抵抗素的研究进展

抵抗素（resistin）是近年来发现的一个新脂肪细胞因子,最初在动物实验被用于联系肥胖、胰岛素抵抗和2型糖尿病。但随着进一步在人类实验的研究中发现,抵抗素能调节炎症反应而非胰岛素敏感性,研究发现抵抗素能促进炎症发生,炎症因子也能调节抵抗素的表达。动脉硬化是一种慢性亚临床性炎症,大量的体外研究提示抵抗素有可能作为一种促炎因子,通过激活内皮功能,诱导平滑肌增殖迁移,促巨噬细胞的脂质沉积,导致脂质代谢紊乱等途径,促进动脉粥样硬化的发生与发展。     

2型糖尿病合并下肢动脉粥样硬化的危险因素

下肢动脉粥样硬化是2型糖尿病(T2DM)患者最常见的大血管并发症之一。作为T2DM患者严重的慢并发症之一,下肢动脉粥样硬化可引起糖尿病足的发生,严重情况下可导致足坏疽。因此,阐明T2DM合并下肢动脉粥样硬化的危险因素,早期预防和治疗糖尿病合并下肢动脉粥样硬化症,不仅提高了患者的生活质量,而且减轻了家庭和社会的经济负担,具有较大的现实意义。影响T2DM患者下肢动脉粥样硬化的因素错综复杂,分为不可调控的和可调控的因素,不可调控的危险因素包括年龄、种族、遗传等,可调控的危险因素包括吸烟、高血糖、高血脂、高血压,以及近年提出的肥胖、胰岛素抵抗、高纤维蛋白血症、炎症等。本文就T2DM合并下肢动脉粥样硬化的危险因素做一综述。     

Macroangiopathy in adults and children with diabetes: from molecular mechanisms to vascular damage (part 1).

Type 2 diabetes mellitus (T2DM) is an increasing problem in childhood; however type 1 diabetes mellitus (T1DM) remains by far the most common type of diabetes in this age group. In this review we will focus on T1DM, because this will have the greatest implication for patients diagnosed in childhood. During the atherosclerotic process, several molecular, receptorial and cellular factors provide a continous mechanism of vascular damage. In diabetic children this state seems to be enhanced and facilitated so that accelerated atherosclerosis is associated with an increased risk of cardiovascular events in respect to the non diabetic population. Hyperglycemia PER SE and associated with diabetes is an important risk factor for atherosclerosis. At present a substantial part of children with diabetes do not reach satisfactory glycemic control. Other risk factors for the development and progression of atherosclerosis may be inherited or develop in the course of the disease: hypertension, dyslipidemia, insulin resistance, obesity, cigarette smoking, physical inactivity, disturbance of platelet function, coagulation and fibrinolysis. The development and progression of atherosclerosis should be blocked at an early age, if possible. Primary prevention to all risk factors for cardiovascular disease is important and intervention is indicated if necessary. At the moment the best therapeutic strategy is to maintain metabolic control at a physiologic level and perform screening and early intervention for vascular complications.     

Mitochondrial dysfunction in diabetes and the regulatory roles of antidiabetic agents on the mitochondrial function

The prevalence of type 2 diabetes mellitus (T2DM) is increasing rapidly with its associated morbidity and mortality. Many pathophysiological pathways such as oxidative stress, inflammatory responses, adipokines, obesity-induced insulin resistance, improper insulin signaling, and beta cell apoptosis are associated with the development of T2DM. There is increasing evidence of the role of mitochondrial dysfunction in the onset of T2DM, particularly in relation to the development of diabetic complications. Here, the role of mitochondrial dysfunction in T2DM is reviewed together with its modulation by antidiabetic therapeutic agents, an effect that may be independent of their hypoglycemic effect.     

Role of inflammatory mechanisms in pathogenesis of type 2 diabetes mellitus

Type 2 diabetes mellitus (T2DM) is characterized by progressive β‐cell dysfunctioning and insulin resistance. This article reviews recent literature with special focus on inflammatory mechanisms that provoke the pathogenesis of T2DM. We have focused on the recent advances in progression of T2DM including various inflammatory mechanisms that might induce inflammation, insulin resistance, decrease insulin secretion from pancreatic islets and dysfunctioning of β‐cells. Here we have also summarized the role of various pro‐inflammatory mediators involved in inflammatory mechanisms, which may further alter the normal structure of β‐cells by inducing pancreatic islet's apoptosis. In conclusion, it is suggested that the role of inflammation in pathogenesis of T2DM is crucial and cannot be neglected. Moreover, the insight of inflammatory responses in T2DM may provide a new gateway for the better treatment of diabetes mellitus. J. Cell. Biochem. 114: 525–531, 2013. © 2012 Wiley Periodicals, Inc.     

The role of melatonin in the treatment of type 2 diabetes mellitus and Alzheimer's disease

In type 2 diabetes mellitus (T2DM) and its related disorders like obesity, the abnormal protein processing, oxidative stress and proinflammatory cytokines will drive the activation of inflammatory pathways, leading to low-grade chronic inflammation and insulin resistance (IR) in the periphery and impaired neuronal insulin signaling in the brain. Studies have shown that such inflammation and impaired insulin signaling contribute to the development of Alzheimer''s disease (AD). Therefore, new therapeutic strategies are needed for the treatment of T2DM and T2DM-linked AD. Melatonin is primarily known for its circadian role which conveys message of darkness and induces night-state physiological functions. Besides rhythm-related effects, melatonin has anti-inflammatory and antioxidant properties. Melatonin levels are downregulated in metabolic disorders with IR, and activation of melatonin signaling delays disease progression. The aim of this Review is to highlight the therapeutic potentials of melatonin in preventing the acceleration of AD in T2DM individuals through its therapeutic mechanisms, including antioxidative effects, anti-inflammatory effects, restoring mitochondrial function and insulin sensitivity.     

Skeletal muscle insulin resistance: role of inflammatory cytokines and reactive oxygen species

The cardiometabolic syndrome (CMS), with its increased risk for cardiovascular disease (CVD), nonalcoholic fatty liver disease (NAFLD), and chronic kidney disease (CKD), has become a growing worldwide health problem. Insulin resistance is a key factor for the development of the CMS and is strongly related to obesity, hyperlipidemia, hypertension, type 2 diabetes mellitus (T2DM), CKD, and NAFLD. Insulin resistance in skeletal muscle is particularly important since it is normally responsible for more than 75% of all insulin-mediated glucose disposal. However, the molecular mechanisms responsible for skeletal muscle insulin resistance remain poorly defined. Accumulating evidence indicates that low-grade chronic inflammation and oxidative stress play fundamental roles in the development of insulin resistance, and inflammatory cytokines likely contribute to the link between inflammation, oxidative stress, and skeletal muscle insulin resistance. Understanding the mechanisms by which skeletal muscle tissue develops resistance to insulin will provide attractive targets for interventions, which may ultimately curb this serious problem. This review is focused on the effects of inflammatory cytokines and oxidative stress on insulin signaling in skeletal muscle and consequent development of insulin resistance.     

2型糖尿病易感基因的连锁和关联研究

2型糖尿病（T2DM）是由于胰岛素抵抗和β细胞分泌缺陷导致高血糖的一种复杂多基因疾病。遗传因素在T2DM的发生发展中起着重要的作用,其遗传率估计为70％～80％。鉴定2型糖尿病基因将有助于阐明其发病机制,发展更好的诊断、预防和治疗策略。2型糖尿病易感基因的鉴定方法主要有候选基因关联研究和全基因组连锁分析。有3种类型的候选基因：功能候选基因、图位候选基因和表达候选基因。虽然许多候选基因与T2DM的关联分析已经进行,但多数都没有得到一致的重复,过氧化物酶体增殖物激活受-γ,体和β-细胞ATP敏感性钾通道基因是目前最好重复的基因。迄今为止,T2DM的全基因组扫描已在20多个不同的群体中进行,包括欧洲人、美国白人、墨西哥裔美国人、美国本地印度人、非洲裔美国人和亚洲人,这些研究鉴定了一些与T2DM相关的QTLs区域。与T2DM显著和证实连锁的区域包括1q25、2q37．3q28、3p24、6q22、8p23、10q26、12q24、18p11、20q13等,与T2DM提示连锁的区域有1q42、2p21、2q24、4q34、5q13、5q31、7q32、9p24、9q21、10p14、11p13、11q13、12q15、14q23、20p12、Xq23等。鉴定这些区域的T2DMQTLs基因及其作用机制是未来的主要挑战。把DNA微阵列和蛋白质组学技术结合起来应用于传统的连锁分析和关联研究,研究基因-基因间、基因-环境间的互作和多个基因对T2DM的加性效应和综合作用,进一步加强国际协作,T2DM的遗传机制可望在不远的将来得到阐明。本文总结了2型糖尿病基因鉴定的现状,重点在一些得到重复的区域和未来的展望。     

Resistin and adiponectin levels in subjects with coronary artery disease and type 2 diabetes

BACKGROUND: Resistin and adiponectin are implicated in insulin resistance and atherosclerosis. The objective of this study was to evaluate the association between plasma resistin levels and the presence of coronary artery disease (CAD) or diabetes compared to the controls. In a cross-sectional study, we measured glucose, fasting lipid panel, resistin, adiponectin, insulin, C-reactive protein (CRP) and TNF-alpha in 57 subjects with CAD, 58 subjects with diabetes compared to 45 normal control subjects. Results: Subjects with CAD compared to the control subjects had increased insulin resistance index (39+/-32 vs. 13.45+/-12.73 with p<0.0001), CRP levels (3.8+/-4.03 vs. 2.0+/-2.0 with p<0.05) and decreased levels of adiponectin (12.5+/-4.8 vs. 17.26+/-10.4 with p<0.0003). Subjects with diabetes compared to the controls had had increased insulin resistance index (69+/-19 vs. 13.45+/-12.73 with p<0.001), CRP levels (4.1+/-4.8 vs. 2.0+/-2.0 with p<0.01) and decreased levels of adiponectin (11.58+/-4.8 vs. 17.26+/-10.4 with p<0.001). Compared to the controls, there was no significant difference in the levels of resistin in subjects with CAD (4.92+/-3.2 vs. 4.1+/-2.4) as well as diabetes (4.92+/-3.2 vs. 4.6+/-2.6). Both CRP and resistin levels correlate with TNF-alpha (r=0.557, p<0.000001; r=0.84, p<0.000001). Conclusions: The present study shows decreased plasma adiponectin levels in subjects with diabetes as well as in subjects with CAD is similar to the literature. Plasma levels of resistin in subjects with CAD or diabetes are similar to the controls. However, there was a strong correlation of resistin levels with inflammatory markers. This suggests resistin as an inflammatory marker associated with CAD.     

Linkage and Association Studies of the Susceptibility Genes for Type 2 Diabetes

Type 2 diabetes mellitus (T2DM) is a complex disease characterized by hyperglycemia, insulin resistance, and impaired insulin secretion. T2DM is under strong genetic control. Identification and characterization of genes involved in determining T2DM will contribute to a greater understanding of the pathogenesis of T2DM, and ultimately might lead to the development of better diagnosis, prevention and treatment strategies. Efforts to identify T2DM susceptibility genes have focused on candidate gene approach (association studies) and genome-wide scans (linkage analyses). In this article, we review the current status for mapping and identification of genes for T2DM, with a focus on some promising regions (or genes) and future prospects.     

Insulin resistance,lipotoxicity and endothelial dysfunction

The number of people with the insulin-resistant conditions of type 2 diabetes mellitus (T2DM) and obesity has reached epidemic proportions worldwide. Eighty percent of people with T2DM will die from the complications of cardiovascular atherosclerosis. Insulin resistance is characterised by endothelial dysfunction, which is a pivotal step in the initiation/progression of atherosclerosis. A hallmark of endothelial dysfunction is an unfavourable imbalance between the bioavailability of the antiatherosclerotic signalling molecule nitric oxide (NO) and proatherosclerotic reactive oxygen species. In this review we discuss the mechanisms linking insulin resistance to endothelial dysfunction, with a particular emphasis on a potential role for a toxic effect of free fatty acids on endothelial cell homeostasis.     

鞘脂类对胰岛素信号的调控——Ⅱ型糖尿病研究的新兴领域

胰岛素抵抗是Ⅱ型糖尿病的病理基础之一,近年来已成为Ⅱ型糖尿病研究的关键和热点．众多研究发现,机体内鞘脂类物质水平的改变直接影响胰岛素信号的强弱．神经酰胺和神经节苷脂GM3对胰岛素信号具有负向调控作用,介导胰岛素抵抗的形成,该调节效应依赖于细胞膜上微囊蛋白．1-磷酸鞘氨醇则通过氧化还原途径增强胰岛素信号．微囊蛋白功能性活动和1-磷酸鞘氨醇的介导作用均与钙信号相关,因此,可通过实时检测细胞外钙内流和细胞内钙瞬间变化,从离子通道水平进一步探索鞘脂类调节胰岛素信号的相关机制．本文综述了鞘脂类物质调控胰岛素信号的机制,干预鞘脂类水平和改善胰岛素抵抗的策略,将为鞘脂类物质在Ⅱ型糖尿病预防和治疗的研究及应用提供有力的帮助．     

Glycemia and Cardiova Scular Disease in Type 1 Diabetes Mellitus

ObjectiveTo evaluate the role of glycemic control in the development of cardiovascular disease (CVD) in type 1 diabetes mellitus (DM).MethodsWe review the literature regarding coronary atherosclerosis, coronary artery calcification, and the epidemiologic studies related to the role of glycemia and the classic risk factors for coronary artery disease (CAD) in type 1 DM.ResultsFour prospective studies (Wisconsin Epidemiologic Study of Diabetic Retinopathy, EURODIAB, Steno Diabetes Center Study of Adults With Type 1 DM, and Pittsburgh Epidemiology of Diabetes Complications study) do not show that glycemic control predicts CAD occurrence. Findings from the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications study show that compared with conventional insulin therapy, intensive insulin therapy reduces CVD among patients with type 1 DM and is associated with lower prevalence of coronary artery calcification. The discrepancies between the findings from the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications study and the Pittsburgh Epidemiology of Diabetes Complication study are likely due to differences between the study populations and the lower prevalence of renal disease in the former study. Besides duration of DM and albuminuria/overt nephropathy, insulin resistance is a major determinant of CAD associated with type 1 DM.ConclusionsDiscrepant study results regarding the relationship between glycemia and CAD/coronary artery calcification may be related to the prevalence of renal disease and the presence of the metabolic syndrome. Published data suggest that addressing traditional risk factors including albuminuria, the metabolic syndrome, and inflammatory markers is better for preventing and treating CAD than focusing exclusively on glycemic control, which is still necessary for preventing microvascular complications. Furthermore, there is a synergistic effect of glycemic control and albuminuria on the development of CVD. (Endocr Pract. 2008;14:912-923)     

Statins research unfinished saga: desirability versus feasibility

Aims

Resistin is an adipocyte-derived factor implicated in obesity-associated type 2 diabetes (T2DM). This study examines the association between human serum resistin, T2DM and coronary heart disease.

Methods

One hundred and fourteen Saudi Arabian patients (male: female ratio 46:68; age 51.4 (mean ± SD)11.7 years; median and range: 45.59 (11.7) years and BMI: 27.1 (mean ± SD) 8.1 Kgm² median and range: 30.3 (6.3) were studied. Serum resistin and C-reactive protein (CRP), a marker of inflammation CRP levels, were measured in all subjects. (35 patients had type 2 diabetes mellitus (T2DM); 22 patients had coronary heart disease (CHD).

Results

Serum resistin levels were 1.2-fold higher in type 2 diabetes and 1.3-fold higher in CHD than in controls (p = 0.01). In addition, CRP was significantly increased in both T2DM and CHD patients (p = 0.007 and p = 0.002 respectively). The use of regression analysis also determined that serum resistin correlated with CRP levels (p = 0.04, R² 0.045).

Conclusion

The findings from this study further implicate resistin as a circulating protein associated with T2DM and CHD. In addition this study also demonstrates an association between resistin and CRP, a marker of inflammation in type 2 diabetic patients.     

肠道菌群与2型糖尿病微血管病变的相关性——

2型糖尿病（T2DM）微血管病变是世界范围内最具热点的难题之一,其发病率和患病率不断上升。诸多研究证实肠道菌群与T2DM微血管病变之间存在复杂的关系。肠道菌群的改变导致胃肠道（GI）内环境紊乱,加快异常代谢产物生成、糖脂代谢紊乱、炎症反应,甚至胰岛素抵抗（IR）。短链脂肪酸（SCFAs）、脂多糖（LPS）、吲哚丙酸（IPA）和支链氨基酸（BCAAs）等通过不同代谢和免疫途径参与T2DM微血管病变的发生发展。本文旨在探讨肠道菌群与T2DM常见微血管病变（如肾病、周围神经病变、视网膜病变等）相关性及其免疫致病机制,以期为T2DM微血管病变的诊断治疗和科学研究提供方法。

     

2 型糖尿病合并非酒精性脂肪肝病患者IGF-1 与胰岛素抵抗关系研究

研究胰岛素样生长因子-1(IGF-1)与2型糖尿病(T2DM)胰岛素抵抗关系。有研究证实给予IGF-1后,可改善胰岛素抵抗、肝脏脂质代谢,IGF-1基因缺失的动物会产生胰岛素抵抗和高胰岛素血症,低水平的IGF-1还可能与非酒精性脂肪肝病(NAFLD)肝纤维化有关,而T2DM和NAFLD与胰岛素抵抗共存,T2DM合并NAFLD患者IGF-1水平更低。IGF-1与胰岛素抵抗关系密切,IGF-1水平能反映胰岛素抵抗的严重程度,为IGF-l在今后治疗T2DM和NAFLD的提供了潜在的临床应用前景。     

脂联素基因单核苷酸多态性与Ⅱ型糖尿病合并肥胖及胰岛素抵抗相关联

脂联素是近年新发现的脂肪组织特异性的细胞因子,其mRNA是脂肪组织中含量最丰富的基因转录产物,该因子可通过多种途径影响个体对胰岛素的敏感性。脂联素基因多态性与肥胖、胰岛素抵抗和2型糖尿病密切相关,而与冠心病相关性研究的报道较少。本研究以中国汉族人群1,098例为对象,其中304例冠心病(CHD)患者,389例糖尿病患者(T2DM),及405例性别年龄相匹配的正常对照,采用PCR-RFLP技术对脂联素基因-4522C/T进行基因分型,并分别对血脂水平、胰岛素抵抗、体重指数等临床数据进行分析比较。研究结果显示,脂联素基因-4522C/T各基因型及等位基因在CHD组与对照组、T2DM组与对照组中的分布差异无显著性;经分组分析发现,T2DM合并肥胖患者BMI≥25kg/m2TT基因型及T等位基因明显多于对照组,差异有显著性,P=0.014和P=0.034;TT基因型T2DM患者胰岛素抵抗指数(HOMA-IR)显著高于携带有C等位基因的T2DM患者,P=0.0069。本研究提示脂联素基因-4522C/T与中国汉族人群T2DM合并肥胖的发生及T2DM患者胰岛素抵抗相关,是引发糖尿病患者肥胖和胰岛素抵抗的重要候选基因,而与冠心病的发生无关联。