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Review
. 2019 Mar 27:10:187.
doi: 10.3389/fendo.2019.00187. eCollection 2019.

Sirtuins and Type 2 Diabetes: Role in Inflammation, Oxidative Stress, and Mitochondrial Function

Munehiro Kitada  1   2 , Yoshio Ogura  1 , Itaru Monno  1 , Daisuke Koya  1   2
Affiliations
Review

Sirtuins and Type 2 Diabetes: Role in Inflammation, Oxidative Stress, and Mitochondrial Function

Munehiro Kitada et al. Front Endocrinol (Lausanne). .

Abstract

The rising incidence of type 2 diabetes mellitus (T2DM) is a major public health concern, and novel therapeutic strategies to prevent T2DM are urgently needed worldwide. Aging is recognized as one of the risk factors for metabolic impairments, including insulin resistance and T2DM. Inflammation, oxidative stress, and mitochondrial dysfunction are closely related to both aging and metabolic disease. Calorie restriction (CR) can retard the aging process in organisms ranging from yeast to rodents and delay the onset of numerous age-related disorders, such as insulin resistance and diabetes. Therefore, metabolic CR mimetics may represent new therapeutic targets for insulin resistance and T2DM. Sirtuin 1 (SIRT1), the mammalian homolog of Sir2, was originally identified as a nicotinamide adenine dinucleotide (NAD+)-dependent histone deacetylase. The activation of SIRT1 is closely associated with longevity under CR, and it is recognized as a CR mimetic. Currently, seven sirtuins have been identified in mammals. Among these sirtuins, SIRT1 and SIRT2 are located in the nucleus and cytoplasm, SIRT3 exists predominantly in mitochondria, and SIRT6 is located in the nucleus. These sirtuins regulate metabolism through their regulation of inflammation, oxidative stress and mitochondrial function via multiple mechanisms, resulting in the improvement of insulin resistance and T2DM. In this review, we describe the current understanding of the biological functions of sirtuins, especially SIRT1, SIRT2, SIRT3, and SIRT6, focusing on oxidative stress, inflammation, and mitochondrial function, which are closely associated with aging.

Keywords: SIRT1; SIRT2; SIRT3; SIRT6; Type 2 diabetes.

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Figures

Figure 1
Figure 1
A vicious cycle among oxidative stress, inflammation, and mitochondrial dysfunction is involved in the pathogenesis of insulin resistance, type 2 diabetes, and aging. Sirtuins, including SIRT1, 2, 3, and 6, may be a therapeutic target for the treatment of age-related insulin resistance and T2DM by breaking this vicious cycle.
Figure 2
Figure 2
(A) In monocytes/macrophages and adipocytes, SIRT1 deacetylates NF-κB(p65), resulting in reduced expression of inflammatory mediators such as TNF-α and MCP-1. SIRT1 inactivation also induces inflammation through the phosphorylation of the NF-κB pathway via impaired autophagy, which is associated with activation of mammalian target of rapamycin (mTOR) and reduced activation of AMP-activated kinase (AMPK). (B) In adipocytes, SIRT1 deacetylates nuclear factor-κB p65 subunit [NF-κB(p65)], resulting in reduced expression of inflammatory mediators such as tumor necrosis factor-α (TNF-α) and chemoattractant protein-1 (MCP-1), and decreased polarization to M1 macrophages and infiltration to adipose tissue. SIRT also induces polarization to M2 macrophages through increased expression of interleukin-4 (IL-4) expression via deacetylation of nuclear factor of activated T-cells 1 (NFATc1). (C) In skeletal muscle, SIRT1 increases mitochondrial biogenesis and fatty acid oxidation through acetylation and activation of the peroxisome proliferator-activated receptor (PPAR)-γ coactivator-1α (PGC-1α). Under conditions of insulin resistance, diabetes, obesity, or aging, mitochondrial oxidative capacity is decreased, contributing to the generation of reactive oxygen species (ROS) in mitochondria. Hyperglycemia, free fatty acids (FFAs) and TNF-α stimulate ROS production from the mitochondria, and increased levels of ROS lead to the serine-phosphorylation of insulin receptor substrate-1 (IRS-1), resulting in reduced insulin signaling. However, SIRT1 interacts with phosphoinositide 3-kinase (PI3K), leading to activation of insulin signaling. Additionally, SIRT1 activates PGC-1α transcriptional activity to induce mitochondrial biogenesis and the induction of antioxidative enzymes, which can inhibit the generation of ROS by mitochondria. Expression of glucose transporter 4 (GLUT4) is enhanced through deacetylation of PGC-1α by SIRT1. Moreover, SIRT1 activates peroxisome proliferator-activated receptor-α (PPAR-α), which induces fatty acid oxidation. (D) SIRT1 deacetylates Forkhead box protein O1 (FOXO1) and enhances its interaction with CCAAT/enhancer binding protein α (C/EBPα), resulting in the enhanced transcription of adiponectin in adipocytes. In skeletal muscle, adiponectin is involved in the regulation of Ca2+ signaling and PGC-1α expression through calcium/calmodulin-dependent protein kinase kinase (CaMKK) and calcium/calmodulin-dependent protein kinase (CaMK) activation. Adiponectin activates SIRT1 through AMPK activation, thereby deacetylating PGC-1α and resulting in mitochondrial biogenesis, increased fatty acid oxidation, and oxidative phosphorylation.
Figure 3
Figure 3
(A) SIRT2 deacetylates nuclear factor-κB p65 subunit [NF-κB (p65)], resulting in decreased expression of inflammatory mediators. Sirt2 also induces Mn-SOD expression by deacetylating Forkhead box protein O3a (FOXO3a). Additionally, SIRT2 increases fusion-related protein mitofusion2 (Mfn2) and decreases mitochondrial-associated dynamin-related protein 1 (Drp1), resulting in an increased number of elongated mitochondria and improved mitochondrial function. SIRT2 also attenuates the downregulation of transcription factor A, mitochondrial (TFAM), a key mitochondrial deoxyribonucleic acid (mtDNA)-associated protein, leading to an increase in mitochondrial mass. (B) Glucose-6-phosphate dehydrogenase (G6PD) plays an important role in the oxidative stress response by producing nicotinamide adenine dinucleotide phosphate (NADPH) and the reduced form glutathione (GSH), which is associated with deacetylating G6PD and binding to nicotinamide adenine dinucleotide phosphate (NADP+). (C) Hypoxia-inducible factor1α (HIF1α), which is accumulated in the adipocytes of hypertrophy, represses SIRT2 expression, resulting in decreased deacetylation of PGC-1α and the expression of β-oxidation and mitochondrial genes.
Figure 4
Figure 4
SIRT3 deacetylates the electron transport chain complexes I, II [deacetylate succinate dehydrogenase (SDH) A] and III, leading to increased oxidative phosphorylation. SIRT3 also attenuates oxidative stress by enhancing the glutathione antioxidant defense system via deacetylation and activation of isocitrate dehydrogenase 2 (IDH2) and manganese superoxide dismutase (Mn-SOD).
Figure 5
Figure 5
SIRT6 also attenuates NF-κB signaling via histone H3K9 deacetylation at the chromatin level. SIRT6 suppresses the high-fat diet (HFD)-, LPS-, and IL-6-induced I-κ kinase (IKK)-nuclear factor-κB (NF-κB) pathway and Janus activating kinase 2 (JAK2)-signal transducer and activator of transcription 3 (STAT3) pathway, resulting in reduced M1 macrophage polarization and macrophage migration. Additionally, SIRT6 deacetylates pyruvate kinase M2 (PKM2), preventing STAT3 from phosphorylation.
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