MG53是人类疾病的“双刃剑”（英文）

Mitsugumin 53(MG53),又名Trim72,是一种在心肌和骨骼肌中大量表达的TRIM家族成员。MG53不仅在多种重要的生理学功能中发挥作用,也是多种疾病的关键致病因素。首先,MG53通过促进细胞膜修复从而维持心肌和骨骼肌细胞的完整性。其次,MG53通过活化PI3K-Akt-GSK3β和ERK1/2细胞生存信号通路,参与心肌缺血预适应和后适应保护作用;而且外源性给予MG53重组蛋白,能够保护包括心脏、骨骼肌、肺脏、肾脏和皮肤在内的多种器官的缺血/再灌注和机械损伤。更重要的是,MG53能够作为E3连接酶,介导胰岛素受体和胰岛素受体底物1的降解,进而引起胰岛素抵抗和代谢性疾病(例如2型糖尿病)及其心血管并发症。另外,MG53还能够抑制骨骼肌分化。总之,在把MG53作为一个人类疾病的治疗靶点的时候,需要综合考虑其多种生物功能和机制,从而最大化其有益作用,并尽量避免其副作用。本综述系统地总结目前对MG53生物学功能,尤其是其作为临床疾病的治疗靶点的研究进展。     

胰岛素受体底物活性调控的分子机制

胰岛素受体底物(insulin receptor substrate,IRS)是胰岛素信号转导通路中一个极其重要的信号分子,对胰岛素信号级联效应具有至关重要的作用。目前有关胰岛素受体底物活性调节的研究主要集中在两个方面,一方面是磷酸化水平的调节机制,另一方面是细胞因子信号阻抑剂(suppressor of cytokine signaling,COCS)所介导的直接和间接调控。了解胰岛素受体底物活性调节机制将有助于进一步探索胰岛素抵抗和Ⅱ型糖尿病的发病机制。     

运动改善胰岛素抵抗与腺苷酸活化蛋白激酶关系的研究进展

腺苷酸活化蛋白激酶(AMP-activated protein kinase,AMPK)广泛存在于骨骼肌、肝脏、胰腺、脂肪组织及中枢神经系统中。作为"细胞能量调节器",AMPK激活后可通过多种机制改善胰岛素抵抗。本文综述了近年来AMPK(骨骼肌、肝脏和脂肪组织)的运动激活以及AMPK介导运动改善心血管胰岛素敏感性的研究进展,展望了AMPK运动激活的研究前景,旨在为全面了解和明确AMPK在运动干预效应中的重要地位提供理论依据。     

雄激素受体及其辅调节因子在肥胖及胰岛素抵抗中作用的研究进展

雄激素受体(androgen receptor,AR)是核受体超家族的成员,主要通过与配体(雄激素)结合的方式发挥其生物学功能。AR在调节男性精子生成和发育,维持男性第二性征等方面起重要作用。此外,AR在前列腺癌、肝癌等疾病的发生发展中起重要作用。更有趣的是,近来研究发现,AR及其介导的靶基因转录在抵抗肥胖,抑制机体产生胰岛素抵抗中也发挥着不可忽视的作用。AR的辅助调节因子参与调控AR介导的基因转录,通过不同的分子机制影响着AR的活性,并且影响机体能量代谢活动。现就AR结构与功能、AR的辅助调节因子的作用机制及其对脂代谢、胰岛素抵抗等影响进行综述。     

AMPK与胰岛素抵抗

糖代谢是物质代谢的基础,运动中骨骼肌糖代谢水平直接影响机体运动能力。近年来研究发现,腺苷酸活化蛋白激酶(AMPK)作为能量代谢变化的感受器能够被运动中ATP/AMP的比值变化所激活,并能直接改善骨骼肌胰岛素抵抗,对机体运动能力有重要的影响。同时AMPK的长期激活可能参与了运动训练引起的胰岛素敏感性增加的调节,虽然其机制尚不清楚。本文通过文献检索法对运动中AMPK的激活机制及其在改善胰岛素抵抗过程中的作用及机制进行综述。     

LncRNAs对肝脏胰岛素抵抗的调控及其机制

胰岛素抵抗是肥胖、2型糖尿病发生的共同病理生理机制。肝脏是胰岛素介导的葡萄糖摄取、代谢、利用的重要靶器官,也是胰岛素抵抗发生的重要部位。研究表明,肝脏糖异生信号通路、胰岛素信号通路、脂质生成信号通路、自噬及活性氧生成与肝脏胰岛素抵抗密切相关。肝脏可产生多种长链非编码RNAs(lncRNAs),当其表达上调(如Blnc1、Risa、MALAT1、MEG3、SRA、Gm10768、H19和Gomafu)或下调(如lncSHGL)时,它们可调控肝脏糖异生信号通路、胰岛素信号通路、脂质生成信号通路、自噬及活性氧生成,从而参与肝脏胰岛素抵抗的发生与发展。该文对lncRNAs与肝脏胰岛素抵抗关系的阐明,将加深人们对lncRNAs功能及肝脏胰岛素抵抗机制的认知,为糖尿病的防治提供新的方向,lncRNAs有望成为治疗胰岛素抵抗和糖尿病的新靶点。     

炎症-内质网应激-肠道菌群在胰岛素抵抗发病中的作用

胰岛素抵抗(insulin resistance,IR)是肥胖导致的代谢综合征的典型表现,因其作用器官广泛和作用机制复杂成为糖尿病等代谢性疾病治疗中的一大难题。胰岛素抵抗涉及多个代谢器官、多种细胞因子和多条信号转导通路的交互作用,呈现出极其复杂的作用网络。目前认为,炎症、内质网应激和肠道菌群失调是引起胰岛素抵抗的最主要的三大机制。本文将综述胰岛素抵抗的三大病理机制,并探讨三者之间的关联性。     

PPARα,γ和δ:胰岛素抵抗治疗的靶点

胰岛素抵抗(insulin resistance,IR)是指外周组织对胰岛素的反应敏感性降低,是肝脏疾病和心血管病发生的共同基础,常常是高脂血症和2型糖尿病发病的前奏.过氧化物酶体增殖物激活受体(peroxisome proliferator-activated receptors,PPARs)属于核受体超家族的成员.PPARs激动剂可通过多种途径改善胰岛素敏感性,例如调节糖脂代谢、抗炎作用以及间接地改善氧化应激状态.这篇综述主要是回顾IR的病理机制及其治疗靶点:PPARα,δ和γ,并阐明针对此类靶点的胰岛素增敏药物的信号转导通路.     

MicroRNAs对骨骼肌胰岛素抵抗的调控及其机制

胰岛素抵抗是肥胖和2型糖尿病发生的共同病理生理机制。骨骼肌是胰岛素介导的葡萄糖摄取、代谢、利用的主要靶器官之一,是胰岛素抵抗发生最早和最重要的部位。研究表明,骨骼肌葡萄糖摄取障碍、胰岛素信号通路受损、线粒体生物合成受阻与骨骼肌胰岛素抵抗密切相关。当骨骼肌发生胰岛素抵抗时,多种microRNAs (miRNAs)表达上调(miR-106b,miR-23a,mi R-761,miR-135a,Let-7,miR-29a)或下调(miR-133a,miR-149,miR-1),它们参与对骨骼肌葡萄糖摄取、胰岛素信号通路及线粒体生物合成的调控,在骨骼肌胰岛素抵抗的发生与发展中发挥了重要作用。这些miRNAs可作为治疗骨骼肌胰岛素抵抗或糖尿病的潜在靶点。     

脂肪因子与代谢综合征关系的研究进展

代谢综合症是一系列代谢和心血管功能失调的临床特征,包括中心性肥胖、高血压、血脂异常、高血糖及胰岛素抵抗等,其发病机制及如何预防及控制代谢综合症正日益成为目前的学术热点。目前已经公认,脂肪不仅是能量存储器官,也是一个重要的内分泌器官。脂肪组织分泌的生物活性分子被称为脂肪因子。近年来的研究表明,脂肪因子广泛参与肥胖、2型糖尿病、高血压病及心血管疾病等一系列代谢相关性疾病的病理生理过程。脂肪因子能通过介导一系列的信号转导通路,并广泛参与机体复杂的代谢平衡网络的调节。脂肪因子的失衡能导致机体发生对胰岛素敏感性改变等一系列的生物学反应,从而在肥胖和代谢综合症的病理过程中发挥重要的作用。本文综述了脂肪因子与代谢综合征的关系的研究进展。     

MG53 and disordered metabolism in striated muscle

MG53 is a member of tripartite motif family (TRIM) that expressed most abundantly in striated muscle. Using rodent models, many studies have demonstrated the MG53 not only facilitates membrane repair after ischemia reperfusion injury, but also contributes to the protective effects of both pre- and post-conditioning. Recently, however, it has been shown that MG53 participates in the regulation of many metabolic processes, especially insulin signaling pathway. Thus, sustained overexpression of MG53 may contribute to the development of various metabolic disorders in striated muscle. In this review, using cardiac muscle as an example, we will discuss muscle metabolic disturbances associated with diabetes and the current understanding of the underlying molecular mechanisms; in particular, the pathogenesis of diabetic cardiomyopathy. We will focus on the pathways that MG53 regulates and how the dysregulation of MG53 leads to metabolic disorders, thereby establishing a causal relationship between sustained upregulation of MG53 and the development of muscle insulin resistance and metabolic disorders. This article is part of a Special issue entitled Cardiac adaptations to obesity, diabetes and insulin resistance, edited by Professors Jan F.C. Glatz, Jason R.B. Dyck and Christine Des Rosiers.     

Molecular mechanisms by which aerobic exercise induces insulin sensitivity

Insulin resistance is a key feature of Type 2 diabetes and an important therapeutic target to address glycemic control to prevent diabetic complications. Lifestyle advice is the first step in the ADA/EASD consensus guidelines followed by metformin therapy. Aerobic exercise (AE) can increase insulin sensitivity by several molecular pathways including upregulation of insulin transporters in the cellular membrane of insulin-dependent cells. In addition, AE improves insulin sensitivity by amelioration of the pathophysiologic pathways involved in insulin resistance such as the reduction of adipokines, inflammatory and oxidative stress responses, and improvement of insulin signal transduction via different molecular pathways. This review details the molecular pathways by which AE induces beneficial effects on insulin resistance     

细胞骨架与胰岛素相关信号转导通路

细胞骨架是蛋白质纤维交织形成的立体网架体系,它是一个动态结构,可随着生理条件的改变不断进行组装和去组装,并受到细胞内外因素的调节.胰岛素是参与机体内诸多生理过程如葡萄糖转运、基因表达和DNA合成等的重要激素, 而胰岛素的正常分泌是其功能发挥的重要前提.越来越多的研究表明,细胞骨架在胰岛素行使功能和胰岛素的分泌过程中起重要作用,其具体机制与胰岛素相关的信号转导通路密切相关.当细胞骨架成分发生改变,继而影响到胰岛素相关的信号转导过程时,就会影响胰岛素的分泌,同时会导致胰岛素抵抗的发生.     

Signal integration and the specificity of insulin action

Insulin is a potent metabolic hormone essential for the maintenance of normal circulating blood glucose level in mammals. The physiologic control of glucose homeostasis results from a balance between hepatic glucose release (glycogenolysis and gluconeogenesis) and dietary glucose absorption versus skeletal muscle and adipose tissue glucose uptake and disposal. Disruption of this delicate balance either through defects in insulin secretion, liver glucose output, or peripheral tissue glucose uptake results in pathophysiological states of insulin resistance and diabetes. In particular, glucose transport into skeletal muscle and adipose tissue is the rate-limiting step in glucose metabolism and reduction in the efficiency of this process (insulin resistance) is one of the earliest predictors for the development of Type II diabetes. Importantly, recent studies have directly implicated an impairment in insulin receptor signal transduction as the prime mechanism for peripheral tissue insulin resistance. In this review, we have focused on recent developments in our understanding of the molecular mechanisms and signal transduction pathways that insulin utilizes to specifically regulate glucose uptake. The detailed understanding of these events will provide a conceptual framework for the development of new therapeutic targets to treat this chronic and debilitating disease process.     

Exercise does not alter subcellular localization, but increases phosphorylation of insulin-signaling proteins in human skeletal muscle

The subcellular localization of insulin signaling proteins is altered by various stimuli such as insulin, insulin-like growth factor I, and oxidative stress and is thought to be an important mechanism that can influence intracellular signal transduction and cellular function. This study examined the possibility that exercise may also alter the subcellular localization of insulin signaling proteins in human skeletal muscle. Nine untrained males performed 60 min of cycling exercise (approximately 67% peak pulmonary O2 uptake). Muscle biopsies were sampled at rest, immediately after exercise, and 3 h postexercise. Muscle was fractionated by centrifugation into the following crude fractions: cytosolic, nuclear, and a high-speed pellet containing membrane and cytoskeletal components. Fractions were analyzed for protein content of insulin receptor, insulin receptor substrate (IRS)-1 and -2, p85 subunit of phosphatidylinositol 3-kinase, Akt, and glycogen synthase kinase-3 (GSK-3). There was no significant change in the protein content of the insulin signaling proteins in any of the crude fractions after exercise or 3 h postexercise. Exercise had no significant effect on the phosphorylation of IRS-1 Tyr612 in any of the fractions. In contrast, exercise increased (P < 0.05) the phosphorylation of Akt Ser473 and GSK-3alpha/beta Ser9/21 in the cytosolic fraction only. In conclusion, exercise can increase phosphorylation of downstream insulin signaling proteins specifically in the cytosolic fraction but does not result in changes in the subcellular localization of insulin signaling proteins in human skeletal muscle. Change in the subcellular protein localization is therefore an unlikely mechanism to influence signal transduction pathways and cellular function in skeletal muscle after exercise.     

Insulin resistance and amyloidogenesis as common molecular foundation for type 2 diabetes and Alzheimer's disease

Characterized as a peripheral metabolic disorder and a degenerative disease of the central nervous system respectively, it is now widely recognized that type 2 diabetes mellitus (T2DM) and Alzheimer's disease (AD) share several common abnormalities including impaired glucose metabolism, increased oxidative stress, insulin resistance and amyloidogenesis. Several recent studies suggest that this is not an epiphenomenon, but rather these two diseases disrupt common molecular pathways and each disease compounds the progression of the other. For instance, in AD the accumulation of the amyloid-beta peptide (Aβ), which characterizes the disease and is thought to participate in the neurodegenerative process, may also induce neuronal insulin resistance. Conversely, disrupting normal glucose metabolism in transgenic animal models of AD that over-express the human amyloid precursor protein (hAPP) promotes amyloid-peptide aggregation and accelerates the disease progression. Studying these processes at a cellular level suggests that insulin resistance and Aβ aggregation may not only be the consequence of excitotoxicity, aberrant Ca²⁺ signals, and proinflammatory cytokines such as TNF-α, but may also promote these pathological effectors. At the molecular level, insulin resistance and Aβ disrupt common signal transduction cascades including the insulin receptor family/PI3 kinase/Akt/GSK3 pathway. Thus both disease processes contribute to overlapping pathology, thereby compounding disease symptoms and progression.     

Effect of Metabolic Syndrome on Mitsugumin 53 Expression and Function

Metabolic syndrome is a cluster of risk factors, such as obesity, insulin resistance, and hyperlipidemia that increases the individual’s likelihood of developing cardiovascular diseases. Patients inflicted with metabolic disorders also suffer from tissue repair defect. Mitsugumin 53 (MG53) is a protein essential to cellular membrane repair. It facilitates the nucleation of intracellular vesicles to sites of membrane disruption to create repair patches, contributing to the regenerative capacity of skeletal and cardiac muscle tissues upon injury. Since individuals suffering from metabolic syndrome possess tissue regeneration deficiency and MG53 plays a crucial role in restoring membrane integrity, we studied MG53 activity in mice models exhibiting metabolic disorders induced by a 6 month high-fat diet (HFD) feeding. Western blotting showed that MG53 expression is not altered within the skeletal and cardiac muscles of mice with metabolic syndrome. Rather, we found that MG53 levels in blood circulation were actually reduced. This data directly contradicts findings presented by Song et. al that indict MG53 as a causative factor for metabolic syndrome (Nature 494, 375-379). The diminished MG53 serum level observed may contribute to the inadequate tissue repair aptitude exhibited by diabetic patients. Furthermore, immunohistochemical analyses reveal that skeletal muscle fibers of mice with metabolic disorders experience localization of subcellular MG53 around mitochondria. This clustering may represent an adaptive response to oxidative stress resulting from HFD feeding and may implicate MG53 as a guardian to protect damaged mitochondria. Therapeutic approaches that elevate MG53 expression in serum circulation may be a novel method to treat the degenerative tissue repair function of diabetic patients.     

运动对线粒体介导骨骼肌细胞凋亡信号通路的影响

细胞凋亡是一种程序化的细胞死亡方式,其信号传导通路分为外源性和内源性两条主要途径,线粒体在内源性细胞凋亡途径中扮演着重要的角色.研究表明,运动可通过调节线粒体介导骨骼肌细胞凋亡的进程,而运动调节线粒体介导骨骼肌细胞凋亡信号通路影响机体细胞生物进程的机制仍有待研究.该文主要阐述了线粒体介导细胞凋亡信号传导通路及运动对其的...     

胰岛素信号转导障碍与胰岛素抵抗的形成

胰岛素生理作用的发挥,起始于胰岛素与其受体的结合,并由此引起细胞内一系列信号转导,最终到达各效应器产生各种生理效应。胰岛素信号转导在胰岛素生理作用的发挥中起着至关重要的作用。胰岛素信号转导减弱或受阻,使得胰岛素生理作用减弱,导致胰岛素抵抗形成。本文综述了胰岛素信号转导失调在胰岛素抵抗形成中的作用。