线粒体功能紊乱与胰岛素抵抗

胰岛素抵抗是2型糖尿病的重要发病机制,而骨骼肌线粒体功能紊乱与胰岛素抵抗密切相关,遗传、环境、衰老以及氧化应激可以导致线粒体功能紊乱.胰岛素抵抗者伴有线粒体功能下降,通过运动或减重等手段改善胰岛素敏感性的同时,线粒体功能也得以改善,其机制可能与线粒体功能异常通过抑制胰岛素受体底物-l活性、干扰胰岛素信号转导系统有关.     

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.     

本刊2011年第5期部分文题介绍

1．自噬与脂质代谢的研究现状及进展2．自噬在胰岛素抵抗发生中的作用3．线粒体功能在骨骼肌胰岛素抵抗中的作用4．线粒体功能紊乱与胰岛素抵抗5．靶组织胰岛素敏感性评估方法及其原理研究进展6．营养物质刺激肠道L细胞分泌GLP-1机制的研究进展7．高迁移率族蛋白B1与2型糖尿病     

肌肉生长抑制素与代谢性疾病的研究进展

代谢性疾病指机体的蛋白质、脂肪和碳水化合物等物质出现代谢紊乱, 其中胰岛素抵抗是其重要的病理基础。近期发现一种肌源性因子——肌肉生长抑制素, 它在胰岛素抵抗人群中高表达, 不仅参与骨骼肌的生长分化, 还调控机体能量代谢, 介导胰岛素抵抗。因此, 肌肉生长抑制素可能在代谢性疾病的发生、发展中发挥重要作用, 有望成为防治代谢性疾病的新靶点。本文在现有文献的基础上对肌肉生长抑制素与代谢性疾病的研究进展进行综述。     

长期锻炼后机体氧化能力的提高可削弱脂类引起的胰岛素抵抗

骨骼肌脂肪堆积以及线粒体氧化能力下降与胰岛素抵抗相关。训练强度高的运动员尽管其肌细胞内脂类水平较高，但对胰岛素高度敏感，线粒体的氧化能力较强。荷兰马斯特里赫特大学医学中心的Phielix等对高氧化能力能否降低脂质引起的胰岛素抵抗进行了探讨。     

线粒体功能在骨骼肌胰岛素抵抗中的作用

线粒体是提供细胞进行各种生命活动所需能量的细胞器,越来越多的证据表明,线粒体功能与骨骼肌胰岛素抵抗状态密切相关,这种机制可能因为线粒体功能损伤引发脂肪酸β-氧化功能障碍,最终影响胰岛素受体后信号转导通路而致胰岛素抵抗的发生;也可因为线粒体融合蛋白或基因调控受损造成线粒体动力学异常或膜电位下降,造成胰岛素抵抗.目前对于线...     

2型糖尿病合并肌少症的发病机制、药物治疗及健康管理研究进展

2型糖尿病(T2DM)是临床常见内分泌疾病,以血糖异常及胰岛素抵抗为主要特征;肌少症则是以骨骼肌质量及力量减少为特征的症候群.两者在发病机制上存在着共同点,临床也常合并出现.T2 DM合并肌少症的发病机制主要涉及骨骼肌代谢平衡紊乱、线粒体损伤、氧化应激及胰岛素抵抗.T2 DM合并肌少症的治疗方法是通过补充外源性胰岛素,...     

CD36与脂肪酸代谢和胰岛素抵抗

CD36是参与脂肪酸代谢的各种组织表面重要的脂肪酸转运体(FAT),介导这些组织对脂肪酸的摄取.鉴于脂肪酸的氧化代谢与胰岛素抵抗和2型糖尿病关系密切,许多研究开始关注FAT/CD36在胰岛素抵抗中的角色.骨骼肌和脂肪组织是人体参与脂防酸代谢的主要器官.其中骨骼肌主要通过细胞表面的CD36摄取及氧化脂肪酸以消耗循环中的游离脂肪酸而提供肌肉收缩的能量,而脂肪组织则通过它将摄取的脂肪酸酯化储存以备能量之需.因此,本文将重点叙述CD36在骨骼肌及脂肪组织中的作用,以探讨其与胰岛素抵抗的关系.     

游离脂肪酸对骨骼肌葡萄糖利用的影响

胰岛素抵抗是2型糖尿病的关键环节,近年来发现在许多胰岛素抵抗状态下均伴有游离脂肪酸水平的升高,游离脂肪酸在胰岛素抵抗的发病机制中占有重要的地位。骨骼肌是胰岛素作用及胰岛素抵抗的主要部位,是葡萄糖代谢的重要组织。游离脂肪酸不仅可以干扰骨骼肌葡萄糖代谢的不同环节,而且还在胰岛素受体及受体后的信号转导方面发挥作用,降低胰岛素刺激的骨骼肌葡萄糖的转运。     

糖尿病性骨骼肌病变的研究进展

骨骼肌是葡萄糖摄取和利用的重要组织,也是胰岛素发挥作用的靶组织.骨骼肌病变可加重胰岛素抵抗(IR),进一步影响机体的糖代谢.糖尿病性骨骼肌病变常因其临床表现不典型而被忽视,其发病机制复杂,与血管性因素、神经性因素、代谢性因素、氧化应激、细胞凋亡、慢性炎性反应等均有关.因此,明确其临床特点及发病机制是近年来研究糖尿病性骨骼肌病变的重点.     

Skeletal muscle triglyceride: Marker or mediator of obesity-induced insulin resistance in type 2 diabetes mellitus?

The inability of insulin to stimulate glucose metabolism in skeletal muscle is a classic characteristic of type 2 diabetes, but this insulin resistance entails altered patterns of lipid metabolism as well. An association between intracellular triglyceride and insulin resistance has been well established in both human and animal studies of obesity-related insulin resistance and type 2 diabetes. Skeletal muscle’s ability to select substrate for fuel metabolism, a metabolic flexibility, is also lost in insulin resistance, and defects in fatty acid metabolism during fasting or postabsorptive conditions likely play an important role in lipid oversupply to insulinresistant muscle. These impairments appear to be at least indirectly centered on the ability of mitochondria to oxidize fatty acids, possibly through mediation of lipid metabolite levels such as ceramide or diacylglycerol, which are known to directly attenuate insulin signaling. Moreover, periodic use of muscle triglyceride by exercise may mediate the association between muscle triglyceride and insulin resistance. Thus, it appears that skeletal muscle triglyceride is perhaps a surrogate for other lipid species having a more direct effect on insulin action. Defining mechanisms by which dysregulation of fatty acid metabolism and persistent lipid oversupply alter insulin action may help to target more effective strategies to prevent or treat type 2 diabetes.     

糖代谢与骨骼肌的关系

骨骼肌是体内胰岛素刺激下摄取葡萄糖的主要组织,在糖代谢平衡中发挥着重要的作用.病理状态下的骨骼肌这种代谢调节能力下降.肌糖原及循环中葡萄糖是维持骨骼肌细胞正常代谢及功能的主要物质.糖代谢紊乱尤其是高血糖对骨骼肌的代谢、结构及功能等都有明显影响,包括高血糖导致骨骼肌胰岛素抵抗、对肌糖原代谢的影响、肌萎缩以及血管异常等,肌组织病变反过来又影响代谢的控制,使病情加重.     

Pathophysiology of insulin resistance

Insulin resistance is a feature of a number of clinical disorders, including type 2 diabetes/glucose intolerance, obesity, dyslipidaemia and hypertension clustering in the so-called metabolic syndrome. Insulin resistance in skeletal muscle manifests itself primarily as a reduction in insulin-stimulated glycogen synthesis due to reduced glucose transport. Ectopic lipid accumulation plays an important role in inducing insulin resistance. Multiple defects in insulin signalling are responsible for impaired glucose metabolism in target tissues of subjects with features of insulin resistance. Inflammatory molecules and lipid metabolites inhibit insulin signalling by stimulating a number of different serine kinases which are responsible for serine phosphorylation of Insulin Receptor Substrate-1 (IRS-1).     

Resistance training,visceral obesity and inflammatory response: a review of the evidence

Intra‐abdominal obesity is an important risk factor for low‐grade inflammation, which is associated with increased risk for diabetes mellitus and cardiovascular disease. For the most part, recommendations to treat or prevent overweight and obesity via physical activity have focused on aerobic endurance training as it is clear that aerobic training is associated with much greater energy expenditure during the exercise session than resistance training. However, due to the metabolic consequences of reduced muscle mass, it is understood that normal ageing and/or decreased physical activity may lead to a higher prevalence of metabolic disorders. Whether resistance training alters visceral fat and the levels of several pro‐inflammatory cytokines produced in adipose tissue has not been addressed in earlier reviews. Because evidence suggests that resistance training may promote a negative energy balance and may change body fat distribution, it is possible that an increase in muscle mass after resistance training may be a key mediator leading to a better metabolic control. Considering the benefits of resistance training on visceral fat and inflammatory response, an important question is: how much resistance training is needed to confer such benefits? Therefore, the purpose of this review was to address the importance of resistance training on abdominal obesity, visceral fat and inflammatory response.     

Role of mitochondrial dysfunction in insulin resistance

Insulin resistance is characteristic of obesity, type 2 diabetes, and components of the cardiometabolic syndrome, including hypertension and dyslipidemia, that collectively contribute to a substantial risk for cardiovascular disease. Metabolic actions of insulin in classic insulin target tissues (eg, skeletal muscle, fat, and liver), as well as actions in nonclassic targets (eg, cardiovascular tissue), help to explain why insulin resistance and metabolic dysregulation are central in the pathogenesis of the cardiometabolic syndrome and cardiovascular disease. Glucose and lipid metabolism are largely dependent on mitochondria to generate energy in cells. Thereby, when nutrient oxidation is inefficient, the ratio of ATP production/oxygen consumption is low, leading to an increased production of superoxide anions. Reactive oxygen species formation may have maladaptive consequences that increase the rate of mutagenesis and stimulate proinflammatory processes. In addition to reactive oxygen species formation, genetic factors, aging, and reduced mitochondrial biogenesis all contribute to mitochondrial dysfunction. These factors also contribute to insulin resistance in classic and nonclassic insulin target tissues. Insulin resistance emanating from mitochondrial dysfunction may contribute to metabolic and cardiovascular abnormalities and subsequent increases in cardiovascular disease. Furthermore, interventions that improve mitochondrial function also improve insulin resistance. Collectively, these observations suggest that mitochondrial dysfunction may be a central cause of insulin resistance and associated complications. In this review, we discuss mechanisms of mitochondrial dysfunction related to the pathophysiology of insulin resistance in classic insulin-responsive tissue, as well as cardiovascular tissue.     

Mitochondrial dysfunction and type 2 diabetes

Insulin resistance plays a major role in the pathogenesis of the metabolic syndrome and type 2 diabetes, and yet the mechanisms responsible for it remain poorly understood. Magnetic resonance spectroscopy studies in humans suggest that a defect in insulin-stimulated glucose transport in skeletal muscle is the primary metabolic abnormality in insulin-resistant patients with type 2 diabetes. Fatty acids appear to cause this defect in glucose transport by inhibiting insulin-stimulated tyrosine phosphorylation of insulin receptor substrate-1 (IRS-1) and IRS-1-associated phosphatidylinositol 3-kinase activity. A number of different metabolic abnormalities may increase intramyocellular and intrahepatic fatty acid metabolites; these include increased fat delivery to muscle and liver as a consequence of either excess energy intake or defects in adipocyte fat metabolism, and acquired or inherited defects in mitochondrial fatty acid oxidation. Understanding the molecular and biochemical defects responsible for insulin resistance is beginning to unveil novel therapeutic targets for the treatment of the metabolic syndrome and type 2 diabetes.     

Mechanisms of insulin resistance in humans and possible links with inflammation

Insulin resistance is a major player in the pathogenesis of the metabolic syndrome and type 2 diabetes, and yet, the mechanisms responsible for it remain poorly understood. Magnetic resonance spectroscopy studies in humans suggest that a defect in insulin-stimulated glucose transport in skeletal muscle is the primary metabolic abnormality in insulin-resistant type 2 diabetics. Fatty acids appear to cause this defect in glucose transport by inhibiting insulin-stimulated tyrosine phosphorylation of insulin receptor substrate-1 (IRS-1) and IRS-1 associated phosphatidylinositol 3-kinase activity. A number of different metabolic abnormalities may increase intramyocellular/intrahepatic fatty acid metabolites; these include increased fat delivery to muscle/liver as a consequence of either excess energy intake or defects in adipocyte fat metabolism and acquired or inherited defects in mitochondrial fatty acid oxidation. Understanding the molecular/biochemical defects responsible for insulin resistance is beginning to unveil novel therapeutic targets for treatment of the metabolic syndrome and type 2 diabetes.