The Role of Adipose Tissue and Lipotoxicity in the Pathogenesis of Type 2 Diabetes

The widespread epidemics of obesity and type 2 diabetes mellitus (T2DM) suggest that both conditions are closely linked. An increasing body of evidence has shifted our view of adipose tissue from a passive energy depot to a dynamic “endocrine organ” that tightly regulates nutritional balance by means of a complex crosstalk of adipocytes with their microenvironment. Dysfunctional adipose tissue, particularly as observed in obesity, is characterized by adipocyte hypertrophy, macrophage infiltration, impaired insulin signaling, and insulin resistance. The result is the release of a host of inflammatory adipokines and excessive amounts of free fatty acids that promote ectopic fat deposition and lipotoxicity in muscle, liver, and pancreatic β cells. This review focuses on recent work on how glucose homeostasis is profoundly altered by distressed adipose tissue. A better understanding of this relationship offers the best chance for early intervention strategies aimed at preventing the burden of T2DM.     

Candidate Genes Expressed in Human Islets and Their Role in the Pathogenesis of Type 1 Diabetes

In type 1 diabetes (T1D), the insulin-producing β cells are destroyed by an immune-mediated process leading to complete insulin deficiency. There is a strong genetic component in T1D. Genes located in the human leukocyte antigen (HLA) region are the most important genetic determinants of disease, but more than 40 additional loci are known to significantly affect T1D risk. Since most of the currently known genetic candidates have annotated immune cell functions, it is generally considered that most of the genetic susceptibility in T1D is caused by variation in genes affecting immune cell function. Recent studies, however, indicate that most T1D candidate genes are expressed in human islets suggesting that the functions of the genes are not restricted to immune cells, but also play roles in the islets and possibly the β cells. Several candidates change expression levels within the islets following exposure to proinflammatory cytokines highlighting that these genes may be involved in the response of β cells to immune attack. In this review, the compiling evidence that many of the candidate genes are expressed in islets and β cells will be presented. Further, we perform the first systematic human islet expression analysis of all genes located in 50 T1D-associated GWAS loci using a published RNA sequencing dataset. We find that 336 out of 857 genes are expressed in human islets and that many of these interact in protein networks. Finally, the potential pathogenetic roles of some candidate genes will be discussed.     

Human Intestinal Microbiota and Type 1 Diabetes

The role of intestinal microbiota in immune-mediated diseases, such as type 1 diabetes, has deservedly received a lot of attention. Evidently, changes in the intestinal microbiota are associated with type 1 diabetes as demonstrated by recent studies. Children with beta-cell autoimmunity have shown low abundance of butyrate-producing bacteria and increase in the abundance of members of the Bacteroidetes phylum in fecal microbiota. These alterations could explain increased gut permeability, subclinical small intestinal inflammation, and dysregulation of oral tolerance in type 1 diabetes. However, these studies do not provide evidence of the causative role of the gut microbiota in the development of beta-cell autoimmunity, yet. In animal models, the composition of gut microbiota modulates the function of both innate and adaptive immunity, and intestinal bacteria are regulators of autoimmune diabetes. Thus, prevention of type 1 diabetes could, in the future, be based on the interventions targeted to the gut microbiota.     

肠道感染在肠易激综合征发病中的作用

肠易激综合征（irritable bowel syndrome，IBS）是一种以腹痛或腹部不适伴排便异常为特征的肠功能紊乱．属常见病。但由于其病因至今仍不完全明了，对本病的防治缺乏足够有效的方法。过去一直认为本病是一种胃肠神经官能症、胃肠动力紊乱或内脏感觉异常。但这些只是表面现象，不是病因。1997年．英国学者Neal等对544例急性胃肠炎患者进行了观察．报道感染后6个月肠功能紊乱的发生率为25％．致病细菌主要为弯曲茵（64．1％）和沙门茵（30．5％），提出了感染后IBS（postinfective IBS，PI—IBS）的概念。但这仅限于西方国家的研究。印度学者对伴有溶组织阿米巴肠道感染的IBS患者进行观察．鉴于根除阿米巴不能降低IBS症状的积分．因而推论感染与IBS不具有相关性闭。     

The Role of Insulin Resistance in the Natural History of Type 1 Diabetes

It is well established that peripheral insulin sensitivity is a critical factor in the aetiology of non-insulin dependent (Type 2) diabetes mellitus (NIDDM). Insulin resistance may also play a role at various stages in the natural history of insulin dependent (Type 1) diabetes (IDDM) and this was the topic of a workshop held in London on Friday 14 July 1995. The mechanisms of insulin resistance in IDDM are ill-defined but probably include ‘glucose toxicity’. In the pre-diabetic period, insulin resistance may affect rates of progression to frank hyperglycaemia. Following the clinical onset of IDDM, insulin resistance could influence the length of the ‘honeymoon period’, diabetic control and patterns of growth during puberty, insulin requirements and blood glucose control at any time, the birth weight of infants born to diabetic mothers, and, through an effect on lipid metabolism and hypertension, ultimately contribute to the excess mortality associated with IDDM. In NIDDM, insulin resistance could influence rates of progression to insulin dependence. Treatment using insulin enhancers in NIDDM patients with autoimmune changes might delay or arrest their usual high-risk of progression to insulin dependence. As it is likely that insulin resistance has a wide-ranging influence on the natural history of diabetes in IDDM patients we suggest that treatment with insulin enhancers may prove beneficial in selected patients. © 1997 by John Wiley & Sons, Ltd.     

The Gut Microbiome as a Target for the Treatment of Type 2 Diabetes

Purpose of Review

The objective of this review is to critically assess the contributing role of the gut microbiota in human obesity and type 2 diabetes (T2D).

Recent Findings

Experiments in animal and human studies have produced growing evidence for the causality of the gut microbiome in developing obesity and T2D. The introduction of high-throughput sequencing technologies has provided novel insight into the interpersonal differences in microbiome composition and function.

Summary

The intestinal microbiota is known to be associated with metabolic syndrome and related comorbidities. Associated diseases including obesity, T2D, and fatty liver disease (NAFLD/NASH) all seem to be linked to altered microbial composition; however, causality has not been proven yet. Elucidating the potential causal and personalized role of the human gut microbiota in obesity and T2D is highly prioritized.

     

Nephropathy in Type 1 Diabetes: the Role of Genetic Factors

Diabetic nephropathy affects up to 30% of all patients with Type 1 (insulin-dependent) diabetes and is associated with a high morbidity and mortality. A number of studies have suggested that, unlike retinopathy or neuropathy, the influence of hereditary factors on the development of nephropathy is strong. Much interest has focused on possible genetic markers indicating an increased risk for developing diabetic nephropathy. It is envisaged that patients with Type 1 diabetes may be screened at diagnosis for increased susceptibility to nephropathy and subsequently have intensified follow up and possibly even prophylactic therapy in order to prevent progression to nephropathy. Two groups of candidate genes have so far been of particular interest: those implicated in the aetiology of hypertension, and those involved in the metabolism of glomerular basement membrane proteins. This article aims to review the evidence suggesting a role for hereditary factors, possible genetic models, and the genetic loci thought to be involved.     

肠道微生态在炎症性肠病发病中的作用

炎症性肠病（IBD）是一类病因不明的肠道炎性疾病,主要包括溃疡性结肠炎和克罗恩病,其发病机制尚未清楚,可能涉及遗传、免疫和环境因素,其中肠道菌群所构成的肠道微生态可能扮演重要角色,已日益引起重视。本文通过对该领域的新进展作一概述,旨在加深对肠道微生态与IBD关系的认识以及探讨治疗IBD的新策略。     

The Role of the CXCL10/CXCR3 System in Type 1 Diabetes

Despite intervention with insulin, type 1 diabetes gradually deteriorates the patients'' quality of life. The disease is characterized by an immune-mediated destruction of pancreatic beta-cells. Its etiology, however, remains controversial. Some studies argue that glutamic acid decarboxylase (GAD) antigen and GAD-reactive T cells are critical players in the development of diabetes by affecting the Th cell balance. A T-helper 1 (Th1)-dominant immune response is considered to be important in beta-cell failure in both human and animal models of type 1 diabetes. The Th1-type chemokine, CXCL10, and its receptor, CXCR3, are involved not only in the immune response, but also in the suppression of beta-cell proliferation. Thus, understanding the CXCL10/CXCR3 system may be important for finding a cure. In this short review, we discuss the role of the CXCL10/CXCR3 system in type 1 diabetes and propose relevant treatment options.     

肠道菌群在炎症性肠病发生中的作用

炎症性肠病（IBD）是一种慢性非特异性肠道炎症性疾病．其明确病因和发病机制至今仍不清楚。近年来随着微生态学的发展．肠道菌群与IBD发病的关系日益受到关注。多项证据表明IBD患者存在肠道菌群紊乱。本文就肠道菌群在IBD发生中作用的研究进展作一综述。     

The Expanding Role of Natural Killer Cells in Type 1 Diabetes and Immunotherapy

Treatments for autoimmune diseases including type 1 diabetes (T1D) are aimed at resetting the immune system, especially its adaptive arm. The innate immune system is often ignored in the design of novel immune-based therapies. There is increasing evidence for multiple natural killer (NK) subpopulations, but their role is poorly understood in autoimmunity and likely is contributing to the controversial role reported for NKs. In this review, we will summarize NK subsets and their roles in tolerance, autoimmune diabetes, and immunotherapy.