Pancreatic Pathology in Type 1 Diabetes Mellitus

Type 1 diabetes is a multifactorial disease resulting from a complex interplay between host genetics, the immune system and the environment, that culminates in the destruction of insulin-producing beta cells. The incidence of type 1 diabetes is increasing at an alarming rate, especially in children under the age of 5 (Gepts in Diabetes 14(10):619-613, 1965; Foulis et al. in Lancet 29(5):267-274, 1986; Gamble, Taylor and Cumming in British Medical Journal 4(5887):260-262 1973). Genetic predisposition, although clearly important, cannot explain this rise, and so, it has been proposed that changes in the ‘environment’ and/or changes in ‘how we respond to our environment’ must contribute to this rising incidence. In order to gain an improved understanding of the factors influencing the disease process, it is important, firstly, to focus on the organ at the centre of the illness—the pancreas. This review summarises our knowledge of the pathology of the endocrine pancreas in human type 1 diabetes and, in particular, explores the progression of this understanding over the past 25 years.     

Extract of Ginkgo Biloba Ameliorates Streptozotocin-Induced Type 1 Diabetes Mellitus and High-Fat Diet-Induced Type 2 Diabetes Mellitus in Mice

Diabetes mellitus (DM) is caused by either destruction of pancreatic β-cells (type 1 DM) or unresponsiveness to insulin (type 2 DM). Conventional therapies for diabetes mellitus have been developed but still needs improvement. Many diabetic patients have complemented conventional therapy with alternative methods including oral supplementation of natural products. In this study, we assessed whether Ginkgo biloba extract (EGb) 761 could provide beneficial effects in the streptozotocin-induced type 1 DM and high-fat diet-induced type 2 DM murine model system. For the type 1 DM model, streptozotocin-induced mice were orally administered EGb 761 for 10 days prior to streptozotocin injection and then again administered EGb 761 for an additional 10 days. Streptozotocin-treated mice administered EGb 761 exhibited lower blood triglyceride levels, lower blood glucose levels and higher blood insulin levels compared to streptozotocin-treated mice. Furthermore, liver LPL and liver PPAR-α were increased whereas IL-1β and TNF-α were decreased in streptozotocin-injected mice treated with EGb 761 compared to mice injected with streptozotocin alone. For the type 2 DM model, mice were given high-fat diet for 60 days and then orally administered EGb 761 every other day for 80 days. We found that mice given a high-fat diet and EGb 761 showed decreased blood triglyceride levels, increased liver LPL, increased liver PPAR-α and decreased body weight compared to mice given high-fat diet alone. These results suggest that EGb 761 can exert protective effects in both type 1 and type 2 DM murine models.     

降糖治疗对新诊断2型糖尿病血清色素上皮衍生因子的影响

目的 观察降糖治疗对新诊断的2型糖尿病患者血清色素上皮衍生因子水平的影响。方法 选取2009年2月~2011年6月新诊断且在重庆医科大学附属第一医院住院治疗的2型糖尿病患者47例,经过短期胰岛素强化治疗后,将患者随机分为以二甲双胍为基础的口服药物组（OAD组）26例和甘精胰岛素组（GLA组）21例,以空腹血糖＜7.2 mmol/L为治疗目标,降糖治疗6个月后,观察两组患者治疗前后血清PEDF 浓度、空腹血糖、HbA1c、HOMA-β、HOMA-IR水平。结果 经过6个月的降糖治疗,与基线比较,两组患者空腹血糖、HbA1C均降低,HOMA-β、PEDF均升高,差异有统计学意义（P＜0.05）;两组间空腹血糖、HbA1c、HOMA-β、PEDF比较,差异无统计学意义（P＞0.05）;HOMA-IR与基线比较,差异无统计学意义（P＞0.05）,两组间HOMA-IR比较,差异有统计学意义（P＜0.05）。结论 以二甲双胍为基础的口服药物降糖治疗和甘精胰岛素降糖治疗均可显著升高2型糖尿病患者的血清PEDF水平。     

Spotlight on Insulin Detemir in Type 1 and 2 Diabetes Mellitus

Insulin detemir (Levemir) is a soluble long-acting human insulin analog acylated with a 14-carbon fatty acid. The fatty acid modification allows insulin detemir to reversibly bind to albumin, thereby providing slow absorption and a prolonged and consistent metabolic effect of up to 24 hours in patients with type 1 or type 2 diabetes mellitus. Insulin detemir has a more predictable, protracted, and consistent effect on blood glucose than neutral protamine Hagedorn (NPH) insulin, with less intrapatient variability in glycemic control than NPH insulin or insulin glargine. Insulin detemir, administered once or twice daily, is at least as effective as NPH insulin in maintaining overall glycemic control, with a similar or lower risk of hypoglycemia, especially nocturnal hypoglycemia, compared with NPH insulin in patients with type 1 or type 2 diabetes. Insulin detemir also provides the added clinical benefit of no appreciable bodyweight gain in patients with type 1 diabetes and less bodyweight gain than NPH insulin in patients with type 2 diabetes. Insulin detemir is, therefore, a promising new option for basal insulin therapy in patients with type 1 or 2 diabetes.     

Pathophysiology of Immune-Mediated (Type 1) Diabetes Mellitus

Type 1 diabetes mellitus is a chronic T cell-mediated disease resulting from autoimmune destruction of pancreatic β-cells. This process leads to progressive and irreversible failure of insulin secretion. Development of the disease involves both genetic and environmental factors. Genetic predisposition is mainly connected with the human leucocyte antigen (HLA) region, which encodes structures responsible for antigen presentation. A comprehensive molecular understanding of the pathogenesis of the disease is essential for the design of rational and well tolerated means of prevention. This paper describes recent experimental and clinical findings and elucidates the current possibilities for immunotherapy of type 1 diabetes. The nature of breakdown of self-tolerance and the mechanisms involved in its recovery are discussed.     

胆囊结石与2型糖尿病的共病机制

随着人们生活水平的提高,饮食结构发生转变,胆囊结石及2型糖尿病的发病率逐年上升,且2型糖尿病患者的胆囊结石患病率明显高于其他人群,以往大量研究认为糖尿病是胆囊结石的危险因素。随着研究的深入,发现胆囊结石的发生机制与血脂、胰岛素抵抗及部分脂肪因子因素密切相关,甚至认为胆囊结石是代谢综合征的另一种表现形式。而这些因素在2型糖尿病的发生发展中同样起着重要作用。本文就对胰岛素抵抗、脂代谢、瘦素及脂联素在胆囊结石与2型糖尿病的发病中的作用机制进行综述,并阐明这种共病机制的研究在实际临床工作中的意义。     

Progress in the Development of Immune-Based Therapies for Type 1 Diabetes Mellitus

Between ten and twenty million people worldwide have type 1 diabetes mellitus (T1DM), which has previously been called juvenile diabetes, childhood diabetes, and insulin-dependent diabetes mellitus. T1DM is undoubtedly a multifactorial disease affecting predisposed individuals with genetic susceptibilities; it is also associated with environmental factors leading to unbalanced immune responses. This chronic disorder is caused by auto-aggressive T lymphocytes entering the pancreatic islets of Langerhans where they destroy the insulin-producing beta-cells. A wide variety of immuno-interventions cure T1DM effectively in different animal models when given early in disease development. However, few of these interventions are efficacious in humans at a later stage of the disease. Indeed, only three immunotherapeutic compounds have demonstrated both safety and efficacy in phase II/III clinical trials. Although much time and resources have been spent on generating potent immune therapies, none of the patients enrolled in these trials have achieved normoglycemia in the absence of insulin injections. Many reasons can account for such a disappointing conclusion. Firstly, the dynamics of disease pathogenesis differs significantly from patient to patient, which directly impacts the therapeutic efficacy. Also, at trial entry, the percentage of remaining pancreatic beta-cells in T1DM patients often reflects the odds of responding positively to treatment. Based on the knowledge we have gained from preclinical studies and clinical trials, several steps have been made in the development of safer and more efficient immune-based therapies. There are, however, a number of concerns that should be addressed in order to improve future therapeutic strategies.     

Long-Acting GLP-1 Analogs for the Treatment of Type 2 Diabetes Mellitus

Type 2 diabetes mellitus is characterized by insulin resistance, impaired glucose-induced insulin secretion, and inappropriately elevated glucagon levels which eventually result in hyperglycemia. The currently available treatment modalities for type 2 diabetes are often unsatisfactory in getting patients to glycemic goals, even when used in combination, and therefore many patients develop microvascular and macrovascular diabetic complications. Additionally, these treatment modalities are often limited by inconvenient dosage regimens and safety and tolerability issues, the latter including hypoglycemia, bodyweight gain, edema, and gastrointestinal intolerance. There is, therefore, a need for new and more efficacious agents, targeting not only treatment, but also prevention of the disease, its progression, and its associated complications. Recently, an entirely new therapeutic option for the treatment of type 2 diabetes has become available in the US (since October 2005) and in Europe (since May 2007): the incretin-based therapies. The incretin-based therapies fall into two different classes: (i) incretin mimetics, i.e. injectable peptide preparations with actions similar to the natural incretin hormones; and (ii) the incretin enhancers, i.e. orally available agents that inhibit the degradation of the incretin hormones in the body and thereby increase their plasma levels and biologic actions. This article focuses on the incretin mimetics and outlines the scientific basis for the development of glucagon-like peptide-1 (GLP-1) analogs, reviews clinical experience gained so far, and discusses future expectations for long-acting forms of GLP-1 analogs.     

Immune Reactivity to GAD25 in Type 1 Diabetes Mellitus

While both isoforms of glutamic acid decarboxylase (GAD) function as important autoantigens in autoimmune diabetes mellitus--GAD65 in humans and GAD67 in the NOD mouse--GAD67 is not synthesized in human pancreatic islets and is thought not to be an autoantigen in human diabetes. We have recently shown, however, that human islets contain a GAD67 splice variant: GAD25. Given the evidence that GAD67 could be a key diabetogenic autoantigen in the NOD mouse and the high prevalence of GAD65 autoantibodies in human type 1 diabetes, it became important to ask whether there is also immune reactivity to GAD25 in type 1 diabetes--possibly implicating it in the pathogenesis of the disease--and whether GAD25 reactivity could, like GAD65 reactivity, function as a clinically useful marker for the disease. We also hypothesized that the presence of autoantibodies to the smaller splice variant could be a cause of the up to 30% prevalence of GAD67 autoreactivity associated with type 1 diabetes. We therefore analyzed GAD25 reactivity in 105 newly-diagnosed children with type 1 diabetes and 74 control subjects. While 14 (13%) of the diabetic subjects were positive for GAD67 autoantibodies, only 3 (3%) were positive for GAD25 reactivity, none of which were GAD67 antibody-positive. Analysis of reactivity to a GAD67 chimera was consistent with GAD67 binding activity being due to cross-reactive GAD65 antibodies. Immunostaining confirmed the presence of GAD25 in human islets, revealing GAD25-positive cells to be sparse. Our results indicate that autoreactivity to GAD25 is rare in newlydiagnosed type 1 diabetes and does not underlie GAD67 reactivity.     

前臂骨密度及血清IGF-1在2型糖尿病的特点

观察 2型糖尿病患者不同性别、不同年龄阶段以及肥胖与非肥胖状态下IGF - 1血清浓度及前臂骨密度水平。 2型糖尿病 10 0人 ,ELISA法测定血清IGF - 1浓度 ,双能X光骨密度检测仪 (DXA)测量前臂超远端及远端 1/ 3交界处骨密度、骨矿含量及T积分。结果表明 ,骨质疏松症的发病率为 14% ( <5 0岁组 )到 73 % ( >70岁组 ) ,总发病率为 3 3 % (超远端 )和2 7% (远端 )。其中女性发病率为 47.7%和 2 2 .7% ,男性为 2 1.4%和 3 0 .4%。BMD、BMC、IGF - 1血清水平随增龄逐渐低降 ,5 0岁以后女性BMD、BMC较男性显著下降。肥胖者的BMD、BMC较非肥胖者高 ,骨质疏松症的发生率低。IGF - 1在男性与女性之间及肥胖与非肥胖者之间均无差异。 2型糖尿病患者骨质疏松症的发病率女性高于男性 ,非肥胖者高于肥胖者 ,IGF- 1、年龄、体重、雌激素是影响骨代谢的相关因素 ,IGF - 1与年龄和体重无关。男性前臂中远端骨质疏松明显 ,而女性则远端明显     

强化健康教育对2型糖尿病病人的效果观察

目的 探讨糖尿病强化教育在2型糖尿病综合治疗中的作用.方法 将120例2型糖尿病病人随机分为强化教育组(IE)和一般教育组(GE).前者进行系统化糖尿病知识教育后,针对每一例患者进行个体化强化教育,后者则仅进行一般的糖尿病教育.于教育前和教育后3个月末、6个月末监测血糖、尿糖、糖化血红蛋白、血脂,进行组内教育前后及同期组间比较.结果 IE组3个月末及6个月末,HbAlc和TC、TG明显改善(P<0.01).GE组6个月末HbAlc和TC、TG水平也明显改善(P<0.01).开展教育后3个月末、6个月末:IE组HbAlc和TC、TG水平均明显低于GE组(P<0.01).结论 糖尿病知识强化教育可以改善糖尿病病人的糖脂代谢水平.     

1型糖尿病模型大鼠白细胞介素-17A和B细胞活化因子水平变化及其作用分析

目的:分析白细胞介素-17A (IL-17A)和B细胞活化因子(BAFF)在1型糖尿病(T1DM)发病中的作用。方法:15只SD大鼠随机分为正常对照组(CON组)、T1DM组和2型糖尿病组(T2DM组),链脲佐菌素(STZ)造模成功6周后,称取每只大鼠体重(BW),检测三组大鼠空腹血糖(FBG)和C肽(FCP)及血清、脾脏组织IL-17A、BAFF水平和脾脏抗凋亡基因Bcl-2mRNA水平,比较各组各指标差异。结果:T1DM组FBG显著高于CON组和T2DM组(P0.01),FCP和BW显著低于CON组和T2DM组(P0.01)。T1DM组血清IL-17A和BAFF水平显著高于CON组和T2DM组(P0.01)。三组间脾组织IL-17A和BAFF蛋白表达T1DM组和T2DM组均高于CON组(P0.01),T1DM组更高于T2DM组(P0.01)。三组间脾组织Bcl-2mRNA表达水平与BAFF蛋白表达趋势一致,T1DM组和T2DM组脾组织Bcl-2 mRNA基因表达均高于CON组(P0.01),T1DM组更高于T2DM组(P0.01)。结论:T1DM大鼠外周血和脾组织IL-17A、BAFF及Bcl-2mRNA表达变化具有相同趋势,提示它们共同参与了T1DM的发生。     

Association of Genetic Variants of SIRT1 With Type 2 Diabetes Mellitus

SIRT1 has been demonstrated in nutrient-sensing and insulin-signaling pathways in in vivo and in vitro experiments, but there is minimal information concerning the association between gene polymorphisms of SIRT1 and type 2 diabetes mellitus (T2DM) in a Chinese Han population. Using case-control design, we recruited 310 unrelated T2DM patients from inpatients at Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, while 301 healthy controls were volunteers from the community for regular medical checkup. All participants were genotyped within the SIRT1 region. The following five SNPs rs10509291, rs12778366, rs10997870, rs10823112, and rs4746720 cover 100% of common genetic variations (minor allele frequency ≥ 0.05) within the SIRT1 gene (r ² ≥ 0.8). The genotypes of SIRT1 gene polymorphisms were analyzed by the Snapshot assay and DNA sequencing. The resulting data show that there was significant genetic differentiation in rs10823112 [p = 0.003; OR (95% CI) = 1.515 (1.152–1.994) for genotype], rs4746720 [p = 0.024; OR (95% CI) = 1.37 (1.037–1.674) for genotype], and rs10509291 [p = 0.002; OR (95% CI) = 1.551 (1.179–2.04) for genotype] between T2DM and control subjects. However, the result of rs4746720 was no longer significant after correction for multiple testing (p after Bonferroni correction = 0.12); the results of rs10509291and rs10823112 were still significantly different between the two groups (p after Bonferroni correction = 0.01 and 0.015, respectively). Linear regression analyses adjusting for age, gender, and body mass index (BMI) showed that HbA1c and HOMA-IR in subjects with rs10509291 AA genotype were higher than those with TT genotype in T2DM group (p = 0.045, p = 0.035, respectively). Together, our data show that genetic variation of the SIRT1 gene is related to insulin resistance and increase risk of T2DM in Chinese Han population. The risk allele A at SIRT1 rs10509291 was closely associated with T2DM, and subjects who were homozygous of the A allele were more likely to develop T2DM.Key words: Type 2 diabetes, Genetic variants, SIRT1, Chinese Han population     

载脂蛋白E基因多态性与2型糖尿病的关系

目的:探讨载脂蛋白E基因型与2型糖尿病的易感性。方法:应用multi-ARMS快速分型法对316例T2DM患者、512例健康对照人群的ApoE基因第4外显子112位Cys/Arg和158位Arg/Cys进行检测;随机抽取分型标本进行DNA测序法验证。结果:ε2/2、ε2/3、ε3/3、ε4/2、ε4/3、ε4/4基因型在二组中的频率分布为:0.6%,5.7%,72.8%,1.9%,14.9%,4.1%(T2DM组);0.6%,9.4%,70.1%,1.8%,17.0%,1.2%(对照组)。二组间差异有显著性统计学意义(χ2=11.45,P<0.05),T2DM组ε4/4基因型频率明显高于对照组(4.11%VS1.17%)。结论:ApoEε4/4基因型可能与T2DM的易感性有关。     

PTPN22 Single-Nucleotide Polymorphisms in Iranian Patients with Type 1 Diabetes Mellitus

Background: PTPN22 plays a crucial role in regulating the function of various cells of the immune system, particularly T cells. Polymorphisms of the PTPN22 gene have been associated with many autoimmune diseases, including type 1 diabetes (T1D) which is a T-cell-mediated disease.

Objective: The present study was aimed at genotyping of an Iranian population for five polymorphisms of the PTPN22 gene.

Methods: The study population consisted of 99 T1D patients and 100 healthy controls. We genotyped five single-nucleotide polymorphisms (SNPs) (rs12760457, rs1310182, rs1217414, rs33996649, and rs2476601) of the PTPN22 gene.

Results: Regarding the variant rs2476601, genotypes AG and GG were increased and decreased in T1D patients compared with controls, respectively. Further, alleles G and A of this SNP were found to be decreased and increased in T1D patients, respectively (p value = 0.001). However, T1D and control groups did not differ on genotype distribution or allele frequency for other investigated SNPs.

Conclusions: The PTPN22 rs2476601 minor allele (A) was associated with T1D in Iran, accounting for its pathophysiology in autoimmune diseases.     

Adolescent Build Plotting on Body Composition Chart and the Type of Diabetes Mellitus

Although the prevalence of type 2 diabetes is increasing, there are cases difficult to categorize into certain type in pediatric diabetic patients. The aims of this study were to detect and choose a proper treatment modality for atypical cases of diabetes mellitus, using the body composition chart. We conducted a retrospective study from August 2005 to 2012 with patients who visited Konkuk University Medical Center, and were diagnosed with diabetes mellitus. The medical records were reviewed for the anthropometric data and indices of body composition. The subjects were grouped by the type of diabetes and gender. We constructed a body composition chart plotting fat free mass index and fat mass index (FMI). Body mass index and all body composition indices were higher in type 2 diabetes, in each gender in analysis with Mann-Whitney test. Significant determinant of diabetes type was revealed as FMI and contributing factors on FMI were analyzed with regression analysis. Six atypical cases were identified by a body composition chart including non-obese type 2 diabetes showing suboptimal growth with lower BMI related to relatively lower insulin secretion and type 1 diabetes with insulin resistance resulted from obesity. Body composition chart analysis might be useful in characterization of diabetes type and detection of atypical cases and early adjustment of diabetes management strategy.     

2型糖尿病患者血清瘦素、NSF-1与血脂的关系研究

目的 研究2型糖尿病患者血清瘦素、NSF-1、载脂蛋白及血脂水平的相关性.方法 选择2016年6月至2017年1月我院收治的2型糖尿病患者64例作为观察组,于同期选择在我院健康体检的健康人群58例为对照组,抽取两组晨起空腹静脉血,比较两组血清总胆固醇、甘油三酯、低密度脂蛋白胆固醇、高密度脂蛋白胆固醇、载脂蛋白A1、载脂蛋白E、瘦素、摄食抑制因子-1水平,并采用Pearson相关分析以上指标的相关性.结果 观察组与对照组血清总胆固醇、甘油三酯、低密度脂蛋白胆固醇、高密度脂蛋白胆固醇、载脂蛋白E、瘦素、摄食抑制因子-1水平差异具有统计意义(P＜0.05),载脂蛋白A1比较无统计学差异.血清总胆固醇与甘油三酯、低密度脂蛋白胆固醇、载脂蛋白E呈正相关(r =0.341,P＜0.001;r=0.836,P＜0.001;r =0.337,P＜0.001),与摄食抑制因子-1呈负相关(r=-0.303,P＜0.001).甘油三酯与载脂蛋白E呈显著正相关(r =0.678,P＜0.001),低密度脂蛋白胆固醇与瘦素呈明显负相关(r=-0.266,P＜0.001),高密度脂蛋白胆固醇与载脂蛋白A1呈明显正相关(r=0.335,P＜0.001),载脂蛋白A1与载脂蛋白E呈显著正相关(r=0.318,P＜0.001).结论 2型糖尿病患者存在血脂代谢异常情况,且与血清载脂蛋白、瘦素、摄食抑制因子-1之间存在一定相关性.