Ⅱ型糖尿病动物模型的构建

动物模型在Ⅱ型糖尿病研究中发挥重要作用,对于深入研究糖尿病及其并发症的发病、预防、诊断和治疗有重要意义。本文就Ⅱ型糖尿病动物模型的构建进行了概述,对发展新型构建糖尿病模型的方法具有重要的参考价值。     

巨噬细胞外泌体在增殖性糖尿病视网膜病变中的研究进展

糖尿病视网膜病变(diabetic retinopathy, DR)是糖尿病患者最常见的微血管系统并发症之一，是视力丧失的主要原因。增殖性糖尿病视网膜病变(proliferative diabetic retinopathy, PDR)是DR的终末期表现，其主要的病理生理学特征是视网膜新生血管形成(retinal neovascularization, RNV)。但PDR现有治疗方式存在局限性。外泌体作为细胞间沟通交流的重要使者，其携带的非编码RNA和生物活性蛋白质等重要信号分子，通过影响血管内皮细胞的增殖和迁移，在RNV中发挥关键作用。巨噬细胞是一种多功能调节细胞，越来越多的研究表明巨噬细胞外泌体在调控新生血管形成中起重要作用。该文就巨噬细胞外泌体在增殖性糖尿病视网膜病变形成中的作用与机制研究进展进行综述。     

2型糖尿病蛋白质组学研究进展

2型糖尿病占糖尿病总数的90％以上,是威胁人类健康的重大疾病。蛋白质组学作为一种新兴的研究手段,它的发展以及在糖尿病研究领域的应用,对了解2型糖尿病的病理生理学分子基础及其治疗有着非常重要的价值。本文主要从2型糖尿病、肥胖、胰岛素抵抗、糖尿病并发症等几个方面,对近年蛋白质组学在2型糖尿病领域取得的一些研究进展进行简要的介绍,并对其目前研究情况和未来的发展方向进行初步探讨。     

硫化氢与糖尿病

硫化氢是继一氧化氮和一氧化碳之后的第三种内源性气体信号分子。近年来,内源性硫化氢的产生及生理意义已经被认识,其代谢异常与多种疾病有关。本文综述了近年报道的硫化氢及其内生酶在糖尿病发病及进展中的变化情况,并重点概述硫化氢效应的细胞机制,包括硫化氢对β细胞胰岛素释放和对脂肪细胞葡萄糖摄取的影响。深入理解硫化氢在糖尿病中的作用将为以硫化氢为靶点的糖尿病治疗和抗糖尿病新药设计提供新的思路。     

硫氧还蛋白相互作用蛋白在糖尿病及其并发症中的作用

硫氧还蛋白相互作用蛋白(thioredoxin-interacting protein,TXNIP)又称维生素D₃上调蛋白1,因其能够与硫氧还蛋白(thioredoxin,Trx)结合并抑制其活性和表达而得名。本文概述了TXNIP的发现与结构,及其自身通过发挥调节糖脂代谢的作用进而影响糖尿病前期的发生发展。并在此基础上总结了TXNIP参与糖尿病发生发展的2条主要途径:TXNIP通过拮抗Trx的抗凋亡作用来激发细胞凋亡信号导致胰岛细胞凋亡;TXNIP过表达促使胰岛细胞磷酸化,进而使抑癌相关蛋白质表达增加,最终引起胰岛细胞衰老。进一步重点阐述了TXNIP在糖尿病心肌病、糖尿病肾病、糖尿病性视网膜病等糖尿病并发症中的作用:TXNIP能通过各种间接途径干预信号通路,进一步参与氧化应激、细胞凋亡、激活炎症、细胞自噬及糖脂代谢等生理生化过程。TXNIP具有极其重要的生物学功能,深入了解TXNIP在糖尿病及其并发症中的影响机制,对糖尿病及其并发症的治疗具有重要意义。最后对TXNIP的研究进行了展望,未来可进一步着手研究TXNIP基因是如何与其他基因或危险因素协同作用,进而共同参与糖尿病及其并发症的发生发展,且TXNIP单个基因甲基化尚不能全面揭示糖尿病及其并发症发生的分子机制,这些后续的深入研究,将为在糖尿病及其并发症的诊断与治疗中作为靶标分子的应用奠定基础。     

PACAP及其衍生物治疗糖尿病及其并发症的研究进展

垂体腺苷酸环化酶激活肽(PACAP)是近年新发现的神经多肽,属于促胰液素/胰高血糖素/血管活性肽(VIP)家族中的新成员,广泛分布于脑和外周组织器官,尤其在内分泌胰腺、性腺、呼吸和生殖系统,在能量代谢、神经保护、免疫系统等发挥重要生理学功能。糖尿病是一种常见的主要以高血糖为特征的慢性代谢性疾病,糖尿病并发症日益严重威胁着人们的身体健康,已成为导致糖尿病患者致死、致残的主要原因。主要对PACAP治疗糖尿病及其并发症国内外研究的最新进展进行论述。     

肠道菌群在糖尿病发生发展中的作用机制研究进展

糖尿病已经成为严重威胁人类健康的疾病之一。目前已有研究证明肠道菌群在糖尿病的发生、发展中发挥着重要作用。肠道菌群在人体中处于动态平衡,但容易受到饮食、环境、细菌的相互作用以及抗菌药物等多种因素的影响。肠道菌群的变化可以导致肥胖、胰岛素抵抗、肠道渗透压改变以及代谢性内毒素血症等,从而促进糖尿病(1型及2型)的发生、发展,而益生菌在预防糖尿病的发生和改善糖尿病预后中的作用不可小视。本文从糖代谢、脂代谢、免疫及并发症等方面分析肠道菌群影响糖尿病发生发展的机制。     

miRNAs在糖尿病及其并发症中的作用

糖尿病是当今众多慢性疾病中的一种,多重复杂的因素包括遗传和生理的改变导致1型和2型糖尿病的发生。然而,关于糖尿病的发病机制尚不明确。新近研究发现,微小RNA(miRNAs)与糖尿病及其并发症的发生有密切联系。本文概述近年关于miRNAs与糖尿病及其并发症的研究进展,为理解糖尿病及其并发症的病理机制提供了新的观点,并可能为寻找治疗糖尿病的新方法提供研究方向。     

长非编码RNA与糖尿病及其并发症

2型糖尿病是一种严重威胁人类健康的慢性非传染性代谢疾病,而胰岛素抵抗和胰岛β细胞功能衰竭被认为是其主要致病原因。在以往对糖尿病及其并发症发病机制的研究中,往往关注传统的蛋白编码基因(mRNA)。长链非编码RNA(long noncoding RNA,LncRNA)是一类长度大于200bp,不编码蛋白的RNA分子。近年来,越来越多的研究发现LncRNA在表观遗传、转录及转录后水平等多个层面上参与调控基因表达及代谢过程。本综述旨在讨论LncRNA在糖脂代谢调控、糖尿病及糖尿病并发症发生中作用的最新研究进展。     

葛根素对糖尿病视网膜细胞凋亡作用的研究进展

糖尿病的发病率逐年上升,其并发症的严重性日趋明显,特别是糖尿病视网膜病变导致视力下降和丧失已经引起了广泛关注,所以研究糖尿病视网膜病变的发病机制及其防治是必要的。糖尿病视网膜病变是一种多种机制共同作用的复杂性疾病,而细胞凋亡在糖尿病视网膜病变的发生和发展中起着重要的作用,所以研究细胞凋亡对糖尿病视网膜病变的治疗有着重要意义。由于细胞凋亡研究的深入,人们将注意力集中于糖尿病视网膜细胞凋亡能否得到抑制和逆转的问题上。研究发现,糖尿病视网膜病变细胞凋亡可能与视网膜新生血管形成、VEGF水平增高等因素有关。当前对葛根素的研究表明,葛根素能有效抑制视网膜新生血管形成,并且对于缺血、缺氧等因素引起的损害有很强的改善作用,葛根素还可以降低糖尿病糖基化终产物水平,甚至对视网膜超微结构的损害具有一定的保护作用,所以葛根素可能是治疗糖尿病性视网膜病变的新策略。本文就近期糖尿病视网膜病变中细胞凋亡的有关研究和葛根素的抗细胞凋亡作用做一综述,提示在糖尿病视网膜病变中葛根素的不可忽视的作用。     

Skin fluorescence as a clinical tool for non-invasive assessment of advanced glycation and long-term complications of diabetes

Glycation is important in the development of complications of diabetes mellitus and may have a central role in the well-described glycaemic memory effect in developing these complications. Skin fluorescence has emerged over the last decade as a non-invasive method for assessing accumulation of advanced glycation endproducts. Skin fluorescence is independently related to micro- and macrovascular complications in both type 1 and type 2 diabetes mellitus and is associated with mortality in type 2 diabetes. The relation between skin fluorescence and cardiovascular disease also extends to other conditions with increased tissue AGE levels, such as renal failure. Besides cardiovascular complications, skin fluorescence has been associated, more recently, with other prevalent conditions in diabetes, such as brain atrophy and depression. Furthermore, skin fluorescence is related to past long-term glycaemic control and clinical markers of cardiovascular disease. This review will discuss the technique of skin fluorescence, its validation as a marker of tissue AGE accumulation, and its use as a clinical tool for the prediction of long-term complications in diabetes mellitus.     

Mitochondrial DNA backgrounds might modulate diabetes complications rather than T2DM as a whole

Mitochondrial dysfunction has been implicated in rare and common forms of type 2 diabetes (T2DM). Additionally, rare mitochondrial DNA (mtDNA) mutations have been shown to be causal for T2DM pathogenesis. So far, many studies have investigated the possibility that mtDNA variation might affect the risk of T2DM, however, when found, haplogroup association has been rarely replicated, even in related populations, possibly due to an inadequate level of haplogroup resolution. Effects of mtDNA variation on diabetes complications have also been proposed. However, additional studies evaluating the mitochondrial role on both T2DM and related complications are badly needed. To test the hypothesis of a mitochondrial genome effect on diabetes and its complications, we genotyped the mtDNAs of 466 T2DM patients and 438 controls from a regional population of central Italy (Marche). Based on the most updated mtDNA phylogeny, all 904 samples were classified into 57 different mitochondrial sub-haplogroups, thus reaching an unprecedented level of resolution. We then evaluated whether the susceptibility of developing T2DM or its complications differed among the identified haplogroups, considering also the potential effects of phenotypical and clinical variables. MtDNA backgrounds, even when based on a refined haplogroup classification, do not appear to play a role in developing T2DM despite a possible protective effect for the common European haplogroup H1, which harbors the G3010A transition in the MTRNR2 gene. In contrast, our data indicate that different mitochondrial haplogroups are significantly associated with an increased risk of specific diabetes complications: H (the most frequent European haplogroup) with retinopathy, H3 with neuropathy, U3 with nephropathy, and V with renal failure.     

Urinary 8-oxo-7,8-dihydro-2'-deoxyguanosine as a biomarker in type 2 diabetes

The increasing prevalence of diabetes together with the associated morbidity and mortality calls for additional preventive and therapeutic strategies. New biomarkers that can be used in therapy control and risk stratification as alternatives to current methods are needed and can facilitate a more individualized and sufficient treatment of diabetes. Evidence derived from both epidemiological and mechanistic studies suggests that oxidative stress has an important role in mediating the pathologies of diabetic complications. A marker of intracellular oxidative stress that potentially could be used as a valuable biomarker in diabetes is the DNA oxidation marker 8-oxo-7,8-dihydro-2′-deoxyguanosine (8-oxodG), which can be assessed noninvasively in the urine, with minimal discomfort for the patient. In this review the analytical validity of 8-oxodG is addressed by highlighting important methodological issues. The available epidemiological evidence regarding urinary 8-oxodG and type 2 diabetes is presented. A possible role for DNA oxidation in cancer development in type 2 diabetes patients is discussed, followed by an evaluation of the potential of urinary 8-oxodG as a clinical biomarker in type 2 diabetes.     

Protecting the heart through MK2 modulation,toward a role in diabetic cardiomyopathy and lipid metabolism

Various signaling pathways have been identified in the heart as important players during development, physiological adaptation or pathological processes. This includes the MAPK families, particularly p38MAPK, which is involved in several key cellular processes, including differentiation, proliferation, apoptosis, inflammation, metabolism and survival. Disrupted p38MAPK signaling has been associated with several diseases, including cardiovascular diseases (CVD) as well as diabetes and its related complications. Despite efforts to translate this knowledge into therapeutic avenues, p38 inhibitors have failed in clinical trials due to adverse effects. Inhibition of MK2, a downstream target of p38, appears to be a promising alternative strategy. Targeting MK2 activity may avoid the adverse effects linked to p38 inhibition, while maintaining its beneficial effects. MK2 was first considered as a therapeutic target in inflammatory diseases such as rheumatoid polyarthritis. A growing body of evidence now supports a key role of MK2 signaling in the pathogenesis of CVD, particularly ischemia/reperfusion injury, hypertrophy, and hypertension and that its inhibition or inactivation is associated with improved heart and vascular functions. More recently, MK2 was shown to be a potential player in diabetes and related complications, particularly in liver and heart, and perturbations in calcium handling and lipid metabolism. In this review, we will discuss recent advances in our knowledge of the role of MK2 in p38MAPK-mediated signaling and the benefits of its loss of function in CVD and diabetes, with an emphasis on the roles of MK2 in calcium handling and lipid metabolism. 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.     

Nrf2及其药理性活化剂在糖尿病心血管并发症中的作用

糖尿病(DM)导致的心脑血管并发症是危害人类健康的重大疾病。氧化应激被认为是DM相关心血管并发症发生、发展的重要机制,但通过补充外源性抗氧化剂并未能使心血管疾病患者远期获益。核因子E2相关因子2(Nrf2)可增加内源性抗氧化酶的活性从而提高机体的抗氧化应激能力,可能是治疗糖尿病心血管并发症的一个重要靶点,提示靶向Nrf2药物的开发可能获得防治糖尿病相关血管并发症的新一代药物。本文就Nrf2在糖尿病相关心血管并发症发生、发展中的作用及其药理性活化剂对糖尿病(DM)相关心血管病变的治疗作用进行综述。     

Salacia oblonga improves cardiac fibrosis and inhibits postprandial hyperglycemia in obese Zucker rats

Diabetes has a markedly greater incidence of cardiovascular disease than the non-diabetic population. The heart shows a slowly developing increase in fibrosis in diabetes. Extended cardiac fibrosis results in increased myocardial stiffness, causing ventricular dysfunction and, ultimately, heart failure. Reversal of fibrosis may improve organ function survival. Postprandial hyperglycemia plays an important role in the development of type 2 diabetes and cardiovascular complications, and has been proposed as an independent risk factor for cardiovascular diseases. Salacia oblonga (S.O.) is traditionally used in the prevention and treatment of diabetes. We investigated the effects of its water extract on cardiac fibrosis and hyperglycemia in a genetic model of type 2 diabetes, the obese Zucker rat (OZR). Chronic administration of the extract markedly improved interstitial and perivascular fibrosis in the hearts of the OZR. It also reduced plasma glucose levels in non-fasted OZR, whereas it had little effect in the fasted animals, suggesting inhibition of postprandial hyperglycemia in type 2 diabetic animals, which might play a role in improvement of the cardiac complications of OZR. Furthermore, S.O. markedly suppressed the overexpression of mRNAs encoding transforming growth factor betas 1 and 3 in the OZR heart, which may be an important part of the overall molecular mechanisms. S.O. dose-dependently inhibited the increase of plasma glucose in sucrose-, but not in glucose-loaded mice. S.O. demonstrated a strong inhibition of alpha-glucosidase activity in vitro, which is suggested to contribute to the improvement of postprandial hyperglycemia.     

Hydrogen sulfide as a vasodilator

Gases such as nitric oxide (NO) and carbon monoxide (CO) play important roles both in normal physiology and in disease. The toxic effects of hydrogen sulphide (H2S) on living organisms have been recognized for nearly 300 years. In recent years, however, interest has been directed towards H2S as the third gaseous mediator, which has been shown to exhibit potent vasodilator activity both in vitro and in vivo most probably by opening vascular smooth muscle K(ATP) channels. Of the two enzymes, cystathionine-gamma-lyase (CSE) and cystathionine-beta-synthetase (CBS), which utilize L-cysteine as substrate to form H2S, CSE is believed to be the key enzyme which forms H2S in the cardiovascular system. Recent studies have shown an important role of the vasodilator action of H2S in health and disease.     

Nonobese, insulin-deficient Ins2Akita mice develop type 2 diabetes phenotypes including insulin resistance and cardiac remodeling

Although insulin resistance has been traditionally associated with type 2 diabetes, recent evidence in humans and animal models indicates that insulin resistance may also develop in type 1 diabetes. A point mutation of insulin 2 gene in Ins2(Akita) mice leads to pancreatic beta-cell apoptosis and hyperglycemia, and these mice are commonly used to investigate type 1 diabetes and complications. Since insulin resistance plays an important role in diabetic complications, we performed hyperinsulinemic-euglycemic clamps in awake Ins2(Akita) and wild-type mice to measure insulin action and glucose metabolism in vivo. Nonobese Ins2(Akita) mice developed insulin resistance, as indicated by an approximately 80% reduction in glucose infusion rate during clamps. Insulin resistance was due to approximately 50% decreases in glucose uptake in skeletal muscle and brown adipose tissue as well as hepatic insulin action. Skeletal muscle insulin resistance was associated with a 40% reduction in total GLUT4 and a threefold increase in PKCepsilon levels in Ins2(Akita) mice. Chronic phloridzin treatment lowered systemic glucose levels and normalized muscle insulin action, GLUT4 and PKCepsilon levels in Ins2(Akita) mice, indicating that hyperglycemia plays a role in insulin resistance. Echocardiography showed significant cardiac remodeling with ventricular hypertrophy that was ameliorated following chronic phloridzin treatment in Ins2(Akita) mice. Overall, we report for the first time that nonobese, insulin-deficient Ins2(Akita) mice develop type 2 diabetes phenotypes including peripheral and hepatic insulin resistance and cardiac remodeling. Our findings provide important insights into the pathogenesis of metabolic abnormalities and complications affecting type 1 diabetes and lean type 2 diabetes subjects.     

铁与2型糖尿病发病的最新进展

糖尿病对人类健康的威胁日益加重,近年来大量的实验、临床及流行病学资料显示体内铁过载与糖尿病发生存在密切关联。作为机体必需的营养元素,铁在机体组织中的稳态平衡对维持正常的生理功能至关重要。同时铁还是一种极强的促氧化剂,机体铁含量升高往往导致氧化压力增强,进而加大罹患2型糖尿病的风险;膳食中血红素铁摄入量增加以及机体铁代谢紊乱都可能导致2型糖尿病及其并发症发生。此外,其他胰岛素抵抗疾病如代谢综合征、妊娠糖尿病以及多囊卵巢综合征都与铁过载呈显著关联,过量铁是诱发这些疾病的主要原因,并直接导致胰岛素抵抗。治疗中可通过铁螯合剂的使用来有效降低机体铁水平,并改善胰岛素抵抗。这些研究成果为2型糖尿病的干预治疗提供了新思路。对铁代谢与2型糖尿病及其并发症的最新研究做简要综述。