胰岛β细胞退分化在β细胞功能衰竭中的作用

正随着生活水平的提高和饮食结构的改变,2型糖尿病患病率逐年增高,预防和治疗2型糖尿病已经成为一个亟待解决的问题~([1-2])。除了胰岛素抵抗之外,胰岛β细胞功能衰竭亦是引起2型糖尿病发生发展的中心环节。通常认为由胰岛β细胞凋亡引起的胰岛细胞数量减少是引起糖尿病的重要致病机制~([3]),然而近年来研究发现,胰岛β细胞凋亡程度与胰岛素下降程度不平行,因而胰岛素分泌功能的研究成为热点。引起β细胞分泌功能缺陷的作用机制     

放射免疫分析测定胰岛素及C-肽在诊断2型糖尿病中的价值

随着社会经济的发展和人们饮食结构的改变,糖尿病的发病率呈现逐年上升趋势[1]。临床上常见的是2型糖尿病,患者体内存在胰岛素抵抗以及胰岛β细胞胰岛素分泌功能缺陷,以慢性高血糖为特征。患者由于体内血糖升高以及胰岛素抵抗的存在,导致分泌功能缺陷的胰岛β细胞持续性地分泌胰岛素,从而加重了胰岛β细胞的损伤,形成恶性循环而加重病     

62例短期胰岛素强化治疗初诊2型糖尿病临床分析

目的 探讨短期胰岛素强化治疗对初诊2型糖尿病患者的血糖控制效果和胰岛β细胞功能保护.方法 回顾近4年初诊62例2型糖尿病患者的治疗方法及疗效.结果 胰岛素强化治疗2月,血糖均控制达标,较传统口服降糖药显著改善胰岛β细胞功能,(P<0.01)差别有显著意义.结论 初诊2型糖尿病短期强化胰岛素治疗,可迅速控制高血糖,保护胰岛β细胞功能,远期疗效好.     

2型糖尿病的分子遗传学研究进展和预防策略

2型糖尿病是一种由遗传因素和环境因素相互作用所导致的复杂疾病。研究表明胰岛β细胞功能缺陷和胰岛素抵抗是导致2型糖尿病发生和发展的重要原因。与胰岛β细胞功能缺陷有关的基因主要有 CDKAL 1、CDKN 2 A／2 B、TCF 7 L 2等,而与胰岛素抵抗有关的基因主要有 PPAR-γ、HHEX、KCNQ 1等。众多大型临床试验研究结果显示,通过改变生活方式以及药物干预可以预防或延缓2型糖尿病的发生。本文综述了基因及其多态性与2型糖尿病胰岛β细胞功能缺陷和胰岛素抵抗的相关性及其作用机制的研究进展,并总结了在世界范围内预防2型糖尿病的基本策略。     

R6/2型亨廷顿病转基因小鼠胰岛β细胞功能损伤

目的：研究R6/2型亨廷顿病(HD) 转基因小鼠胰岛β细胞的功能,揭示HD转基因小鼠继发糖尿病的机制。方法：利用R6/2 型HD转基因小鼠模型,检测正常和HD小鼠空腹血糖以及血清胰岛素水平;并应用HE染色和免疫荧光技术分析正常和HD小鼠胰岛形态学差异。结果：与正常小鼠相比,R6/2 型HD小鼠空腹血糖显著增高,血清胰岛素水平明显降低,胰岛萎缩,β细胞数量减少,细胞功能指数降低,而胰岛素抵抗指数正常。结论：胰岛β细胞功能损伤是引起R6/2 HD转基因小鼠继发糖尿病发生的主要因素。     

糖尿病小鼠胰岛β细胞结构的光镜和电镜研究

目的观察2型糖尿病模型db/db小鼠胰岛β细胞的超微结构、胰岛素表达及数量变化,探讨β细胞的病理改变与2型糖尿病病因的关系。方法分别选取3、5、8月龄尾静脉空腹血糖高于10.1mmol/L,且肥胖的db/db自发性糖尿病小鼠,每组8只,作为糖尿病组;选取相应年龄段尾静脉空腹血糖低于6.0mmol/L,体重正常的db/+m表型正常小鼠,每组8只,作为对照组。于相应年龄段取胰尾,用于透射电镜观察、免疫组织化学观察和图像分析。结果电镜下随病情进展,db/db小鼠胰岛β细胞内的分泌颗粒数量明显减少,有的细胞甚至缺如,致密芯电子密度降低,β细胞可见凋亡的早期改变以及细胞核和细胞器的病理改变,细胞间髓样小体增多。免疫组织化学显示同月龄糖尿病组小鼠胰岛β细胞阳性率和胰岛素蛋白平均光密度值(OD值)低于相应对照组(p<0.05),且随着病程的进展,db/db小鼠胰岛β细胞阳性率和胰岛素表达呈现递减趋势(p<0.05)。结论2型糖尿病β细胞的超微结构遭到破坏,引起β细胞合成分泌胰岛素障碍和数量减少,与2型糖尿病病情的轻重有关,反映了2型糖尿病病程不同阶段的病机特点。     

短期胰岛素治疗新发Ⅱ型糖尿病的临床观察

目的观察短期胰岛素治疗对新发Ⅱ型糖尿病病人的胰岛β细胞功能和血糖控制的影响。方法采用自身前后对照，观察18例新诊断Ⅱ型糖尿病人接受短期胰岛素强化治疗前后血糖及C肽释放试验的变化，了解胰岛素治疗前后胰岛β细胞功能的变化。结果经短期胰岛素治疗后，患者血糖明显下降，各点C肽水平明显升高，且有高峰出现，胰岛β细胞功能有恢复。结论对明显高血糖的新发Ⅱ型糖尿病患者短期胰岛素治疗，能显著改善其胰岛β细胞功能，有利于以后长远控制好血糖。     

新诊断早发DM2患者胰岛素抵抗及胰岛β细胞功能分析

近几年,2型糖尿病（DM2）年轻化趋势明显,儿童和青少年人数逐渐增多。目前糖尿病学界趋向于将诊断年龄≤40岁者定义为早发DM2,〉40岁为晚发DM2[1]。DM2的主要发病机制是胰岛素抵抗和β细胞功能减退。影响DM2患者胰岛素抵抗及胰岛β细胞功能的因素很多（包括高血糖、高血脂、肥胖等）。本文通过56例新诊断早发DM2患者及56例正常对照组的临床资料进行分析,探讨影响早发DM2患者胰岛素抵抗及胰岛β细胞功能减退的相关因素。     

2型糖尿病β细胞功能和胰岛素抵抗的测定方法及评价

2型糖尿病发病与胰岛素抵抗或机体对胰岛素敏感性的降低，继而所致胰岛β细胞功能减损有着密切关系。2型糖尿病β细胞功能的评价、胰岛素抵抗的判断、血清胰岛素、血葡萄糖浓度测定、胰岛素释放试验(IRT)以及胰岛素释放指数(IRI)、敏感指数(ISI)的应用，在2型糖尿病诊断和指导治疗中有非常重要的作用。本文就有关     

α1-抗胰蛋白酶在胰岛移植和Ⅰ型糖尿病中的作用

世界范围内,糖尿病患病率呈急剧上升趋势,而Ⅰ型糖尿病的患病率每年就增加约2%～5%.Ⅰ型糖尿病是由于T细胞介导的自身免疫破坏β细胞而引起,胰岛β细胞功能持续恶化是一种不可逆的过程.因此,科学家们将目光投向了替代和恢复胰岛β细胞功能治疗上.虽然胰岛细胞移植可以纠正Ⅰ型糖尿病患者的代谢紊乱,在短时间内达到停用胰岛素的目的,但在胰岛移植治疗的各个环节上仍面临供体缺乏、免疫排斥等问题.     

Naturally occurring and experimental diabetes in cynomolgus monkeys: a comparison of carbohydrate and lipid metabolism and islet pathology

Diabetes is a major health problem of increasing incidence in the United States. Diabetes research has been limited by lack of availability of good animal models, particularly for the study of comorbidities associated with diabetes. We investigated the use of cynomolgus monkeys as an animal model of both type 1 and type 2 diabetes and compared these naturally occurring diseases with streptozotocin-induced diabetes. Both type 1 diabetics and streptozotocin-induced diabetics present with sudden onset of hyperglycemia and are ketosis prone without exogenous insulin. Type 2 diabetics can have a very long period of moderate hyperglycemia and hypertriglyceridemia and only require exogenous insulin therapy if pancreatic islet reserves are depleted. Type 2 diabetes is preceded by a relatively long period of insulin resistance that is associated with obesity and dyslipidemia. As insulin resistance progresses, islet size and insulin content increases initially. However, with sustained periods of insulin resistance, islet amyloid polypeptide (IAPP) is deposited in islets and can replace normal islet architecture, resulting in an insulin-deficient state. Appearance of IAPP also occurs in human type 2 diabetics but not in conventional rodent models. Unlike type 2 diabetes, neither type 1 nor streptozotocin-induced diabetes is associated with IAPP. Rather, islets can appear normal histologically, but have decreased insulin secretion and immunostaining. Further, the amount of insulin present in the islet is correlated with plasma insulin levels following glucose challenge. Studies are ongoing to determine the pathogenic changes associated with the progression of diabetes and to find novel drug treatments for diabetics.     

Type 1 1/2 diabetes: myth or reality?

The disease process in classical Type 1 diabetes patients (IDDM) is believed to be autoimmune. In contrast, the disease process in classical Type 2 diabetes patients (NIDDM) is not autoimmune and a decreased sensitivity to insulin action is the main abnormality. The clinical distinction of Type 1 diabetes versus Type 2 diabetes is recognized to be imperfect and has limitations. There is a group of individuals (Type 1 1/2 diabetes), who present like typical NIDDM, but have some of the immunological and clinical features of IDDM. We review the current medical literature on Type 1 1/2 diabetes with special reference to its clinical characteristics, natural history and pathophysiology. Since the distinction between these two forms of diabetes may have important therapeutic implications especially with regards to the benefits of insulin therapy in patients with Type 1 1/2 diabetes and because of the need for uniformity in its diagnosis we recommend that both clinical plus biochemical criteria (the presence of ICA and/or GAD Ab, HLA typing and tests to quantify beta cell function) be used to make a diagnosis. Comparative studies in the area of cytokine production, T cell reactivity and autoantibody clustering between classic Type 1 diabetes and Type 1 1/2 diabetes patients are needed as are studies with the animal model of Type 1 1/2 diabetes, Psammomys obesus.     

Stem cell-based therapy for the treatment of Type 1 diabetes mellitus

Diabetes mellitus is the most common metabolic disorder, which occurs in two forms: Type 1 diabetes (juvenile or insulin-dependent diabetes mellitus) and Type 2 diabetes (adult or noninsulin-dependent diabetes mellitus). Type 1 diabetes mellitus is a T-cell-mediated, organ-specific autoimmune disorder, in which the body's own immune system attacks beta-cells and damages them sufficiently resulting in reduced insulin production. To overcome autoimmunity, immunosuppressive therapy, gene therapy, islet cell regeneration or encapsulation of islet cells offer dramatic treatment solutions. At present, efforts for finding ways to replace damaged insulin-secreting beta-cells by implanting new cells is an active field of research. Various therapeutic strategies are under investigation and stem cell-based therapy with the combination of other treatments offers exciting possibilities for the development of treatment for such diseases. In the current review, we focus on stem cells and their potential clinical applications and summarize the recent progress in this field.     

Different islet protein expression profiles during spontaneous diabetes development vs. allograft rejection in BB-DP rats

Type 1 diabetes (T1D) is characterized by selective autoimmune destruction of the insulin producing beta-cells in the islets of Langerhans. When the beta-cells are destroyed exogenous administration of insulin is necessary for maintenance of glucose homeostasis. Allogeneic islet transplantation has been used as a means to circumvent the need for insulin administration and has in some cases been able to restore endogenous insulin production for years. However, long life immunosuppression is needed to prevent the graft from being rejected and destroyed. Changes in protein expression pattern during spontaneous diabetes development in the diabetes prone BioBreeding rat (BB-DP) have previously been described. In the present study, we have investigated if any of the changes seen in the protein expression pattern during spontaneous diabetes development are also present during allograft rejection of BB-DP rat islets. Two hundred neonatal islets were syngeneically transplanted under the kidney capsule of 30 day old BB-DP rats and removed prior to and at onset of diabetes. Allogeneically transplanted islets from BB-DP rats were removed before onset of allograft rejection and at maximal islet graft inflammation (rejection). The protein expression profiles of the transplants were visualised by two-dimensional gel (2-DG) electrophoresis, analysed and compared. In total, 2590 protein spots were visualised and of these 310 changed expression (p < 0.01) in syngeneic islet transplants in the BB-DP rats from 7 days after transplantation until onset of diabetes. In BB-DP islets transplanted to WK rats 53 protein spots (p < 0.01) showed changes in expression when comparing islet grafts removed 7 days after transplantation with islet grafts removed 12 days after transplantation where mononuclear cell infiltration is at its maximum. Only four protein spots (1%) were significantly changed in both syngeneic (autoimmune) and allogeneic islet destruction. When comparing protein expression changes in syngeneic BB-DP islet transplants from 37 days after transplantation to onset of diabetes with protein expression changes in allografts from day 7 to 12 after transplantation only three spot were found to commonly change expression in both situations. In conclusion, a large number of protein expression changes were detected in both autoimmune islet destruction and allogeneic islet rejection, only two overlaps were detected, suggesting that autoimmune islet destruction and allogeneic islet rejection may result from different target cell responses to signals induced by the cellular infiltrate. Whether this reflects activation of distinct signalling pathways in islet cells is currently unknown and need to be further investigated.     

Different islet protein expression profiles during spontaneous diabetes development vs. allograft rejection in BB-DP rats

Type 1 diabetes (T1D) is characterized by selective autoimmune destruction of the insulin producing β-cells in the islets of Langerhans. When the β-cells are destroyed exogenous administration of insulin is necessary for maintenance of glucose homeostasis. Allogeneic islet transplantation has been used as a means to circumvent the need for insulin administration and has in some cases been able to restore endogenous insulin production for years. However, long life immunosuppression is needed to prevent the graft from being rejected and destroyed. Changes in protein expression pattern during spontaneous diabetes development in the diabetes prone BioBreeding rat (BB-DP) have previously been described. In the present study, we have investigated if any of the changes seen in the protein expression pattern during spontaneous diabetes development are also present during allograft rejection of BB-DP rat islets.

Two hundred neonatal islets were syngeneically transplanted under the kidney capsule of 30 day old BB-DP rats and removed prior to and at onset of diabetes. Allogeneically transplanted islets from BB-DP rats were removed before onset of allograft rejection and at maximal islet graft inflammation (rejection). The protein expression profiles of the transplants were visualised by two-dimensional gel (2-DG) electrophoresis, analysed and compared.

In total, 2590 protein spots were visualised and of these 310 changed expression (p < 0.01) in syngeneic islet transplants in the BB-DP rats from 7 days after transplantation until onset of diabetes. In BB-DP islets transplanted to WK rats 53 protein spots (p < 0.01) showed changes in expression when comparing islet grafts removed 7 days after transplantation with islet grafts removed 12 days after transplantation where mononuclear cell infiltration is at its maximum. Only four protein spots (1%) were significantly changed in both syngeneic (autoimmune) and allogeneic islet destruction. When comparing protein expression changes in syngeneic BB-DP islet transplants from 37 days after transplantation to onset of diabetes with protein expression changes in allografts from day 7 to 12 after transplantation only three spot were found to commonly change expression in both situations.

In conclusion, a large number of protein expression changes were detected in both autoimmune islet destruction and allogeneic islet rejection, only two overlaps were detected, suggesting that autoimmune islet destruction and allogeneic islet rejection may result from different target cell responses to signals induced by the cellular infiltrate. Whether this reflects activation of distinct signalling pathways in islet cells is currently unknown and need to be further investigated.     

Microchip-based engineering of super-pancreatic islets supported by adipose-derived stem cells

Type 1 diabetes mellitus (T1DM) is a chronic disorder characterized by targeted autoimmune-mediated destruction of the β cells of Langerhans within pancreatic islets. Currently, islet transplantation is the only curative therapy; however, donor shortages and cellular damage during the isolation process critically limit the use of this approach. Here, we describe a method for creating viable and functionally potent islets for successful transplantation by co-culturing single primary islet cells with adipose-derived stem cells (ADSCs) in concave microwells. We observed that the ADSCs segregated from the islet cells, eventually yielding purified islet spheroids in the three-dimensional environment. Thereafter, the ADSC-exposed islet spheroids showed significantly different ultrastructural morphologies, higher viability, and enhanced insulin secretion compared to mono-cultured islet spheroids. This suggests that ADSCs may have a significant potential to protect islet cells from damage during culture, and may be employed to improve islet cell survival and function prior to transplantation. In vivo experiments involving xenotransplantation of microfiber-encapsulated spheroids into a mouse model of diabetes revealed that co-culture-transplanted mice maintained their blood glucose levels longer than mono-culture-transplanted mice, and required less islet mass to reverse diabetes. This method for culturing islet spheroids could potentially help overcome the cell shortages that have limited clinical applications and could possibly be developed into a bioartificial pancreas.     

Physiological and pathophysiological regulation of regional adipose tissue in the development of insulin resistance and type 2 diabetes

Aim: To survey the latest state of knowledge concerning the regulation of regional adipocytes and their role in the development of insulin resistance and type 2 diabetes. Methods: Data from the English‐language literature on regional adipocytes, including abdominal, intramyocellular, intrahepatic and intra‐islet fat as well as the adipokines and their relations to insulin resistance and type 2 diabetes, were reviewed. Results: It is not the total amount of fat but the fat that resides within skeletal muscle cell (intramyocellular fat), hepatocytes and intra‐abdominally (visceral fat), via systemic and local secretion of several adipokines, that influences insulin resistance. Among the adipokines that relate to insulin resistance, adiponectin and leptin appear to have clinical relevance to human insulin resistance and others may also contribute, but their role is still inconclusive. The intra‐islet fat also adversely affects β‐cell function and number (β‐cell apoptosis), eventually leading to deterioration of glucose tolerance. The abnormal location of fat observed in patients with type 2 diabetes and their relatives is conceivably partly the results of the genetically determined, impaired mitochondrial fatty acid oxidative capacity. Restriction or elimination of the fat load by weight control, regular exercise and thiazolidinediones has been shown to improve insulin resistance and β‐cell function and to delay the development of type 2 diabetes. Conclusion: These data support the plausibility of an essential role of regional adipose tissue in the development of insulin resistance and type 2 diabetes.     

Activated T lymphocytes from patients with high risk of type I diabetes mellitus have different ability to produce interferon-gamma, interleukin-6 and interleukin-10 and undergo anti-CD95 induced apoptosis after insulin stimulation

Type I Diabetes mellitus (DM1) is the effect of T cell dependent autoimmune destruction of insulin producing beta cells in the pancreas islet. T cells are activated in response to islet dominant autoantigens, the result being the development of DM1. Insulin is one of the islet autoantigens responsible for activation of T lymphocyte functions, inflammatory cytokine production and development of DM1. The experiments reported in this study have shown the spontaneous increase of CD95 molecule expression on lymphocytes of the first-degree relatives of DM1 patients. The autoantigen insulin is responsible for stimulation in vitro of potentially hazardous 'memory' lymphocytes to produce interleukin-6 (IL-6) and interleukin-10 (IL-10) interleukins. Insulin induced stimulation of lymphocytes in vitro was observed in patients at high risk of developing diabetes mellitus (prediabetics). Phytohaemagglutinin (PHA) stimulates lymphocytes of all groups in the same way. Stimulated lymphocytes in second cultures undergo apoptosis induced with anti-Fas specific antibodies. The deletion in vitro of resting peripheral lymphocytes is nonfunctional. Insulin activated T lymphocytes, which undergo apoptosis were not observed in peripheral blood of healthy people and in patients with DM1. This observation suggests that insulin is involved as autoantigen in DM1 progression in patients with high risk of diabetes type I. The autoreactive T lymphocytes may persist in peripheral blood of patients with high risk DM1. Defective elimination of autoreactive T cells may result in autodestructive damage of islets beta cells in the prediabetic stage and disease progression to DM1.     

Approaches for the cure of type 1 diabetes by cellular and gene therapy

Type 1 diabetes results from insulin deficiency caused by autoimmune destruction of insulin-producing pancreatic beta cells. Islet transplantation, beta cell regeneration, and insulin gene therapy have been explored in an attempt to cure type 1 diabetes. Major progress on islet transplantation includes substantial improvements in islet isolation technology to obtain viable and functionally intact islets and less toxic immunosuppressive drug regimes to prevent islet graft failure. However, the availability of human islets from cadaveric pancreata is limited. Regeneration of pancreatic beta cells from embryonic or adult stem cells may overcome the limited source of islets and transplant rejection if beta cells are regenerated from endogenous stem cells. However, it is difficult to overcome the persisting hostile beta cell-specific autoimmune response that may destroy the regenerated beta cells. Insulin gene therapy might overcome the weakness of islet transplantation and beta cell regeneration with respect to their vulnerability to autoimmune attack. This method replaces the function of beta cells by introducing various components of the insulin synthetic and secretory machinery into non- beta cells, which are not targets of beta cell-specific autoimmune responses. However, there is no regulatory system that results in the expression and release of insulin in response to glucose with satisfactory kinetics. Although there is no perfect solution for the cure of type 1 diabetes at the present time, research on a variety of potential approaches will offer the best choices for the cure of human type 1 diabetes.