Endothelial dysfunction and microvascular complications in type 1 diabetes mellitus

We examined whether alterations in vascular endothelial function and early structural changes in atherosclerosis are associated with microvascular complications in patients with type 1 diabetes mellitus (DM). Flow-mediated dilation (FMD) of the brachial artery and carotid intima-media thickness (IMT) measurement were performed in 70 young adults (aged 19 to 35 yr), 48 with type 1 DM, and 22 normal controls. Patients with diabetes had a lower peak FMD response (7.8+/-3.9 vs. 11.1+/-1.9%, p<0.001) and increased IMT (0.51+/-0.10 vs. 0.42+/-0.07 mm, p<0.001) compared with controls. Twenty (41.7%) of the patients had microvascular complications including neuropathy, nephropathy, or retinopathy. In these complicated diabetic patients, we found a lower FMD response (6.1+/-2.5 vs. 9.9+/-3.5%, p=0.001) compared with diabetics without microvascular complications. The presence of microvascular complications was also associated with older age and longer duration of the disease. However, no differences were observed in IMT, body size, blood pressure, HbA1c, C-reactive protein, low-density lipoprotein or high-density lipoprotein cholesterol levels between complicated and non-complicated patients. Endothelial dysfunction and early structural atherosclerotic changes are common manifestations in type 1 DM, and endothelial dysfunction is thought to be an early event in the atherosclerotic process and important in the pathogenesis of microvascular complications.     

糖尿病早期脑损伤与线粒体功能障碍

目的:研究1型糖尿病早期阶段脑损伤的主要病理原因,是否影响线粒体功能及其可能机制。方法:SD大鼠经股静脉单次注射链脲佐菌素(streptozotocin,STZ)诱导高血糖,持续高血糖2个月后,检测外周血、脑脊液及脑组织中葡萄糖、甘油三酯和总胆固醇水平。取大鼠前额皮层,分离线粒体,检测线粒体氧化及抗氧化水平,Western blotting检测腺苷酸活化蛋白激酶(AMP-activated protein kinase,AMPK)磷酸化水平。全脑冰冻切片,Fluo-Jade-C染色检测神经细胞损伤程度。电镜检测皮层锥体细胞自噬-溶酶体变化。结果:1型糖尿病神经损伤主要原因是高血糖,可以导致皮层Fluo-Jade-C阳性细胞增多,线粒体氧化水平升高,抗氧化能力下降,AMPK磷酸化水平下降。同时发现1型糖尿病大鼠皮层锥体细胞自噬体增多,自噬体内包裹有线粒体或线粒体残余。结论:1型糖尿病早期所致的脑损伤,与持续高血糖增加氧化应激,进而损伤线粒体功能有关,伴随有自噬激活。     

Autoantibody-mediated acquired deficiency of C1 inhibitor

During the past 25 years, three forms of deficiency of the inhibitor of the first component of complement (C1 inhibitor) with angioedema have been recognized; two forms are hereditary and one is acquired. As compared with hereditary angioedema, the syndrome of acquired C1-inhibitor deficiency is rare, and it is usually associated with lymphoproliferative diseases. We report another type of acquired C1-inhibitor deficiency with angioedema. Two patients with recurrent angioedema but no associated diseases were found to have IgG1 autoantibodies against C1 inhibitor. The anti-C1-inhibitor antibodies prevented binding of C1 inhibitor to activated C1s. Both patients had 60 to 70 percent of normal levels of C1 inhibitor, but it was functionally inactive, with a molecular weight of 96,000 (normal C1 inhibitor, 105,000). In vitro studies of the patients' serum revealed degradation of 125I-labeled 105,000-dalton C1 inhibitor into the inactive 96,000-dalton molecule, caused by activated C1s and not found in normal human serum. We conclude that these cases of acquired C1-inhibitor deficiency resulted from a blockade of C1-inhibitor function by the anti-C1-inhibitor antibodies and from subsequent inactivation of C1 inhibitor by the now uncontrolled enzyme, activated C1s. As in other forms of C1-inhibitor deficiency, the unopposed activation of the complement system led to angioedema.     

Autoantibodies to calcium channels in type 1 diabetes mediate autonomic dysfunction by different mechanisms in colon and bladder and are neutralized by antiidiotypic antibodies

Autoantibodies (Abs) directed against L-type voltage-gated calcium channels (VGCCs) have been shown to contribute to autonomic dysfunction of the gastrointestinal tract and bladder in patients with Type 1 diabetes mellitus (T1D). We used a passive transfer model to determine whether the functional activity of the Ab requires crosslinking of channels in colon and bladder and can be neutralized by intravenous immunoglobulin (IVIg). Mice were injected with mono- and divalent F(ab) fragments of patient IgG with anti-VGCC activity and tested for gut and bladder function using a colonic migrating motor complex (MMC) assay and bladder-filling cystometry. The ability of IVIg to neutralize anti-VGCC IgG-mediated autonomic dysfunction was investigated by injection of mice with an equimolar concentration of IVIg prior to T1D IgG injection, or by injection with T1D IgG passed over a sepharose 4B column coupled with F(ab')(2) from IVIg. Passive transfer of T1D IgG and its F(ab')(2) or F(ab) fragments reduced the amplitude of spontaneous colonic motility. In contrast, intact IgG and F(ab')(2,) but not F(ab), produced the urodynamics features of an overactive bladder. T1D IgG-mediated colonic and bladder dysfunction was neutralized in vivo by prior injection of animals with equimolar IVIg. Moreover, anti-VGCC activity was depleted by preabsorption of patient IgG on a IVIg F(ab')(2) column. The activity of anti-VGCC IgG is mediated by the antigen-binding site consistent with a true functional Ab. The pathogenic effect on the bladder requires crosslinking of the channel, whereas monovalent binding of Ab is sufficient for disruption of colon motility. The anti-VGCC Abs are neutralized by antiidiotypic antibodies present in IVIg that may prevent the emergence of these Abs in healthy individuals.     

肌肽对1型糖尿病大鼠心脏的保护作用

目的:探讨肌肽(CAR)对1型糖尿病(T1DM)大鼠心功能的影响及保护机制。方法:采用链脲佐菌素(STZ)单次腹腔注射的方法制作大鼠1型糖尿病模型。将40只雄性SD大鼠随机分为正常对照(C)组,肌肽对照(C+CAR)组,糖尿病模型(DM)组和糖尿病CAR治疗(DM+CAR)组,每组10只。12周后处死大鼠,颈总动脉插管测定心功能;酶联免疫吸附法测定左心室肌超氧化物歧化酶(SOD)活性和丙二醛(MDA)含量;real-time PCR法检测肿瘤坏死因子α(TNF-α)、白细胞介素1β(IL-1β)和IL-6的mRNA表达;免疫荧光法检测缝隙连接蛋白43(Cx43)的分布;Western blot法检测Cx43及蛋白激酶C(PKC)各亚型的蛋白表达。结果:与C组相比,DM组大鼠左心室舒张末压(LVEDP)升高,左心室内压最大上升和下降速率(±dp/dt_(max))降低(P 0. 01);左心室肌组织SOD活性降低,MDA含量升高(P 0. 01);TNF-α、IL-1β和IL-6的mRNA表达水平升高(P 0. 01);Cx43分布紊乱;磷酸化Cx43和PKCε蛋白水平升高(P 0. 01)。与DM组相比,DM+CAR组的LVEDP降低,±dp/dt升高(P 0. 01);左心室肌组织的SOD活性升高,MDA含量降低(P 0. 05);TNF-α、IL-1β和IL-6的mRNA表达水平降低(P 0. 01);Cx43分布好转;磷酸化的Cx43及PKCε蛋白水平降低(P 0. 01)。结论:肌肽治疗能改善1型糖尿病大鼠心功能障碍,其机制可能与降低左心室氧化应激和炎症反应,通过PKCε抑制Cx43磷酸化,并改善其分布有关。     

Autoantibodies in type 1 diabetes

Diabetes mellitus is a disorder characterized by hyperglycemia in both the fasting and post-prandial states. The two most common forms of diabetes mellitus, type 1 and type 2 (previously called juvenile-onset and adult-onset, respectively), comprise the vast majority of cases. Type 1 diabetes (T1DM) has been shown to be a disease characterized by immune-mediated destruction of the insulin-secreting cells of the pancreas; it comprises the majority of cases of diabetes seen in childhood and approximately, 5-10% of all cases of diabetes mellitus in the USA and perhaps accounts for an even higher percentage in those nations with lower rates of obesity. The process of beta-cell destruction, marked by the production of autoantibodies to the beta-cell, occurs over many years and ultimately results in metabolic abnormalities first manifested as impaired glucose tolerance and then progressing to symptomatic hyperglycemia. It has been reported that approximately 50% of the genetic risk for T1DM can be attributed to the HLA region. The highest risk HLA-DR3/4 DQ8 genotype has been shown to be highly associated with beta-cell autoimmunity. The first antibodies described in association with the development of T1DM were islet cell autoantibodies (ICA). Subsequently, antibodies to insulin (IAA), glutamic acid decarboxylase (GAA or GAD) and protein tyrosine phosphatase (IA2 or ICA512) have all been defined. The number of antibodies, rather than the individual antibody, is thought to be most predictive of progression to overt diabetes.     

Manipulating the type 1 vs type 2 balance in type 1 diabetes

Virus infections cause a strong inflammatory reaction that is dominated by the expression of type 1 cytokines and chemokines. Such an aggressive immune response by the host is necessary to eliminate intracellular pathogens. However, because of this shift in the type 1 vs type 2 balance of the immune response, virus infections are potential candidates for triggering autoimmune diseases, such as type 1 diabetes (T1D), herpes stromal keratitis, or multiple sclerosis (MS). In this review we will focus on the pathogenesis of T1D in a virus-induced transgenic mouse model and discuss possibilities of how an aggressive type 1-dominated immune response can be restrained and autoimmunity be abrogated.     

含硫氨基酸对糖尿病大鼠窦房结损伤的保护作用

目的　探讨补充半胱氨酸或牛磺酸对糖尿病大鼠窦房结损伤的作用。 方法　SD大鼠随机分为正常对照组（C）组、糖尿病（DM）组、糖尿病+半胱氨酸（DM+Cys）组和糖尿病+牛磺酸（DM+Tau）组。检测SOD和MDA含量;测定窦房结功能SNRT、CSNRT、SACT和IHR;检测窦房结SOD2、HO-1、NOX2、NOX4、HCN2、HCN4表达。 结果　与C组比较,DM组血SOD降低,MDA升高;SNRT、CSNRT和SACT延长,IHR减慢;窦房结SOD2、HO-1、HCN2和HCN4表达降低,NOX2和NOX4表达升高（P<0.05）。与DM组比较,DM+Cys和DM+Tau组血SOD升高;IHR增加;窦房结SOD2、HO-1、HCN2和HCN4表达升高,NOX2和NOX4表达降低（P<0.05）。 结论　补充Cys或Tau能降低STZ大鼠窦房结氧化应激损伤,增加HCN4和HCN2表达,改善窦房结功能障碍。     

Autoimmune mechanisms in type 1 diabetes

Type 1 diabetes (T1D) is perceived as a chronic immune-mediated disease with a subclinical prodromal period characterized by selective loss of insulin-producing beta-cells in the pancreatic islets in genetically susceptible subjects. Autoreactive T cells, both CD4 and CD8 cells, have been implicated as active players in beta-cell destruction. A series of autoantigens have been identified in T1D including insulin, glutamic acid decarboxylase (GAD), the protein tyrosine phosphatase-related islet antigen 2 (IA-2), and most recently the zinc transporter Slc30A8 residing in the insulin secretory granule of the beta-cell. The issue whether there is any primary autoantigen in T1D has remained controversial. Given that there are two major HLA haplotypes conferring disease susceptibility, i.e. the DR3-DQ2 haplotype and the DR4-DQ8 haplotype, one may assume that there will be at least two primary antigens in T1D. The first signs of beta-cell autoimmunity might appear already during the first year of life. Autoantibodies may be considered as markers of an ongoing disease process in the pancreatic islets, and they can be used for prediction of T1D in non-diabetic individuals. Autoantigen-specific T-cell responses have been detected from peripheral blood in both patients with T1D and in unaffected subjects, but a clear discrimination between diabetic and non-diabetic subjects have rarely been seen until recently.     

Immune intervention in type 1 diabetes

Type 1 diabetes (T1D) is a chronic autoimmune disease that results in the specific immune destruction of insulin producing beta cells. Currently there is no cure for T1D and treatment for the disease consists of lifelong administration of insulin. Immunotherapies aimed at preventing beta cell destruction in T1D patients with residual c-peptide or in individuals developing T1D are being evaluated. Networks of researchers such as TrialNet and the Immune Tolerance Network in the U.S. and similar networks in Europe have been established to evaluate such immunotherapies. This review focuses on immune intervention for the prevention and amelioration of human T1D with a focus on potential immune suppressive, antigen specific and environmental therapies.     

Immunotherapy of type 1 diabetes

Type 1 diabetes (T1D) is an autoimmune disease in which the insulin-producing beta cells are destroyed. Diabetic patients manage their hyperglycemia by daily insulin injections. However, insulin therapy is by no means a cure. Accordingly, a significant effort has been ongoing to develop immunotherapies that effectively prevent and/or treat T1D in the clinic. This review focuses on antigen- and antibody-based immunotherapies and discusses the respective strengths and weaknesses of these approaches.     

The pancreas in human type 1 diabetes

Type 1 diabetes (T1D) is considered a disorder whose pathogenesis is autoimmune in origin, a notion drawn in large part from studies of human pancreata performed as far back as the 1960s. While studies of the genetics, epidemiology, and peripheral immunity in T1D have been subject to widespread analysis over the ensuing decades, efforts to understand the disorder through analysis of human pancreata have been far more limited. We have reviewed the published literature pertaining to the pathology of the human pancreas throughout all stages in the natural history of T1D. This effort uncovered a series of findings that challenge many dogmas ascribed to T1D and revealed data suggesting the marked heterogeneity in terms of its pathology. An improved understanding and appreciation for pancreatic pathology in T1D could lead to improved disease classification, an understanding of why the disorder occurs, and better therapies for disease prevention and management.