线粒体功能损伤与胰岛素抵抗

胰岛素抵抗在肥胖、代谢综合症、心血管类疾病和2型糖尿病及其并发症等疾病的病理病程中起了重要的作用。近年来,研究发现线粒体功能损伤与胰岛素抵抗有着密切的联系。一些遗传因素、老化现象、ROS生成的增多、线粒体生物合成降低或一些线粒体相关蛋白变化,都可能损伤线粒体功能,而这些因素也都是诱发胰岛素抵抗的主要诱因。了解线粒体损伤与胰岛素抵抗的关系将为胰岛素抵抗的研究和治疗提供新的思路。该文将从遗传因素、老化、ROS、生物合成、UCP、Sirt3等可影响线粒体功能的几个方面阐述线粒体功能损伤与胰岛素抵抗的关系,并介绍胰岛素抵抗治疗中与线粒体相关的药物作用机制。     

线粒体脂质过载与胰岛素抵抗

胰岛素抵抗(insulin resistance,IR)是肥胖和2型糖尿病的共同病理基础,虽然引起IR的具体机制仍不明确,但是近年来人们认为脂质剩余可能是其分子基础之一.线粒体是调控代谢的重要细胞器,胰岛素靶细胞线粒体脂质过载导致线粒体功能障碍在IR发生发展中具有重要作用,且两者互为影响.因此,减轻线粒体脂质过载有利于防治IR,为治疗2型糖尿病提供新的思路.     

胰岛β细胞功能紊乱与2型糖尿病以及中药的干预

胰岛素抵抗和胰岛功能紊乱是2型糖尿病的两个重要病理特征,其中胰岛功能紊乱一直伴随着2型糖尿病的发生和发展.糖毒性、脂毒性以及高级糖基化终末产物(AGEs)在2型糖尿病发展中起着关键性的作用.从胰岛β细胞功能代偿期,胰岛β细胞功能轻度失代偿期、胰岛β细胞功能重度失代偿期,演变到胰岛β细胞功能完全失代偿期需要较长的时间.前三期通过中西药物干预可以保护及改善胰岛β细胞功能,从而延缓糖尿病的病程,减少并发症的发生,提高患者的生活质量.     

GLP-1改善内质网应激研究进展

胰高血糖素样肽-1(glucagon-like peptide-1,GLP-1)主要由肠道L细胞产生和分泌,可以促进胰岛素分泌、抑制胰高血糖素分泌、延缓胃排空及促进胰岛β细胞分化和增殖。内质网应激(endoplasmic reticulum stress,ERS)是2型糖尿病发生发展中重要的环节,近年,GLP-1临床应用于糖尿病日益增多,有关它改善胰岛β细胞功能机制研究不断深入,尤其是有关内质网应激方面的研究,现对此综述如下。     

2型糖尿病大鼠模型的建立及其氧化应激特征分析

目的建立一种与人类2型糖尿病发病特点相似的动物模型。方法将体质量180～220g的SD雄性大鼠30只随机分为5组,分别为:对照组、高脂高糖组(HH)、高脂高糖+60Co照射组(HH+R)、高脂高糖除抗氧化剂组(HH-AntiO)及高脂高糖除抗氧化剂+60Co照射组(HH+R-AntiO)。HH+R组和HH+R-AntiO组于实验第15、30、60天给予剂量为4Gy的60Co-γ射线全身照射。在指定时间点检测各处理组动物的氧化应激指标,实验第60天时进行静脉糖耐量实验。大鼠出现胰岛素抵抗后,腹腔注射链脲佐菌素(20mg/kg),每周1次,连续4周,大鼠诊断为2型糖尿病后,进行胰腺灌流实验检测胰岛B细胞功能。整个实验进行过程中监测血糖和胰岛素水平。结果各组动物在不同时间点出现不同程度的氧化损伤改变。第60天时,除HH组外,其余各组动物均出现胰岛素抵抗。结合小剂量链脲佐菌素注射后,大鼠出现比较稳定的中度高血糖,其中HH-AntiO组大鼠对葡萄糖刺激的反应最为接近2型糖尿病患者胰岛素分泌的两相性特点;同时胰腺中胰岛素也有一定的贮存量,约为对照组的40%。结论与遗传因素在发病过程中起主导作用的转基因大鼠模型相比,本研究建立的大鼠2型糖尿病模型能更好地观察环境因素对机体的影响,可以用于预防和治疗2型糖尿病的药物研究。     

TFP5 attenuates cyclin-dependent kinase 5-mediated islet β-cell damage in diabetes

Islet β-cell damage and dysfunction represent the pathophysiological basis of diabetes. Excessive activation of cyclin-dependent kinase 5 (CDK5) is involved in the pathogenesis of type 2 diabetes mellitus (T2DM), although the exact mechanism remains unclear. Therefore, this study investigated the role of a CDK5 inhibitor (TFP5) in islet β-cell damage under diabetic conditions by regulating the expression of CDK5 in vitro and in vivo. CDK5 was upregulated under high glucose conditions in vivo and in vitro, which resulted in inflammation, oxidative stress, and apoptosis of islet β-cells, thereby decreasing insulin secretion. However, TFP5 treatment inhibited the overexpression of CDK5; reduced the inflammatory response, oxidative stress, and apoptosis of islet β cells; and restored insulin secretion. In conclusion, CDK5 is involved in islet β-cell damage under high glucose conditions, and TFP5 may represent a promising candidate for the development of treatments for T2DM.     

新型餐后血糖调节剂——格列奈类药物的研究进展

早期相胰岛素分泌能力的损害是引起2型糖尿病及其并发症的重要因素，格列奈类药物作为一种新型促胰岛素分泌的药物，起效快，作用时间短，较磺酰脲类能更好地控制餐时血糖的增高，降低餐后血糖高峰，与双胍类合用可以发挥协同效应。其安全性良好，极少发生餐后低血糖，并能预防糖尿病的心血管并发症等。本文就早期相胰岛素分泌与糖尿病的关系、格列奈类药物的药理特性及临床应用等作一概述。     

Targeting mitochondrial biogenesis for preventing and treating insulin resistance in diabetes and obesity: Hope from natural mitochondrial nutrients

Insulin resistance is an important feature of type 2 diabetes and obesity. The underlying mechanisms of insulin resistance are still unclear and may involve pathological changes in multiple tissues. Mitochondrial dysfunction, including mitochondrial loss and over-production of oxidants, has been suggested to be involved in the development of insulin resistance. Increasing evidence suggests that targeting mitochondria to protect mitochondrial function as a unique measure, i.e. mitochondrial medicine, could prevent and ameliorate various diseases associated with mitochondrial dysfunction. In this review, we have summarized recent progress in pharmaceutical and nutritional studies of drugs and nutrients to targeting mitochondria by stimulating mitochondrial metabolism (biogenesis and degradation) to improve mitochondrial function and decrease oxidative stress for preventing and ameliorating insulin resistance. We have focused on nutrients from natural sources to stimulating mitochondrial biogenesis in cellular systems and in animal models. The in vitro and in vivo studies, especially our own work on the effects and mechanisms of mitochondrial targeting nutrients or their combinations, may help us to understand the importance and mechanisms of mitochondrial biogenesis in insulin resistance, and provide hope for developing mitochondria-targeting agents for preventing and treating insulin resistance in type 2 diabetes and obesity.     

The discovery of vanadyl and zinc complexes for treating diabetes and metabolic syndromes

The incidence of diabetes mellitus has increased over the decades because of lifestyle changes. The number of people with diabetes mellitus worldwide is expected to increase from 150 million to 220 million by 2010 and to 300 million by 2025. There are two main types of diabetes mellitus. Type 1 diabetes mellitus is due to the autoimmune-mediated destruction of pancreatic β cells, resulting in absolute insulin deficiency; the patients require exogenous insulin injections. Type 2 is characterized by insulin resistance and abnormal insulin secretion and the patients require exercise, diet control and/or oral hypoglycemics. However, each treatment has some adverse effects, including physical burden, formation of self-antibodies for insulin injections, the severe side effects of hypoglycemics and the discontinuation of insulin synthesis in the pancreas. To overcome these adverse effects and replace the use of these agents, the author attempted to develop new antidiabetic agents with novel structures and mechanisms. This review focuses on the authors' recent development of vanadium and zinc complexes for antidiabetic and antimetabolic syndromes.     

The insulin receptor concept and its relation to the treatment of diabetes

The initial step in insulin action is binding to specific receptors. Two covalent receptor modifications possibly involved in producing pharmacodynamic effects as a result of insulin receptor binding are autophosphorylation and disulphide insulin binding. Insulin receptor numbers are 'down regulated' by insulin, but this effect may be minimised by pulsatile insulin secretion. Insulin receptor affinity is modulated rapidly by fasting, exercise and dietary composition. In non-insulin-dependent diabetes coupling of receptor binding to bioeffects is impaired. Binding is also reduced in those subjects with hyperinsulinaemia and non-insulin-dependent diabetes. Insulin-dependent diabetics have reduced insulin sensitivity, which is only partially reversed by conventional insulin therapy. 'Post-binding defects' in some diabetics could be related to defective covalent receptor modifications resulting from genetic receptor defects. High carbohydrate diets improve diabetes control through effects on the binding and coupling defects. In addition to stimulating insulin secretion, oral hypoglycaemics stimulate post-binding insulin action in vivo and in vitro. Insulin therapy in diabetes also tends to reverse post-binding defects. Pulsatile insulin delivery is more effective in lowering blood sugar than continuous administration, and produces less 'down regulation' of receptors. Combined insulin and sulphonylurea drugs reduce insulin requirements only in insulin-dependent diabetics with some endogenous insulin secretion, whereas metformin reduces insulin requirement in C-peptide negative insulin-dependent diabetes mellitus.     

2型糖尿病合并视网膜病变病人的胰岛功能分析

目的　研究 2型糖尿病视网膜病变病人的胰岛分泌情况。方法　应用葡萄糖 胰岛素释放实验对2型糖尿病病人 98例 (其中 6 6例视网膜病变病人 ,无视网膜病变组病人 32例 )、正常对照组 32例进行血糖、胰岛素测定 ,计算血糖及胰岛素曲线面积、胰岛素敏感性指数、胰岛素分泌指数并进行比较。结果　糖尿病两组各时相血糖值及血糖面积均非常显著高于正常对照组 ;糖尿病有视网膜病变组各时相血糖值及血糖面积均显著高于无视网膜病变组 (P <0 0 1) ;糖尿病有视网膜病变组各时相胰岛素值及胰岛素面积均显著低于无视网膜病变组 (P <0 0 1) ;糖尿病有视网膜病变组的胰岛素分泌指数显著低于无视网膜病变组 (P <0 0 1)。多元逐步回归分析表明 ,视网膜病变与病程呈正相关 ,与胰岛素分泌指数负相关 (P <0 0 1)。结论　 2型糖尿病视网膜病变的病人存在着严重的持续高血糖 ,胰岛素分泌障碍是 2型糖尿病视网膜病变的危险因素。     

二肽基肽酶Ⅳ抑制剂辅助胰岛素治疗1型糖尿病的研究进展

二肽基肽酶Ⅳ（DPP-4）抑制剂为一类在2型糖尿病中应用广泛的口服降糖药,其疗效确切、给药方便、总体耐受性好,但目前尚未被批准用于1型糖尿病。国内外相关文献表明在1型糖尿病患者体内DPP-4抑制剂可以辅助胰岛素改善血糖、保护胰岛β细胞功能、降低谷氨酸脱羧酶抗体（GADA）滴度、减少胰岛素剂量,且不增加低血糖风险和体质量。因此,DPP-4抑制剂可能可作为1型糖尿病患者胰岛素的辅助治疗,作用机制可能源于其抑制胰岛α细胞分泌胰高血糖素,通过免疫机制使胰岛β细胞免受摧毁。     

Nrf2信号通路与胰腺β细胞功能障碍

核转录因子E2相关因子2（nuclear factor elytroid-derived factor 2-related factor,Nrf2）是维持细胞氧化还原稳态的中枢调节者,激活Nrf2在细胞水平和动物模型中均能拮抗氧化应激,表现出抗氧化、抗凋亡作用。近年来,大量的实验研究表明,氧化应激与2型糖尿病的形成和发展有着密切关系,而Nrf2信号通路在调节胰腺β细胞功能障碍和胰岛素分泌过程中具有重要作用。本文围绕Nrf2在胰腺β细胞功能障碍中的作用及其机制展开综述,以进一步了解Nrf2在2型糖尿病形成、发展及防治中的作用。     

老年2型糖尿病患者甲状腺功能状况及其与心率变异性的关系

目的：探讨老年2型糖尿病（DM）患者甲状腺功能状况及其与心率变异性（HRV）的关系。方法：分别测定20例老年健康对照组和老年2型DM患者的甲状腺功能及DM患者的HRV。结果：DM组的血FT3、TT3水平降低，与对照组相比具有显著性差异，DM组的FT3、FT4与超低频段功率/高频段功率之比值密切正相关。结论：老年2型DM患者在病程较长，病情控制不佳时可出现低T3现象，其游离甲状腺激素水平可能是影响DM患者HRV的原因之一。     

Pathogenesis of non-insulin-dependent (type II) diabetes mellitus (NIDDM) - genetic predisposition and metabolic abnormalities

Non-insulin-dependent diabetes mellitus (NIDDM), also known as type II diabetes, is characterized by abnormal glucose homeostasis, resulting in hyperglycemia, and is associated with microvascular, macrovascular, and neuropathic complications. NIDDM is a complex disease with many causes. Both genetic and environmental factors play important roles in the pathogenesis of NIDDM. Cumulative evidence on the high prevalence of NIDDM in certain ethnic groups, the high concordance rate for the disease in monozygotic twins, familial aggregation, and familial transmission patterns suggests that the genetic component plays an important etiological role in the development of NIDDM. In genetically predisposed individuals, there is a slow progression from a normal state to hyperglycemia, largely due to a combination of insulin resistance and defects in insulin secretion. Although numerous candidate genes responsible for insulin resistance and for the defects in insulin secretion have been reported, no specific gene(s) accounting for the majority of cases of the common type of NIDDM has been identified. Considerable evidence indicates that environmental and other factors, including diet, stress, physical activity, obesity and aging, also play an important role in the development of the disease. In conclusion, the pathogenic process of NIDDM depends on a complex interaction between genetic and environmental factors.     

Peripheral origin exosomal microRNAs aggravate glymphatic system dysfunction in diabetic cognitive impairment

Cognitive dysfunction is one of the common central nervous systems (CNS) complications of diabetes mellitus, which seriously affects the quality of life of patients and results in a huge economic burden. The glymphatic system dysfunction mediated by aquaporin-4 (AQP4) loss or redistribution in perivascular astrocyte endfeet plays a crucial role in diabetes-induced cognitive impairment (DCI). However, the mechanism of AQP4 loss or redistribution in the diabetic states remains unclear. Accumulating evidence suggests that peripheral insulin resistance target tissues and CNS communication affect brain homeostasis and that exosomal miRNAs are key mediators. Glucose and lipid metabolism disorder is an important pathological feature of diabetes mellitus, and skeletal muscle, liver and adipose tissue are the key target insulin resistance organs. In this review, the changes in exosomal miRNAs induced by peripheral metabolism disorders in diabetes mellitus were systematically reviewed. We focused on exosomal miRNAs that could induce low AQP4 expression and redistribution in perivascular astrocyte endfeet, which could provide an interorgan communication pathway to illustrate the pathogenesis of DCI. Furthermore, the mechanisms of exosome secretion from peripheral insulin resistance target tissue and absorption to the CNS were summarized, which will be beneficial for proposing novel and feasible strategies to optimize DCI prevention and/or treatment in diabetic patients.     

Genes and engineered cells as drugs for type I and type II diabetes mellitus therapy and prevention

Despite the manageability of diabetes mellitus, complications associated with the disorder necessitate novel approaches to prevent immune-mediated impairment and destruction in type 1 diabetes, as well as the pancreatic insufficiency and peripheral resistance to insulin in type 2 diabetes. Islet transplantation is evolving into a clinical reality to treat type 1 diabetics and novel uses of gene engineering technology promise to result in tolerance to auto-, allo- and xenoantigens as well as microenvironment-specific immunosuppression. Through the use of a variety of gene delivery vehides, an increasing number of studies demonstrate the feasibility of shielding islet transplants and surrogate beta cells from immune rejection by the local secretion of immunosuppressive soluble molecules and anti-apoptotic factors. Although the achievements of gene and cell therapy in type 2 diabetes mellitus are less clear, seminal studies demonstrate the relevance of this approach to the treatment and perhaps prevention of the underlying causes of the disease, including obesity and insulin resistance. In this review, we attempt to illustrate pivotal studies demonstrating the suitability of genes and cells as drugs in type 1 and type 2 diabetes mellitus, and also provide some other targets that may be suitable for clinical utility.     

初诊2型糖尿病患者胰高血糖素水平的变化及临床意义

目的探讨初诊断2型糖尿病胰高血糖素水平的变化和其与胰岛素抵抗的关系。方法98例初诊断2型糖尿病患者和20例血糖正常的健康人,分别为糖尿病组和正常对照组,两组患者均行标准馒头餐试验,分别测定餐前0min和餐后30、60、120rain时点的血糖、胰岛素和胰高血糖素水平。结果（1）糖尿病组餐前0rain和餐后30、60、120rain的胰高血糖素水平与正常对照组对应的各时点比较,均显著增高,两组间差异有统计学意义。（2）糖尿病组餐后各时点胰高血糖素水平与胰岛素抵抗指数HOMA-IR相关。结论胰高血糖素分泌紊乱是2型糖尿病患者发生高血糖的重要因素,胰岛α细胞存在胰岛素抵抗。     

New insights into antidiabetic drugs: Possible applications in cancer treatment

Globally at 2014, it was estimated that there was 347 million people with diabetes in which 90 percent of them were diagnosed with type 2 diabetes mellitus (T2DM). Although the association between diabetes mellitus and cancer risk was found about 100 years ago, the issue is not still clear. Many studies especially cohort and case–control studies have suggested a higher risk of cancer in patients with diabetes mainly in those with type 2 diabetes. Insulin concentration is high in these patients, and due to its mitogenic effects, it may be a possible hypotheses for higher risk of cancer in diabetic patients. Therefore, antidiabetic drugs, which are involved in insulin secretion and sensitivity, may have beneficial effects in cancer treatment. Several groups of drugs with different mechanisms of action, mostly prescribed orally, are used for the treatment of type 2 diabetes mellitus including, insulin sensitizers (thiazolidinediones), insulin secretagogues (sulfonylureas), and biguanides. In this review, the possible effects of antidiabetic drugs (biguanides, thiazolidinediones, and sulfonylureas) and some of their mechanisms for overcoming cancer will be discussed.