PMID- 27904654 OWN - NLM STAT- MEDLINE DCOM- 20170428 LR - 20220408 IS - 1868-7083 (Electronic) IS - 1868-7075 (Print) IS - 1868-7075 (Linking) VI - 8 DP - 2016 TI - Augmentation of histone deacetylase 3 (HDAC3) epigenetic signature at the interface of proinflammation and insulin resistance in patients with type 2 diabetes. PG - 125 LID - 125 AB - BACKGROUND: 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. RESULTS: HDAC3 activity 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 of HDAC3. Expression levels of Sirt1 which represents the class III HDAC were decreased significantly in T2DM (p < 0.05). Plasma levels of both TNF-alpha 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-beta, NFkappaB, 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, HDAC3 activity/HDAC3 mRNA levels positively correlated to proinflammation, poor glycemic control, and insulin resistance. CONCLUSIONS: 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 to HDAC3 appears promising. FAU - Sathishkumar, Chandrakumar AU - Sathishkumar C AD - 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. FAU - Prabu, Paramasivam AU - Prabu P AD - 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. FAU - Balakumar, Mahalingam AU - Balakumar M AD - 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. FAU - Lenin, Raji AU - Lenin R AD - 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. FAU - Prabhu, Durai AU - Prabhu D AD - 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. FAU - Anjana, Ranjith Mohan AU - Anjana RM AD - 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. FAU - Mohan, Viswanathan AU - Mohan V AD - 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. FAU - Balasubramanyam, Muthuswamy AU - Balasubramanyam M AD - 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. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20161124 PL - Germany TA - Clin Epigenetics JT - Clinical epigenetics JID - 101516977 RN - 0 (Adaptor Proteins, Signal Transducing) RN - 0 (CCAR2 protein, human) RN - 0 (Cytokines) RN - EC 3.5.1.- (SIRT1 protein, human) RN - EC 3.5.1.- (Sirtuin 1) RN - EC 3.5.1.98 (Histone Deacetylases) RN - EC 3.5.1.98 (histone deacetylase 3) SB - IM MH - Adaptor Proteins, Signal Transducing/*genetics MH - Adult MH - Body Mass Index MH - Cytokines/*blood MH - Diabetes Mellitus, Type 2/genetics/immunology/*metabolism MH - Epigenesis, Genetic MH - Female MH - Gene Expression Regulation MH - Histone Deacetylases/blood/genetics/*metabolism MH - Humans MH - *Insulin Resistance MH - Male MH - Middle Aged MH - Sirtuin 1/*genetics PMC - PMC5122206 OTO - NOTNLM OT - Epigenetics OT - HDAC3 OT - Histone modification OT - Inflammation OT - Insulin resistance OT - Sirt1 OT - Type 2 diabetes EDAT- 2016/12/03 06:00 MHDA- 2017/04/30 06:00 PMCR- 2016/11/24 CRDT- 2016/12/02 06:00 PHST- 2016/05/29 00:00 [received] PHST- 2016/11/15 00:00 [accepted] PHST- 2016/12/02 06:00 [entrez] PHST- 2016/12/03 06:00 [pubmed] PHST- 2017/04/30 06:00 [medline] PHST- 2016/11/24 00:00 [pmc-release] AID - 293 [pii] AID - 10.1186/s13148-016-0293-3 [doi] PST - epublish SO - Clin Epigenetics. 2016 Nov 24;8:125. doi: 10.1186/s13148-016-0293-3. eCollection 2016.