Development and characterization of a novel rat model of type 2 diabetes mellitus: the UC Davis type 2 diabetes mellitus UCD-T2DM rat

The prevalence of type 2 diabetes (T2DM) is increasing, creating a need for T2DM animal models for the study of disease pathogenesis, prevention, and treatment. The purpose of this project was to develop a rat model of T2DM that more closely models the pathophysiology of T2DM in humans. The model was created by crossing obese Sprague-Dawley rats with insulin resistance resulting from polygenic adult-onset obesity with Zucker diabetic fatty-lean rats that have a defect in pancreatic beta-cell function but normal leptin signaling. We have characterized the model with respect to diabetes incidence; age of onset; longitudinal measurements of glucose, insulin, and lipids; and glucose tolerance. Longitudinal fasting glucose and insulin data demonstrated progressive hyperglycemia (with fasting and fed glucose concentrations >250 and >450 mg/dl, respectively) after onset along with hyperinsulinemia resulting from insulin resistance at onset followed by a progressive decline in circulating insulin concentrations, indicative of beta-cell decompensation. The incidence of diabetes in male and female rats was 92 and 43%, respectively, with an average age of onset of 6 mo in males and 9.5 mo in females. Results from intravenous glucose tolerance tests, pancreas immunohistochemistry, and islet insulin content further support a role for beta-cell dysfunction in the pathophysiology of T2DM in this model. Diabetic animals also exhibit glycosuria, polyuria, and hyperphagia. Thus diabetes in the UC Davis-T2DM rat is more similar to clinical T2DM in humans than in other existing rat models and provides a useful model for future studies of the pathophysiology, treatment, and prevention of T2DM.     

在实验动物水平通过恢复和改善胰岛β细胞功能的糖尿病治疗新进展

糖尿病是一个世界性问题,在中国就有超过1.3亿人患有糖尿病.糖尿病主要分为1型糖尿病和2型糖尿病.遗憾的是,糖尿病至今尚未达成有效的预防和治愈手段.但是,近年来的一系列突破性的研究成果,让我们看到了治愈糖尿病的希望.在这里我们回顾了目前关于1型糖尿病和2型糖尿病可能的治愈途径的研究进展.这些途径包括胰岛移植和1型糖尿病...     

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.     

Combined treatment with lisofylline and exendin-4 reverses autoimmune diabetes

Type 1 diabetes mellitus (T1DM) is an autoimmune disease leading to near complete pancreatic beta-cell destruction. New evidence suggests that beta-cell regeneration is possible, but ongoing autoimmune damage prevents restoration of beta-cell mass. We tested the hypothesis that simultaneously blocking autoimmune cytokine damage and supplying a growth-promoting stimulus for beta-cells would provide a novel approach to reverse T1DM. Therefore, in this study we combined lisofylline to suppress autoimmunity and exendin-4 to enhance beta-cell proliferation for treating autoimmune-mediated diabetes in the non-obese diabetic (NOD) mouse model. We found that this combined therapy effectively reversed new-onset diabetes within a week of therapy, and even maintained euglycemia up to 145 days after treatment withdrawal. The therapeutic effect of this regimen was associated with improved beta-cell metabolism and insulin secretion, while reducing beta-cell apoptosis. It is possible that such combined therapy could become a new strategy to defeat T1DM in humans.     

IMPARO: inferring microbial interactions through parameter optimisation

Type 2 diabetes mellitus (T2DM) is a worldwide disease that have an impact on individuals of all ages causing micro and macro vascular impairments due to hyperglycemic internal environment. For ultimate treatment to cure T2DM, association of diabetes with immune components provides a strong basis for immunotherapies and vaccines developments that could stimulate the immune cells to minimize the insulin resistance and initiate gluconeogenesis through an insulin independent route. Immunoinformatics based approach was used to design a polyvalent vaccine for T2DM that involved data accession, antigenicity analysis, T-cell epitopes prediction, conservation and proteasomal evaluation, functional annotation, interactomic and in silico binding affinity analysis. We found the binding affinity of antigenic peptides with major histocompatibility complex (MHC) Class-I molecules for immune activation to control T2DM. We found 13-epitopes of 9 amino acid residues for multiple alleles of MHC class-I bears significant binding affinity. The downstream signaling resulted by T-cell activation is directly regulated by the molecular weight, amino acid properties and affinity of these epitopes. Each epitope has important percentile rank with significant ANN IC50 values. These high score potential epitopes were linked using AAY, EAAAK linkers and HBHA adjuvant to generate T-cell polyvalent vaccine with a molecular weight of 35.6 kDa containing 322 amino acids residues. In silico analysis of polyvalent construct showed the significant binding affinity (− 15.34 Kcal/mol) with MHC Class-I. This interaction would help to understand our hypothesis, potential activation of T-cells and stimulatory factor of cytokines and GLUT1 receptors. Our system-level immunoinformatics approach is suitable for designing potential polyvalent therapeutic vaccine candidates for T2DM by reducing hyperglycemia and enhancing metabolic activities through the immune system.     

Human pluripotent stem cell-derived β cells: Truly immature islet β cells for type 1 diabetes therapy?

A century has passed since the Nobel Prize winning discovery of insulin, which still remains the mainstay treatment for type 1 diabetes mellitus (T1DM) to this day. True to the words of its discoverer Sir Frederick Banting, “insulin is not a cure for diabetes, it is a treatment”, millions of people with T1DM are dependent on daily insulin medications for life. Clinical donor islet transplantation has proven that T1DM is curable, however due to profound shortages of donor islets, it is not a mainstream treatment option for T1DM. Human pluripotent stem cell derived insulin-secreting cells, pervasively known as stem cell-derived β cells (SC-β cells), are a promising alternative source and have the potential to become a T1DM treatment through cell replacement therapy. Here we briefly review how islet β cells develop and mature in vivo and several types of reported SC-β cells produced using different ex vivo protocols in the last decade. Although some markers of maturation were expressed and glucose stimulated insulin secretion was shown, the SC-β cells have not been directly compared to their in vivo counterparts, generally have limited glucose response, and are not yet fully matured. Due to the presence of extra-pancreatic insulin-expressing cells, and ethical and technological issues, further clarification of the true nature of these SC-β cells is required.     

Advances in the cellular immunological pathogenesis of type 1 diabetes

Type 1 diabetes is an autoimmune disease caused by the immune‐mediated destruction of insulin‐producing pancreatic β cells. In recent years, the incidence of type 1 diabetes continues to increase. It is supposed that genetic, environmental and immune factors participate in the damage of pancreatic β cells. Both the immune regulation and the immune response are involved in the pathogenesis of type 1 diabetes, in which cellular immunity plays a significant role. For the infiltration of CD4⁺ and CD8⁺ T lymphocyte, B lymphocytes, natural killer cells, dendritic cells and other immune cells take part in the damage of pancreatic β cells, which ultimately lead to type 1 diabetes. This review outlines the cellular immunological mechanism of type 1 diabetes, with a particular emphasis to T lymphocyte and natural killer cells, and provides the effective immune therapy in T1D, which is approached at three stages. However, future studies will be directed at searching for an effective, safe and long‐lasting strategy to enhance the regulation of a diabetogenic immune system with limited toxicity and without global immunosuppression.     

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.     

Accumulation of autophagosomes contributes to enhanced amyloidogenic APP processing under insulin-resistant conditions

Alzheimer disease (AD) is sometimes referred to as type III diabetes because of the shared risk factors for the two disorders. Insulin resistance, one of the major components of type II diabetes mellitus (T2DM), is a known risk factor for AD. Insulin resistance increases amyloid-β peptide (Aβ) generation, but the exact mechanism underlying the linkage of insulin resistance to increased Aβ generation in the brain is unknown. In this study, we investigated the effect of insulin resistance on amyloid β (A4) precursor protein (APP) processing in mice fed a high-fat diet (HFD), and diabetic db/db mice. We found that insulin resistance promotes Aβ generation in the brain via altered insulin signal transduction, increased BACE1/β-secretase and γ-secretase activities, and accumulation of autophagosomes. Using an in vitro model of insulin resistance, we found that defects in insulin signal transduction affect autophagic flux by inhibiting the mechanistic target of rapamycin (MTOR) pathway. The insulin resistance-induced autophagosome accumulation resulted in alteration of APP processing through enrichment of secretase proteins in autophagosomes. We speculate that the insulin resistance that underlies the pathogenesis of T2DM might alter APP processing through autophagy activation, which might be involved in the pathogenesis of AD. Therefore, we propose that insulin resistance-induced autophagosome accumulation becomes a potential linker between AD and T2DM.     

Accumulation of autophagosomes contributes to enhanced amyloidogenic APP processing under insulin-resistant conditions

Alzheimer disease (AD) is sometimes referred to as type III diabetes because of the shared risk factors for the two disorders. Insulin resistance, one of the major components of type II diabetes mellitus (T2DM), is a known risk factor for AD. Insulin resistance increases amyloid-β peptide (Aβ) generation, but the exact mechanism underlying the linkage of insulin resistance to increased Aβ generation in the brain is unknown. In this study, we investigated the effect of insulin resistance on amyloid β (A4) precursor protein (APP) processing in mice fed a high-fat diet (HFD), and diabetic db/db mice. We found that insulin resistance promotes Aβ generation in the brain via altered insulin signal transduction, increased BACE1/β-secretase and γ-secretase activities, and accumulation of autophagosomes. Using an in vitro model of insulin resistance, we found that defects in insulin signal transduction affect autophagic flux by inhibiting the mechanistic target of rapamycin (MTOR) pathway. The insulin resistance-induced autophagosome accumulation resulted in alteration of APP processing through enrichment of secretase proteins in autophagosomes. We speculate that the insulin resistance that underlies the pathogenesis of T2DM might alter APP processing through autophagy activation, which might be involved in the pathogenesis of AD. Therefore, we propose that insulin resistance-induced autophagosome accumulation becomes a potential linker between AD and T2DM.     

Screening for celiac disease in poorly controlled type 2 diabetes mellitus: worth it or not?

Background

Recent studies have demonstrated that immune factors might have a role in the pathophysiology of insulin resistance and type 2 diabetes mellitus (T2DM). Inappropriate glycemic control in patients with T2DM is an important risk factor for the occurrence of diabetes complications. The prevalence of celiac disease (CD) is high in type 1 diabetes mellitus however, there are scarce data about its prevalence in T2DM. Our aim was to investigate the prevalence of celiac disease among insulin-using type 2 diabetes patients with inappropriate glycemic control.

Methods

IgA tissue transglutaminase antibodies (tTGA IgA) test was performed as a screening test. A total of 135 patients with T2DM whose control of glycemia is inappropriate (HbAlc value >7%) in spite of using insulin treatment for at least 3-months (only insulin or insulin with oral antidiabetic drugs) and 115 healthy controls were enrolled in the study. Upper gastrointestinal endoscopy with duodenal biopsy was performed to all patients with raised tTGA IgA or selective lgA deficiency.

Results

Gender, age, body mass index (BMI) and tTGA IgA, kreatinin, calcium, LDL-cholesterol (LDL-C), total cholesterol, 25-OH vitamin D₃ levels were similar between groups. Systolic and diastolic blood pressure, waist circumference, fasting plasma glucose, postprandial plasma glucose, urea, sodium, HbA1c, LDL-C, triglyceride, vitamin B12 levels were significantly higher in DM group (p < 0.0001). BMI, high-sensitive CRP, microalbuminuria, and AST, ALT, potassium, phosphorus levels were significantly higher in the T2DM group (p < 0.05). HDL-cholesterol and parathormone levels were significantly lower in the T2DM group (p < 0.05). Two of the 135 patients with T2DM were diagnosed with CD (1.45%).

Conclusions

The prevalence of celiac disease among patients with type 2 diabetes, with poor glycemic control despite insulin therapy, is slightly higher than the actual CD prevalence in general population. Type 2 diabetic patients with inappropriate control of glycemia in spite of insulin treatment might be additionally tested for Celiac disease especially if they have low C-peptide levels.

     

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。     

NF-κB/NLRP3 inflammasome axis and risk of Parkinson's disease in Type 2 diabetes mellitus: A narrative review and new perspective

Parkinson's disease (PD) is the second most common neurodegenerative disease after Alzheimer's disease (AD). Genetic predisposition and immune dysfunction are involved in the pathogenesis of PD. Notably, peripheral inflammatory disorders and neuroinflammation are associated with PD neuropathology. Type 2 diabetes mellitus (T2DM) is associated with inflammatory disorders due to hyperglycaemia-induced oxidative stress and the release of pro-inflammatory cytokines. Particularly, insulin resistance (IR) in T2DM promotes the degeneration of dopaminergic neurons in the substantia nigra (SN). Thus, T2DM-induced inflammatory disorders predispose to the development and progression of PD, and their targeting may reduce PD risk in T2DM. Therefore, this narrative review aims to find the potential link between T2DM and PD by investigating the role of inflammatory signalling pathways, mainly the nuclear factor kappa B (NF-κB) and the nod-like receptor pyrin 3 (NLRP3) inflammasome. NF-κB is implicated in the pathogenesis of T2DM, and activation of NF-κB with induction of neuronal apoptosis was also confirmed in PD patients. Systemic activation of NLRP3 inflammasome promotes the accumulation of α-synuclein and degeneration of dopaminergic neurons in the SN. Increasing α-synuclein in PD patients enhances NLRP3 inflammasome activation and the release of interleukin (IL)-1β followed by the development of systemic inflammation and neuroinflammation. In conclusion, activation of the NF-κB/NLRP3 inflammasome axis in T2DM patients could be the causal pathway in the development of PD. The inflammatory mechanisms triggered by activated NLRP3 inflammasome lead to pancreatic β-cell dysfunction and the development of T2DM. Therefore, attenuation of inflammatory changes by inhibiting the NF-κB/NLRP3 inflammasome axis in the early T2DM may reduce future PD risk.     

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.     

2 型糖尿病患者血浆成纤维细胞生长因子-21 水平的变化及意义

目的:探讨2型糖尿病(type 2 diabetes mellitus,T2DM)患者血浆成纤维细胞生长因子-21(fibroblast growth factor 21,FGF-21)水平变化以及观察短期胰岛素强化治疗对FGF-21水平的影响。方法:选择我院2013年1月至2015年1月收治的T2DM患者64例,其中初诊T2DM患者32例(T2DM组),T2DM合并大血管病变患者32例(合并大血管病变组),并选择同期体检健康者30例(对照组)。采用酶联免疫法测定三组血浆FGF-21水平以及胰岛素强化治疗前后的变化,分析血浆FGF-21水平与体质量指数(BMI)、腰臀比(WHR)、血脂、血糖、空腹血浆胰岛素(FINS)和糖化血红蛋白(Hb A1C)等水平的关系。结果:T2DM组及T2DM合并大血管病变组患者空腹血浆FGF-21水平明显高于对照组(P0.05),T2DM合并大血管病变组患者空腹血浆FGF-21水平明显高于T2DM组和对照组(P0.05)。空腹血浆FGF-21水平与T2DM患者FPG、Hb A1C水平呈明显正相关,WHR、舒张压、Hb A1C是影响血浆FGF-21水平的独立相关因素。经胰岛素强化治疗后,血浆FGF-21水平较治疗前明显下降(P0.05)。结论:T2DM患者血浆FGF-21水平明显升高,可能参与了T2DM及其大血管病变的发生和发展,胰岛素强化治疗可明显降低T2DM患者血浆FGF-21水平,血浆FGF-21可能作为T2DM病情和疗效评估的参考指标。     

用抗糖尿病药物GLP-1及其类似物治疗阿尔茨海默病

流行病学和基础研究表明阿尔茨海默病（Alzheimert＇s disease,AD）与2型糖尿病（type 2 diabetes mellitus,T2DM）存在密切关联：T2DM是AD的危险因素之一;而AD脑内也出现胰岛素信号异常、胰岛素抵抗状态,因而被称为“第3类型的糖尿病”。近年来治疗T2DM的新药——胰高血糖素样肽-1（glucagon-1ike peptide-1,GLP-1）及其类似物,已被证实具有神经保护作用,且能改善AD模型的记忆和认知功能,为AD治疗药物的研究提供了新的策略。     

Macroangiopathy in adults and children with diabetes: risk factors (part 2).

Autoimmune or type 1 diabetes mellitus (T1DM), accounts for 90-95% of all cases of diabetes, while type 2 diabetes mellitus (T2DM), characterized by impaired insulin sensitivity and production, accounts for the other 5-10%. Atherosclerotic process starts during childhood and recognize several mechanisms that are activated in response to NOXIUS STIMULI and participate in a complex state which is accepted to be a chronic inflammatory state. T1DM patients, especially those with a non-optimal metabolic control, have a higher risk of developing all macrovascular complications such as myocardial infarction, stroke and silent ischemia. Macrovascular disease is mainly associated with hyperglycemia, dyslipidemia, obesity, hypertension, hypercoagulable state, cigarette smoking, lack of exercise, endothelial dysfunction, hyperhomocysteinemia and vascular wall abnormalities. In this paper we review the importance of traditional and non-traditional risk factors for macrovascular complications in children with T1DM and discuss their role in the pathogenesis of the excess cardiovascular mortality in these patients.     

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.