that down-regulation of SIRT1 and SIRT3 in C2C12 cells results in impairment of insulin signaling and induces insulin resistance. However, we have observed an altogether different role of SIRT2 in skeletal muscle. This implicates a differential regulation of insulin resistance by sirtuins which otherwise share a conserved catalytic domain. The study significantly directs towards future approaches in targeting inhibition of SIRT2 for therapeutic treatment of insulin resistance which is the major risk factor in Type 2 diabetes.
authors.affiliation: Kusuma School of Biological Sciences, Indian Institute of Technology-Delhi, Hauz Khas, New Delhi 110016, India.
authors.forename: Amita
authors.initials: A
authors.lastname: Arora
authors.affiliation: Kusuma School of Biological Sciences, Indian Institute of Technology-Delhi, Hauz Khas, New Delhi 110016, India. Electronic address: csdey@bioschool.iitd.ac.in.
authors.forename: Chinmoy Sankar
authors.initials: CS
authors.lastname: Dey
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002454:Cell Differentiation; D049109:Cell Proliferation; D002478:Cells, Cultured; D005947:Glucose / Q000378:metabolism; D007004:Hypoglycemic Agents / Q000494:pharmacology; D047468:Immunoprecipitation; D007328:Insulin / Q000494:pharmacology*; D007333:Insulin Resistance; D051379:Mice; D018482:Muscle, Skeletal / Q000378:metabolism / Q000473:pathology*; D010766:Phosphorylation / Q000187:drug effects; D034741:RNA, Small Interfering / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects; D056565:Sirtuin 2 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
chemical_list: D007004:Hypoglycemic Agents; D007328:Insulin; D034741:RNA, Small Interfering; C418743:Sirt2 protein, mouse; D056565:Sirtuin 2; D005947:Glucose
keywords: Insulin resistance; Insulin signaling; SIRT2; Sirtuins; Skeletal muscle