Visfatin与胰岛素抵抗及糖尿病肾病的发病机制

Visfatin是哺乳动物合成烟酰胺腺嘌呤二核苷酸(NAD)的限速酶,同时具有类炎性反应因子样作用,可通过cAMP反应元件结合蛋白/蛋白激酶A途径调控肝脏糖异生及葡萄糖代谢,通过NAD、沉默信息调节因子1参与调节胰岛素敏感性及胰岛β细胞功能.此外,visfatin还可调节肾细胞的胰岛素信号转导及葡萄糖代谢,与炎性因子、肾素-血管紧张素系统相互作用,参与糖尿病肾病的发生、发展,为糖尿病及糖尿病肾病的治疗提供新思路.     

SIRT1与血管性疾病的研究进展

沉默信息调节因子2相关酶1 (SIRT1)是一种高度保守的NAD+依赖的第Ⅲ类组蛋白去乙酰化酶,主要通过翻译后修饰调节DNA损伤修复、氧化应激、炎症、细胞衰老、凋亡与增殖等,从而参与血管性疾病的发生发展.因此,SIRT1可能成为治疗血管性疾病的潜在靶点.本文主要对SIRT1的主要生理作用及其在动脉粥样硬化、高血压、肺动脉高压、糖尿病肾病及糖尿病视网膜病变等常见血管性疾病中的作用作一综述.     

SIRT1在神经退行性疾病中的作用研究新进展

SIRT1是高度保守的去乙酰化酶家族成员,是酵母沉默信息调节因子Sir2的同源物。SIRT1具有组蛋白/非组蛋白去乙酰化酶活性,通过其可逆的乙酰化—去乙酰化循环反应参与调节多种细胞功能,可参与抗凋亡、抗炎、抗氧化应激、调节能量代谢、调控细胞周期等过程。近年来,其在神经退行性疾病中的作用受到越来越广泛关注,本文就SIRT1在神经退行性疾病中的作用研究新进展作一综述。     

SIRT1在糖脂代谢中的作用

SIRT1是一种NAD+依赖的组蛋白脱乙酰基蛋白酶,参与体内众多蛋白酶和转录因子的活性调节.在哺乳动物中,SIRT1促进脂肪动员、脂肪酸氧化、葡萄糖产生和胰岛素分泌.SIRT1激动剂可明显改善机体的胰岛素敏感性,降低血浆葡萄糖水平.因此,SIRT1激动剂的使用将可能成为2型糖尿病的新的治疗途径.     

沉默信息调节因子2与基因转录调控

沉默信息调节因子2(silence information regulator 2,Sir2)家族是一类保守的去乙酰化酶蛋白家族,广泛存在于古细菌到哺乳动物的多种生物中,具有依赖NAD+的去乙酰化酶和ADP-核糖转移酶活性。Sir2在染色质沉默、基因调控、代谢调节和细胞寿命调节等众多生命活动中发挥着重要作用。它主要是通过去乙酰化酶活性以及与其他蛋白相互作用从而调节染色质结构、修饰转录相关因子,实现对基因转录的调节。本文重点对Sir2参与基因转录调控的研究进展作一综述。     

沉默信息调节因子T1在心血管疾病中的作用

细胞生物学的最新进展表明沉默信息调节因子2(SIR2)相关酶类在心脏应激条件下的病理生理机制中扮演着重要角色。目前大部分物种均存在SIR2同源基因,统称为sirtuins(SIRT)家族,其中研究最广泛的是沉默信息调节因子T1(SIRT1),它是许多心血管疾病发生和发展的关键调节因子。本文综述了SIRT1的基本特征以及其在心血管疾病中的作用及可能机制,为心血管疾病的预防、诊断和治疗提供了新的思路。     

足细胞自噬与糖尿病肾病

自噬是机体主要防御机制之一,在代谢器官和疾病的发展中发挥重要的作用.高糖状态可抑制足细胞自噬活性,导致糖尿病肾病的发生、发展.研究表明,哺乳动物雷帕霉素靶蛋白(mTOR)、AMP活化蛋白激酶(AMPK)、沉默信息调节因子1(Sirt1)、内质网应激(ERS)和晚期糖基化终末产物(AGE)等营养信号通路对自噬有重要的调控作用,可能参与糖尿病肾病的发生、发展,有望成为糖尿病肾病防治新的靶点.     

足细胞能量代谢调节因子与糖尿病肾病

足细胞结构和功能异常是糖尿病肾病(DN)发生蛋白尿并不断进展的重要原因.足细胞主要通过糖酵解供能,而线粒体稳态对于足细胞正常发挥生物学功能极为重要.研究发现,糖尿病时足细胞胰岛素敏感性下降,线粒体功能障碍进而导致足细胞能量利用障碍和足细胞损伤.AMP激活的蛋白激酶(AMPK)/沉默信息调节因子1(SIRT1)/过氧化物...     

SIRT3与胰岛素抵抗

沉默信息调节因子(SIRT)3是哺乳动物类NAD+依赖性组蛋白去乙酰化酶家族中的一员.研究表明,SIRT3可以改善胰岛素抵抗、增加胰岛素敏感性.其通过保护胰岛β细胞、促进骨骼肌葡萄糖摄取、调节骨骼肌代谢、减轻氧化应激、抵抗高糖诱导的细胞毒性等途径发挥作用.SIRT3为治疗2型糖尿病、肥胖、线粒体功能障碍等疾病带来了新的研究方向.     

SIRT1的神经保护机制

Sirtuin是一类作用于组蛋白的去乙酰化酶,Sirtuin-1(SIRT1)是哺乳动物中与沉默调控基因SIR2同源性最高的同系物.SIRT1的主要功能是调控机体能最代谢、细胞衰老以及对应激的反应.SIRT1通过与多种参与应激反应中的转录因子相互作用抑制细胞凋亡,是一种神经保护药.     

Sirtuin 3 regulates mouse pancreatic beta cell function and is suppressed in pancreatic islets isolated from human type 2 diabetic patients

Aims/hypothesis

Sirtuin (SIRT)3 is a mitochondrial protein deacetylase that regulates reactive oxygen species (ROS) production and exerts anti-inflammatory effects. As chronic inflammation and mitochondrial dysfunction are key factors mediating pancreatic beta cell impairment in type 2 diabetes, we investigated the role of SIRT3 in the maintenance of beta cell function and mass in type 2 diabetes.

Methods

We analysed changes in SIRT3 expression in experimental models of type 2 diabetes and in human islets isolated from type 2 diabetic patients. We also determined the effects of SIRT3 knockdown on beta cell function and mass in INS1 cells.

Results

SIRT3 expression was markedly decreased in islets isolated from type 2 diabetes patients, as well as in mouse islets or INS1 cells incubated with IL1β and TNFα. SIRT3 knockdown in INS1 cells resulted in lowered insulin secretion, increased beta cell apoptosis and reduced expression of key beta cell genes. SIRT3 knockdown also blocked the protective effects of nicotinamide mononucleotide on pro-inflammatory cytokines in beta cells. The deleterious effects of SIRT3 knockdown were mediated by increased levels of cellular ROS and IL1β.

Conclusions/interpretation

Decreased beta cell SIRT3 levels could be a key step in the onset of beta cell dysfunction, occurring via abnormal elevation of ROS levels and amplification of beta cell IL1β synthesis. Strategies to increase the activity or levels of SIRT3 could generate attractive therapies for type 2 diabetes.     

Association between low SIRT1 expression in visceral and subcutaneous adipose tissues and metabolic abnormalities in women with obesity and type 2 diabetes

Aims

To assess the importance of adipose tissue sirtuin 1 (SIRT1) in the regulation of whole-body metabolism in humans with obesity and type 2 diabetes.

Methods

In total, 19 non-diabetic obese women, 19 type 2 diabetic women undergoing gastric bypass surgery, and 27 normal-weight women undergoing gynecological surgery (total 65 women) were enrolled. Their anthropometric variables, abdominal fat distribution and metabolic parameters, serum adiponectin concentrations, and SIRT1 mRNA and protein and adiponectin mRNA expressions in visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) were measured.

Results

SIRT1 mRNA levels in VAT and SAT were similar and these levels were suppressed in obese and type 2 diabetic women compared to normal-weight subjects. These decreases in SIRT1 expression were observed in both adipocytes and non-fat cells. There was a strong association between adipose tissue SIRT1 mRNA and protein levels. Adipose SIRT1 expression correlated inversely with HOMA-IR and other insulin resistance-related parameters. Adipose SIRT1 and adiponectin mRNA expression correlated very strongly and positively. SIRT1 mRNA level in VAT correlated inversely with visceral obesity whereas its expression in SAT correlated negatively with body mass index.

Conclusions

Adipose tissue SIRT1 may play a key role in the regulation of whole body metabolic homeostasis in humans. Downregulation of SIRT1 in VAT may contribute to the metabolic abnormalities that are associated with visceral obesity.     

The Tellurium compound, AS101, increases SIRT1 level and activity and prevents type 2 diabetes

The histone deacetylase, SIRT1, plays a major role in glucose regulation and lipid metabolism. Ammonium Trichloro (dioxoethylene-o,o') Tellurate, AS101, is a potent in vitro and in vivo immunomodulator, with several potential therapeutic applications. AS101 administration resulted in upregulation of SIRT1 protein expression and activity. These effects were associated with decreased levels of serum insulin like growth factor-1 (IGF-1) and of insulin. The properties of AS101 prompted us to investigate its potential therapeutic role in rats with type 2 diabetes (T2D). T2D was induced by a high fat diet combined with a low dose of Streptozotocin (STZ). Treatment with AS101 before manifestation of hyperglycemia, resulted in increased insulin sensitivity, and decreased blood glucose levels, and prevented symptoms of diabetes including defective glucose clearance, fatty liver, and abnormal distribution of insulin-producing beta cells in the pancreas. Treatment after disease emergence resulted in partial restoration of normal glucose homeostasis. Diabetic rats showed a reduction in liver SIRT1 levels. In both treatment regimens the reduction in SIRT1 levels in the liver were blocked by AS101 consumption. Together, these findings demonstrate the therapeutic potential of AS101 for treating T2D, and for reversing impaired fat and glucose metabolism.     

Emerging beneficial roles of sirtuins in heart failure

Sirtuins are a highly conserved family of histone/protein deacetylases whose activity can prolong the lifespan of model organisms such as yeast, worms and flies. In mammalian cells, seven sirtuins (SIRT1-7) modulate distinct metabolic and stress-response pathways, SIRT1 and SIRT3 having been most extensively investigated in the cardiovascular system. SIRT1 and SIRT3 are mainly located in the nuclei and mitochondria, respectively. They participate in biological functions related to development of heart failure, including regulation of energy production, oxidative stress, intracellular signaling, angiogenesis, autophagy and cell death/survival. Emerging evidence indicates that the two sirtuins play protective roles in failing hearts. Here, we summarize current knowledge of sirtuin functions in the heart and discuss its translation into therapy for heart failure.     

Melatonin prevents Drp1‐mediated mitochondrial fission in diabetic hearts through SIRT1‐PGC1α pathway

Myocardial contractile dysfunction is associated with an increase in mitochondrial fission in patients with diabetes. However, whether mitochondrial fission directly promotes diabetes‐induced cardiac dysfunction is still unknown. Melatonin exerts a substantial influence on the regulation of mitochondrial fission/fusion. This study investigated whether melatonin protects against diabetes‐induced cardiac dysfunction via regulation of mitochondrial fission/fusion and explored its underlying mechanisms. Here, we show that melatonin prevented diabetes‐induced cardiac dysfunction by inhibiting dynamin‐related protein 1 (Drp1)‐mediated mitochondrial fission. Melatonin treatment decreased Drp1 expression, inhibited mitochondrial fragmentation, suppressed oxidative stress, reduced cardiomyocyte apoptosis, improved mitochondrial function and cardiac function in streptozotocin (STZ )‐induced diabetic mice, but not in SIRT 1^?/? diabetic mice. In high glucose‐exposed H9c2 cells, melatonin treatment increased the expression of SIRT 1 and PGC ‐1α and inhibited Drp1‐mediated mitochondrial fission and mitochondria‐derived superoxide production. In contrast, SIRT 1 or PGC ‐1α siRNA knockdown blunted the inhibitory effects of melatonin on Drp1 expression and mitochondrial fission. These data indicated that melatonin exerted its cardioprotective effects by reducing Drp1‐mediated mitochondrial fission in a SIRT 1/PGC ‐1α‐dependent manner. Moreover, chromatin immunoprecipitation analysis revealed that PGC ‐1α directly regulated the expression of Drp1 by binding to its promoter. Inhibition of mitochondrial fission with Drp1 inhibitor mdivi‐1 suppressed oxidative stress, alleviated mitochondrial dysfunction and cardiac dysfunction in diabetic mice. These findings show that melatonin attenuates the development of diabetes‐induced cardiac dysfunction by preventing mitochondrial fission through SIRT 1‐PGC 1α pathway, which negatively regulates the expression of Drp1 directly. Inhibition of mitochondrial fission may be a potential target for delaying cardiac complications in patients with diabetes.     

Inhibition of silent information regulator 1 induces glucose metabolism disorders of hepatocytes and enhances hepatitis C virus replication

Background and objective

Glucose metabolism disorders including insulin resistance (IR) and type 2 diabetes are frequent and important cofactors of chronic hepatitis C (CHC). Silent information regulator 1 (SIRT1) plays a key role in the regulation of hepatic glucose metabolism. We investigated the possible effect of HCV replication on glucose metabolism of hepatocytes and expression of SIRT1 using Huh-7.5 cells harboring the HCV replicon.

Methods

The level of reactive oxygen species (ROS) and value of NAD⁺/NADH and ATP/ADP were detected. Glucose uptake by hepatocytes and glucose production were measured. The activity and expression levels of SIRT1 and expression of its downstream glucose-metabolism genes were measured.

Results

In replicon cells, the level of ROS increased and the value of nicotinamide adenine dinucleotide (NAD⁺)/NADH decreased, then the activity and expression level of mRNA and protein of SIRT1 decreased. Inhibition of SIRT1 not only increased insulin receptor substrate-1 phosphorylation and decreased Akt phosphorylation, inhibited cell surface expression of glucose transporter 2 and suppressed cellular glucose uptake, but it also decreased phosphorylation of forkhead box O1, then upregulated phosphoenolpyruvate carboxykinase and glucose 6-phosphatase genes and downregulated the glucokinase gene, thus promoting glucose production. Interferon treatment restored the aforementioned changes. SIRT1 activator improved glucose metabolism disorders by an increase in glucose uptake and a decrease in glucose production, and it inhibited HCV replication.

Conclusions

HCV replication decreasing the NAD⁺/NADH ratio may downregulate the activity and expression of SIRT1, then change the expression profile of glucose metabolism-related genes, thereby causing glucose metabolism disorders of hepatocytes and promoting HCV replication. Treatment with SIRT1 activator improves glucose metabolic disorders and inhibits HCV replication, suggesting that restoration of SIRT1 activity may be a promising new therapeutic approach for CHC patients with IR.     

Hypothalamic AMP-activated protein kinase as a mediator of whole body energy balance

The AMP-activated protein kinase (AMPK) is the downstream constituent of a kinase cascade that acts as a sensor of cellular energy levels. Current data unequivocally indicate that hypothalamic AMPK plays a key role in the control of the whole body energy balance, by integrating peripheral signals, such as hormones and metabolites, with central signals, such as neuropeptides, and eliciting allostatic changes in energy homeostasis. Although the molecular details of these interactions are not fully understood, recent evidence has suggested that the interaction between AMPK with hypothalamic lipid metabolism and other metabolic sensors, such as the uncoupling protein 2 (UCP-2), the mammalian target of rapamycin (mTOR) and the deacetylase sirtuin 1 (SIRT1), may play a main role in the hypothalamic control of feeding and energy expenditure. Here, we summarize the role of hypothalamic AMPK as whole body energy gauge. Understanding this key molecule and especially its functions at central level may provide new therapeutic targets for the treatment of metabolic alterations and obesity.     

糖尿病心肌病变的研究进展

糖尿病心肌病变是糖尿病心脏并发症的重要组成部分,主要表现为心室舒张功能受损和心功能不全。研究提示,糖尿病时,心肌细胞能量代谢紊乱,功能改变,凋亡增加,促使心肌纤维化的一些细胞因子和炎症因子异常表达。这些发现揭示,糖尿病从多个方面损害心肌细胞,引起心室重构,这为进一步阐明糖尿病心肌病变发病机制提供了有力证据。     

Role of sirtuins in ischemia-reperfusion injury

Ischemia-reperfusion injury(IRI)remains an unresolved and complicated situation in clinical practice,especially in the case of organ transplantation.Several factors contribute to its complexity;the depletion of energy during ischemia and the induction of oxidative stress during reperfusion initiate a cascade of pathways that lead to cell death and finally to severe organ injury.Recently,the sirtuin family of nicotinamide adenine dinucleotide-dependent deacetylases has gained increasing attention from researchers,due to their involvement in the modulation of a wide variety of cellular functions.There are seven mammalian sirtuins and,among them,the nuclear/cytoplasmic sirtuin 1(SIRT1)and the mitochondrial sirtuin 3(SIRT3)are ubiquitously expressed in many tissue types.Sirtuins are known to play major roles in protecting against cellular stress and in controlling metabolic pathways,which are key processes during IRI.In this review,we mainly focus on SIRT1 and SIRT3 and examine their role in modulating pathways against energy depletion during ischemia and their involvement in oxidative stress,apoptosis,microcirculatory stress and inflammation during reperfusion.We present evidence of the beneficial effects of sirtuins against IRI and emphasize the importance of developing new strategies by enhancing their action.