title: Augmentation of histone deacetylase 3 (HDAC3) epigenetic signature at the interface of proinflammation and insulin resistance in patients with type 2 diabetes.
abstract: A role of proinflammation has been implicated in the pathogenesis of diabetes, but the up-stream regulatory signals and molecular signatures are poorly understood. While histone modifications such as changes in histone deacetylase (HDAC) are emerging as novel epigenetic biomarkers, there is lack of studies to demonstrate their clinical relevance in diabetes. Therefore, we investigated the extent of HDAC machinery and inflammatory signals in peripheral blood mononuclear cells (PBMCs) from patients with type 2 diabetes mellitus (T2DM) compared to control subjects.
  
  
  
  HDAC3activity was significantly (p< 0.05) increased in patients with T2DM compared to control subjects. While subtypes of HDACs were differentially expressed at their transcriptional levels in patients with type 2 diabetes, the most prominent observation is the significantly (p< 0.05) elevated messenger RNA (mRNA) levels ofHDAC3. Expression levels of Sirt1 which represents the class III HDAC were decreased significantly in T2DM (p< 0.05). Plasma levels of both TNF-α and IL-6 were significantly higher (p< 0.05) in patients with type 2 diabetes compared to control subjects. Among the proinflammatory mediators, the mRNA expression of MCP-1, IL1-β, NFκB, TLR2, and TLR4 were also significantly (p< 0.05) increased in T2DM. Transcriptional levels of DBC1 (deleted in breast cancer 1, which is a negative regulator of HDAC3) were seen significantly reduced in PBMCs from T2DM. Interestingly,HDAC3activity/HDAC3 mRNA levels positively correlated to proinflammation, poor glycemic control, and insulin resistance.
  
  
  
  Striking message from this study is that while looking for anti-inflammatory strategies and drugs with novel mode of action for T2DM, discovering and designing specific inhibitors targeted toHDAC3appears promising.
authors.affiliation: Department of Cell and Molecular Biology and Dr. Rema Mohan High-Throughput Screening (HTS) Lab, Madras Diabetes Research Foundation and Dr. Mohan's Diabetes Specialties Centre, Gopalapuram, Chennai, 600086 India.
authors.forename: Chandrakumar
authors.initials: C
authors.lastname: Sathishkumar
authors.affiliation: Department of Cell and Molecular Biology and Dr. Rema Mohan High-Throughput Screening (HTS) Lab, Madras Diabetes Research Foundation and Dr. Mohan's Diabetes Specialties Centre, Gopalapuram, Chennai, 600086 India.
authors.forename: Paramasivam
authors.initials: P
authors.lastname: Prabu
authors.affiliation: Department of Cell and Molecular Biology and Dr. Rema Mohan High-Throughput Screening (HTS) Lab, Madras Diabetes Research Foundation and Dr. Mohan's Diabetes Specialties Centre, Gopalapuram, Chennai, 600086 India.
authors.forename: Mahalingam
authors.initials: M
authors.lastname: Balakumar
authors.affiliation: Department of Cell and Molecular Biology and Dr. Rema Mohan High-Throughput Screening (HTS) Lab, Madras Diabetes Research Foundation and Dr. Mohan's Diabetes Specialties Centre, Gopalapuram, Chennai, 600086 India.
authors.forename: Raji
authors.initials: R
authors.lastname: Lenin
authors.affiliation: Department of Cell and Molecular Biology and Dr. Rema Mohan High-Throughput Screening (HTS) Lab, Madras Diabetes Research Foundation and Dr. Mohan's Diabetes Specialties Centre, Gopalapuram, Chennai, 600086 India.
authors.forename: Durai
authors.initials: D
authors.lastname: Prabhu
authors.affiliation: Department of Cell and Molecular Biology and Dr. Rema Mohan High-Throughput Screening (HTS) Lab, Madras Diabetes Research Foundation and Dr. Mohan's Diabetes Specialties Centre, Gopalapuram, Chennai, 600086 India.
authors.forename: Ranjith Mohan
authors.initials: RM
authors.lastname: Anjana
authors.affiliation: Department of Cell and Molecular Biology and Dr. Rema Mohan High-Throughput Screening (HTS) Lab, Madras Diabetes Research Foundation and Dr. Mohan's Diabetes Specialties Centre, Gopalapuram, Chennai, 600086 India.
authors.forename: Viswanathan
authors.initials: V
authors.lastname: Mohan
authors.affiliation: Department of Cell and Molecular Biology and Dr. Rema Mohan High-Throughput Screening (HTS) Lab, Madras Diabetes Research Foundation and Dr. Mohan's Diabetes Specialties Centre, Gopalapuram, Chennai, 600086 India.
authors.forename: Muthuswamy
authors.initials: M
authors.lastname: Balasubramanyam
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D000328:Adult; D015992:Body Mass Index; D016207:Cytokines / Q000097:blood*; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D044127:Epigenesis, Genetic; D005260:Female; D005786:Gene Expression Regulation; D006655:Histone Deacetylases / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007333:Insulin Resistance; D008297:Male; D008875:Middle Aged; D056564:Sirtuin 1 / Q000235:genetics*; D000099186:Histone Deacetylase 3
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D016207:Cytokines; D006655:Histone Deacetylases; D056564:Sirtuin 1; D000099186:Histone Deacetylase 3; C527450:CCAR2 protein, human; C447939:SIRT1 protein, human
keywords: Epigenetics; HDAC3; Histone modification; Inflammation; Insulin resistance; Sirt1; Type 2 diabetes