2型糖尿病胰岛细胞胰岛素抵抗的机制

胰岛素抵抗是2型糖尿病(T2DM)主要病理生理机制之一.肝脏、肌肉和脂肪组织存在胰岛素抵抗.近年来研究显示,胰岛α细胞与β细胞也存在胰岛素抵抗.高糖、高游离脂肪酸(FFA)、氧化应激、炎性反应均可导致胰岛素抵抗:高糖作用可下调胰岛α、β细胞磷脂酰肌醇3激酶(PI3K)/蛋白激酶B(PKB)途径;高FFA抑制胰岛素受体底物(IRS)及PI3K活性;氧化应激使胰岛α、β细胞的IRS表达下降;炎性因子可干扰IRS/PI3K信号通路.     

血清淀粉样蛋白A与胰岛素抵抗及糖尿病肾病

研究提示,胰岛素抵抗和糖尿病肾病都是慢性非特异性炎性反应过程.血清淀粉样蛋白A(SAA)作为一种急性时相反应蛋白,能够刺激多种免疫活细胞,产生大量炎性细胞因子,介导炎性反应,并能诱导单核细胞表达趋化因子,使各种炎性细胞尤其是单核/巨噬细胞及T细胞聚集到病变部位.而这种免疫和炎性反应过程可能促进了胰岛素抵抗和糖尿病肾病的发生和发展.     

C1q/肿瘤坏死因子相关蛋白12与糖代谢

C1q/肿瘤坏死因子相关蛋白(CTRP) 12是一种新型脂肪因子,属于CTRP超家族成员.其主要在脂肪组织表达及分泌,通过增强脂肪组织和肝脏中胰岛素信号,改善胰岛素抵抗,增加胰岛素敏感性.同时CTRP12还能降低脂肪组织炎性反应.CTRP12通过胰岛素依赖和非依赖的方式发挥作用,有望成为治疗胰岛素抵抗和2型糖尿病的新靶点.     

脂肪组织在脂肪性肝病发生发展中的作用

肥胖和饮酒容易导致脂肪性肝病,两者均可引起脂肪组织发生改变,主要的改变包括脂肪组织炎性反应、胰岛素抵抗、瘦素等细胞因子异常分泌以及免疫细胞浸润等。脂肪组织和肝脏通过多种途径相互作用,共同参与脂肪性肝病的发生、发展。减肥或使用药物减轻脂肪组织炎性反应均可改善肝脏损伤,提示针对脂肪组织的干预对治疗脂肪性肝病有着重要的作用。该文对脂肪组织在脂肪性肝病发生、发展中的作用作一综述。     

2型糖尿病的抗炎治疗

胰岛素抵抗与胰岛β细胞功能障碍是2型糖尿病发病的主要病理生理基础,而炎性反应因子介导的慢性非特异性低度炎性反应状态与胰岛素抵抗及β细胞功能障碍密切相关.传统意义上的降糖药物如二甲双胍、噻唑烷二酮类药物、胰岛素、胰高血糖素样肽-1以及他汀类降脂药都具有抗炎效应.新型的抗炎药物如白细胞介素1受体拮抗剂、白藜芦醇、姜黄素等可以通过多种途径改善炎性反应状态而降低血糖.因此,针对炎性反应因子的抗炎治疗有望成为一种崭新的糖尿病治疗u方法.     

调节性T细胞亚群在肥胖发病中的作用

CD4+CD25+Foxp3+调节性T细胞(Treg细胞)与效应性T细胞数量和(或)功能状态的失衡触发炎性反应.在健康小鼠及人体内脏脂肪组织中Treg细胞丰富存在,而在肥胖小鼠及人体脂肪中Treg细胞的数量及功能状态存在异常.Treg细胞亚群的异常将直接造成脂肪组织的慢性低度炎性反应状态.由于慢性低度炎性反应状态在肥胖及肥胖相关的胰岛素抵抗的发生、发展中扮演重要角色,Treg细胞将成为其未来研究的一个新热点.     

颗粒蛋白前体与糖尿病及肥胖的关系

颗粒蛋白前体是一种分泌性蛋白,广泛表达于各种组织,尤其是快速增殖的细胞中,参与胚胎发育、损伤修复、细胞周期等病理生理过程.炎性反应与2型糖尿病及肥胖相关,并且是胰岛素抵抗形成的重要机制之一.最新研究发现,颗粒蛋白前体在2型糖尿病及肥胖患者的体内表达明显升高,并通过白细胞介素-6炎性反应信号通路参与慢性炎性反应状态及胰岛素抵抗的形成,提示颗粒蛋白前体可能与2型糖尿病及肥胖的发病密切相关.     

脂肪组织巨噬细胞浸润与胰岛素抵抗

肥胖是一种低度炎性反应状态.近年来发现肥胖个体脂肪组织中巨噬细胞的浸润显著增加,并有研究表明脂肪组织的炎性反应因子主要由浸润的巨噬细胞分泌.目前对脂肪组织巨噬细胞的来源以及影响其浸润的因素还有争论.研究发现,巨噬细胞可以通过抑制脂肪细胞分化,增加炎性反应因子的表达等导致胰岛素抵抗的发生、发展.     

维生素D和糖尿病

维生素D最重要的功能是维持人体钙离子代谢的平衡.随着研究的深入,维生素D在炎性反应、自身免疫性疾病、胰岛素分泌及胰岛素抵抗等方面的作用已经成为研究的热点.维生素D缺乏或不足与糖尿病发病相关.维生素D可通过抑制炎性反应、促进胰岛素释放、减轻胰岛素抵抗等机制参与糖尿病的发病.大量的临床研究发现补充足量的维生素D不仅可以减少...     

自然杀伤细胞与2型糖尿病

近年来,免疫-代谢的相互关系已成为目前新的研究热点之一.自然杀伤细胞(NK细胞)作为固有免疫的主要成员,与2型糖尿病有着密切的联系:一方面,2型糖尿病患者外周血中NK细胞的数量出现异常以及功能出现紊乱,肥胖、胰岛素抵抗和氧化应激均可能参与2型糖尿病患者NK细胞的损伤机制.另一方面,NK细胞不仅可作为联系内脏脂肪炎性反应和脂肪应激的桥梁,参与内脏脂肪胰岛素抵抗,还可作为炎性细胞,促进2型糖尿病患者动脉粥样硬化的形成和进展,从而加剧糖尿病血管损伤.     

Macrophage infiltration into adipose tissue: initiation, propagation and remodeling

It has long been known that adipose tissue in obesity is in a heightened state of inflammation. Recently, our understanding of this has been transformed by the knowledge that immune cells such as macrophages and T cells can infiltrate adipose tissue and are responsible for the majority of inflammatory cytokine production. These seminal findings have opened up a new area in biology that is garnering the interest of scientists involved in research relating to cell motility, inflammation, obesity, physiology, diabetes and cardiovascular disease. Some important general questions relevant to this field are: how are macrophages recruited to adipose tissue in obesity? What are the physiological consequences of macrophage-adipocyte interactions? Do these inflammatory macrophages contribute to pathophysiological conditions associated with obesity, such as insulin resistance, dyslipidemia, diabetes and cardiovascular disease? This review focuses on the first of these important questions.     

From neutrophils to macrophages: differences in regional adipose tissue depots

Currently, we do not fully understand the underlying mechanisms of how regional adiposity promotes metabolic dysregulation. As adipose tissue expands, there is an increase in chronic systemic low‐grade inflammation due to greater infiltration of immune cells and production of cytokines. This chronic inflammation is thought to play a major role in the development of metabolic complications and disease such as insulin resistance and diabetes. We know that different adipose tissue depots contribute differently to the risk of metabolic disease. People who have an upper body fat distribution around the abdomen are at greater risk of disease than those who tend to store fat in their lower body around the hips and thighs. Thus, it is conceivable that adipose tissue depots contribute differently to the inflammatory milieu as a result of varied infiltration of immune cell types. In this review, we describe the role and function of major resident immune cells in the development of adipose tissue inflammation and discuss their regional differences in the context of metabolic disease risk. We find that although initial studies have found regional differences, a more comprehensive understanding of how immune cells interrupt adipose tissue homeostasis is needed.     

Mast cells in human adipose tissue: link with morbid obesity, inflammatory status, and diabetes

Aims and Hypothesis: Mast cells are immune cells known for their role in several inflammatory and fibrotic diseases. Recent works in mice suggest that mast cells could be cellular actors involved in the pathophysiology of obesity, a disease characterized by white adipose tissue (WAT) and systemic inflammation. The aim of the study was to better characterize mast cells in WAT of obese with or without type 2 diabetes and lean subjects as well as to explore the relationship with WAT inflammation and fibrosis. Methods: Subcutaneous and omental adipose tissue from six lean subjects, 10 obese nondiabetic, and 10 diabetic patients was analyzed by immunohistochemistry and real-time PCR for inflammatory and fibrosis markers. Cytokines secretion of mast cells isolated from WAT and cultured in different conditions was estimated by cytokine array kit. Results: We found that mast cells are activated in human adipose tissue and localized preferentially in fibrosis depots, a local condition that stimulates their inflammatory state. Mast cells with tryptase(+) chymase(+) staining tended to be higher in obese omental adipose tissue. We found positive links between mast cell number and several characteristics of obese WAT including fibrosis, macrophage accumulation, and endothelial cell inflammation. Mast cell number and their inflammatory phenotype are associated with diabetes parameters. Conclusion and Interpretation: Mast cells are cellular actors of WAT inflammation and possibly fibrotic state found in obesity and diabetes. Whether mast cells could be involved in the pathophysiology of diabetes needs additional study as well as the positioning of these cells in driving pathological alterations of WAT in these chronic metabolic diseases.     

Mast cells participate in chronic low‐grade inflammation within adipose tissue

Obesity is reckoned as one of the civilization diseases, posing a considerable global health issue. Evidence points towards a contribution of multitude immune cell populations in obesity pathomechanism and the development of chronic low‐grade inflammation in the expanded adipose tissue. Notably, adipose tissue is a reservoir of mast cells which number in individuals with obesity particularly increased. Some of them tend to degranulation what generate secretion of strong pro‐inflammatory and regulatory mediators, as well as cytokines/chemokines. Several lines of evidence suggest that mast cells are strictly associated with pro‐inflammatory status in adipose tissue by their indirect impact on immune cell attraction and activation. Furthermore, mast cells affect adipose tissue remodelling and fibrosis by adipocyte differentiation, fibroblast proliferation and enhancing extracellular matrix proteins expression. This review will summarize current knowledge on mast cell features and their role in the development of chronic low‐grade inflammation within adipose tissue.     

Subacute endotoxemia induces adipose inflammation and changes in lipid and lipoprotein metabolism in cats

Acute inflammation in humans is associated with transient insulin resistance (IR) and dyslipidemia. Chronic low-grade inflammation is a pathogenic component of IR and adipose tissue dysfunction in obesity-induced type 2 diabetes. Because feline diabetes closely resembles human type 2 diabetes, we studied whether lipopolysaccharide (LPS)-induced subacute inflammation, in the absence of obesity, is the potential primary cause of IR and metabolic disorders. Cats received increasing iv doses (10-1000 ng/kg(-1) · h(-1)) of LPS (n = 5) or saline (n = 5) for 10 d. Body temperature, proinflammatory and metabolic markers, and insulin sensitivity were measured daily. Tissue mRNA and protein expression were quantified on d 10. LPS infusion increased circulating and tissue markers of inflammation. Based on the homeostasis model assessment, endotoxemia induced transient IR and β-cell dysfunction. At the whole-body level, IR reverted after the 10-d treatment; however, tissue-specific indications of IR were observed, such as down-regulation of adipose glucose transporter 4, hepatic peroxisome proliferative activated receptor-γ1 and -2, and muscle insulin receptor substrate-1. In adipose tissue, increased hormone-sensitive lipase activity led to reduced adipocyte size, concomitant with increased plasma and hepatic triglyceride content and decreased total and high-density lipoprotein cholesterol levels. Prolonged LPS-induced inflammation caused acute IR, followed by long-lasting tissue-specific dysfunctions of lipid-, glucose-, and insulin metabolism-related targets; this ultimately resulted in dyslipidemia but not whole-body IR. Endotoxemia in cats may provide a promising model to study the cross talk between metabolic and inflammatory responses in the development of adipose tissue dysfunction and IR.     

Immune cells in adipose tissue: key players in metabolic disorders

Obesity, defined as the excess development of adipose tissue, is an important risk factor for metabolic and cardiovascular diseases such as type 2 diabetes, hypertension and atherosclerosis. Over the past few years, metabolic inflammation has emerged as a major process underlying the link between obesity and its associated pathologies. Adipose tissue appears to play a primary and crucial role as a source and site of inflammation. Accumulation of immune cells within adipose tissue occurs in obese conditions. The present review focuses on the relationship between adipose tissue and immune cells, including macrophages, dendritic cells, T and B lymphocytes, and natural killer cells, in both the physiological state and under obese conditions. The factors involved in the accumulation of both myeloid and lymphoid cells in adipose tissue are also described. In addition, the role of adipose-tissue immune cells on adipocyte metabolism and cells of the adipose tissue stromal–vascular fraction are discussed, with particular emphasis on the cross-talk between macrophages and adipocytes, together with recent reports of T lymphocytes in adipose tissue.     

An immune origin of type 2 diabetes?

Subclinical, low-grade systemic inflammation has been observed in patients with type 2 diabetes and in those at increased risk of the disease. This may be more than an epiphenomenon. Alleles of genes encoding immune/inflammatory mediators are associated with the disease, and the two major environmental factors the contribute to the risk of type 2 diabetes—diet and physical activity—have a direct impact on levels of systemic immune mediators. In animal models, targeting of immune genes enhanced or suppressed the development of obesity or diabetes. Obesity is associated with the infiltration and proinflammatory activity of macrophages in adipose tissue, and immune mediators may be important regulators of insulin resistance, mitochondrial function, ectopic lipid storage and beta cell dysfunction or death. Intervention studies targeting these pathways would help to determine the contribution of an activated innate immune system to the development of type 2 diabetes.An erratum to this article can be found at     

Macrophage recruitment in obese adipose tissue

Obesity is characterized as a chronic state of low‐grade inflammation with progressive immune cell infiltration into adipose tissues. Adipose tissue macrophages play critical roles in the establishment of the chronic inflammatory state and metabolic dysfunctions. The novel discovery that pro‐inflammatory macrophages are recruited to obese adipose tissue prompted an increased interest in the interplay between immune cells and metabolism. Since this discovery, many works have been published investigating the factors that lead to macrophage recruitment, the phenotypic change of adipose tissue macrophages, and metabolic dysfunctions. Adipokines and chemokines are key mediators that play crucial roles in crosstalk between adipocytes and macrophages and in regulating the adipose tissue inflammation. In the present review, we discuss the obesity‐mediated adipose tissue remodelling, and particularly, the role of adipokines/chemokines in macrophage recruitment to obese adipose tissue. This review provides new insights into the physiological role of these factors and identifies a potential therapeutic target for obesity and associated disorders.     

Diabetes Mellitus and Inflammation

Type 2 diabetes mellitus (T2DM) is increasingly common worldwide. Related complications account for increased morbidity and mortality, and enormous healthcare spending. Knowledge of the pathophysiological derangements involved in the occurrence of diabetes and related complications is critical for successful prevention and control solutions. Epidemiologic studies have established an association between inflammatory biomarkers and the occurrence of T2DM and complications. Adipose tissue appears to be a major site of production of those inflammatory biomarkers, as a result of the cross-talk between adipose cells, macrophages, and other immune cells that infiltrate the expanding adipose tissue. The triggering mechanisms of the inflammation in T2DM are still ill-understood. Inflammatory response likely contributes to T2DM occurrence by causing insulin resistance, and is in turn intensified in the presence of hyperglycemia to promote long-term complications of diabetes. Targeting inflammatory pathways could possibly be a component of the strategies to prevent and control diabetes and related complications.     

Peripheral blood leucocyte subclasses as potential biomarkers of adipose tissue inflammation and obesity subphenotypes in humans

While obesity is clearly accepted as a major risk factor for cardio‐metabolic morbidity, it is also apparent that some obese patients largely escape this association, forming a unique obese subphenotype(s). Current approaches to define such subphenotypes include clinical biomarkers that largely reflect already manifested comorbidities, such as markers of dyslipidaemia, hyperglycaemia and impaired regulation of vascular tone, and anthropometric or imaging‐based assessment of adipose tissue distribution. Low‐grade inflammation, evident both systemically and within adipose tissue (particularly intra‐abdominal fat depots), seems to characterize the more cardio‐metabolically morbid forms of obesity. Indeed, several systemic inflammatory markers (C‐reactive protein), adipokines (retinol‐binding protein 4, adiponectin) and cytokines have been shown to correlate in humans with adipose tissue inflammation and with obesity‐associated health risks. Circulating leucocytes constitute a diverse group of cells that form a major arm of the immune system. They are both major sources of cytokines and likely also of infiltrating adipose tissue immune cells in obesity. In the present review, we summarize currently available literature on ‘classical’ blood white cell classes and on more specific leucocyte subclasses present in the circulation in human obesity. We critically raise the possibility that leucocytes may constitute clinically available markers for the more morbidity‐associated obesity subphenotype(s), and when available, for intra‐abdominal adipose tissue inflammation.