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      Epigenetic Regulation Associated With Sirtuin 1 in Complications of Diabetes Mellitus


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          Diabetes mellitus (DM) has been one of the largest health concerns of the 21st century due to the serious complications associated with the disease. Therefore, it is essential to investigate the pathogenesis of DM and develop novel strategies to reduce the burden of diabetic complications. Sirtuin 1 (SIRT1), a nicotinamide adenosine dinucleotide (NAD +)-dependent deacetylase, has been reported to not only deacetylate histones to modulate chromatin function but also deacetylate numerous transcription factors to regulate the expression of target genes, both positively and negatively. SIRT1 also plays a crucial role in regulating histone and DNA methylation through the recruitment of other nuclear enzymes to the chromatin. Furthermore, SIRT1 has been verified as a direct target of many microRNAs (miRNAs). Recently, numerous studies have explored the key roles of SIRT1 and other related epigenetic mechanisms in diabetic complications. Thus, this review aims to present a summary of the rapidly growing field of epigenetic regulatory mechanisms, as well as the epigenetic influence of SIRT1 on the development and progression of diabetic complications, including cardiomyopathy, nephropathy, and retinopathy.

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          Most cited references 101

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          IDF Diabetes Atlas: Global estimates of diabetes prevalence for 2017 and projections for 2045

          Since the year 2000, IDF has been measuring the prevalence of diabetes nationally, regionally and globally.
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            Poly(ADP-ribose): novel functions for an old molecule.

            The addition to proteins of the negatively charged polymer of ADP-ribose (PAR), which is synthesized by PAR polymerases (PARPs) from NAD(+), is a unique post-translational modification. It regulates not only cell survival and cell-death programmes, but also an increasing number of other biological functions with which novel members of the PARP family have been associated. These functions include transcriptional regulation, telomere cohesion and mitotic spindle formation during cell division, intracellular trafficking and energy metabolism.
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              Small molecule activators of SIRT1 as therapeutics for the treatment of type 2 diabetes.

              Calorie restriction extends lifespan and produces a metabolic profile desirable for treating diseases of ageing such as type 2 diabetes. SIRT1, an NAD+-dependent deacetylase, is a principal modulator of pathways downstream of calorie restriction that produce beneficial effects on glucose homeostasis and insulin sensitivity. Resveratrol, a polyphenolic SIRT1 activator, mimics the anti-ageing effects of calorie restriction in lower organisms and in mice fed a high-fat diet ameliorates insulin resistance, increases mitochondrial content, and prolongs survival. Here we describe the identification and characterization of small molecule activators of SIRT1 that are structurally unrelated to, and 1,000-fold more potent than, resveratrol. These compounds bind to the SIRT1 enzyme-peptide substrate complex at an allosteric site amino-terminal to the catalytic domain and lower the Michaelis constant for acetylated substrates. In diet-induced obese and genetically obese mice, these compounds improve insulin sensitivity, lower plasma glucose, and increase mitochondrial capacity. In Zucker fa/fa rats, hyperinsulinaemic-euglycaemic clamp studies demonstrate that SIRT1 activators improve whole-body glucose homeostasis and insulin sensitivity in adipose tissue, skeletal muscle and liver. Thus, SIRT1 activation is a promising new therapeutic approach for treating diseases of ageing such as type 2 diabetes.

                Author and article information

                Front Endocrinol (Lausanne)
                Front Endocrinol (Lausanne)
                Front. Endocrinol.
                Frontiers in Endocrinology
                Frontiers Media S.A.
                18 January 2021
                : 11
                1 School of Nursing, Cheeloo College of Medicine, Shandong University , Jinan, China
                2 Department of Cardiology at the First Hospital of Jilin University , Changchun, China
                3 Department of Orthopedic Surgery, The First Affiliated Hospital of Shandong First Medical University , Jinan, China
                4 Department of Cardiology at the First Hospital of China Medical University, and Department of Cardiology at the People’s Hospital of Liaoning Province , Shenyang, China
                Author notes

                Edited by: Hao Wu, Shandong University, China

                Reviewed by: Madhu Khullar, Post Graduate Institute of Medical Education and Research (PGIMER), India; Daniele Pereira Santos-Bezerra, University of São Paulo, Brazil

                *Correspondence: Junlian Gu, junlian_gu@ 123456sdu.edu.cn

                This article was submitted to Diabetes: Molecular Mechanisms, a section of the journal Frontiers in Endocrinology

                Copyright © 2021 Wang(a), Wang, Wang(b), Xiao, Guo, Tang, Zhang and Gu

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                Page count
                Figures: 2, Tables: 2, Equations: 0, References: 101, Pages: 13, Words: 7501
                Funded by: Shandong University 10.13039/100009108
                Award ID: 21330089963007
                Funded by: National Natural Science Foundation of China 10.13039/501100001809
                Award ID: 81700329
                Funded by: National Natural Science Foundation of China 10.13039/501100001809
                Award ID: 81770375
                Funded by: Department of Science and Technology of Jilin Province 10.13039/501100011789
                Award ID: 20200801061GH

                Endocrinology & Diabetes

                diabetes mellitus, diabetic complications, sirt1, epigenetics, deacetylation


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