胰岛细胞移植，1型糖尿病治愈的希望

新闻回顾:病理学家保罗·雷思于2005年2月18日在美国俄亥俄州去世,享年81岁。保罗·雷思被尊称为胰岛移植之父。雷思博士是最早研究胰岛细胞的科学家之一。1972年,雷思博士首次用实验鼠成功完成了胰岛移植,治愈了老鼠的糖尿病。之后,他继续用狗、猴子实验,并于1980年在人身上成功进行了同样的试验。 胰岛细胞移植无疑有着治愈糖尿病的希望。将成千上万个胰岛细胞植入体中,使糖尿病患者恢复胰岛素分泌能力,这种方法就是胰岛细胞移植。人类研究胰岛细胞移植治疗糖尿病,已有30年的历史了。经历了从动物实验到人体试验,最终应用于临床的阶段…     

胰岛移植治疗1型糖尿病的研究进展

胰岛移植治疗1型糖尿病具有简单，安全的优点，但存在组织来源匮乏和免疫移植排斥等障碍。目前新的分离纯化方法可以为胰岛移植提供伉纯度，高活性的胰岛。异种移植可望解决供体缺乏的难题。随着分子生物学技术的发展，采用基因重组，转基因技术及诱导干细胞分化技术，产生可替代的移植物将成为可能。而新型免疫抑制剂，免疫诱导剂的研发，则提高了临床胰岛移植的成功率。     

调节性T细胞在1型糖尿病和胰岛移植中的作用

调节性T细胞是一种免疫抑制性细胞,在维持免疫耐受中起重要作用.研究相继发现了多种调节性T细胞的表面标记和调节性T细胞的作用机制.调节性T细胞的数量和(或)功能缺陷与1型糖尿病的发生、发展密切相关.输注调节性T细胞可以预防和治疗1型糖尿病,延长移植胰岛的存活时间和改善移植物功能.目前,关于调节性T细胞治疗的临床试验研究已经开展,如果后续实验能证实调节性T细胞体内输注治疗的安全性及有效性,调节性T细胞免疫治疗将成为治疗1型糖尿病和预防胰岛移植后免疫排斥的有效方法.     

胰岛B细胞凋亡与1型糖尿病

胰岛B细胞凋亡与死亡受体Fas及其配体（FasL）系统、Bcl－2家族、胱氨酸门冬氨酸蛋白裂解酶（caspase）家族及线粒体的功能密切相关,同时受胰岛素、葡萄糖等多种因素的影响。浸润细胞可通过FasL、穿孔素／颗粒酶B,肿瘤坏死因子－α、干扰素－γ、白介素－1β以及一氧化氮等多效应分子导致胰岛B细胞凋亡,而通过去除和（或）抑制促凋亡因素如诱导免疫耐受、免疫豁免,阻断凋亡效应分子作用以及直接干预细胞凋亡过程等均可阻止或延缓胰岛B细胞的凋亡,将为临床1型糖尿病的防治提供新的途径。     

胰岛β细胞移植的三大关键点

近年来，人们越来越重视对胰岛β细胞功能的研究，基础研究和临床实践的证据都显示，在糖尿病的自然病程中，胰岛β细胞功能的持续恶化是一个不可逆的过程。众所周知，胰岛素由胰岛β细胞产生，而无论是1型糖尿病或是2型糖尿病都存在胰岛β细胞的衰竭问题，区别仅仅在于前者发病时即表现为需要外源性胰岛素维持生存，而2型糖尿病的β细胞功能衰竭则发生在疾病的晚期。因此，恢复胰岛β细胞功能一直是医学界和糖尿病患者追求的目标，也是根治糖尿病的希望所在。     

胰岛B细胞凋亡与1型糖尿病

胰岛B细胞凋亡与死亡受体Fas及其配体 (FasL)系统、Bcl 2家族、胱氨酸门冬氨酸蛋白裂解酶 (caspase)家族及线粒体的功能密切相关 ,同时受胰岛素、葡萄糖等多种因素的影响。浸润细胞可通过FasL、穿孔素 /颗粒酶B ,肿瘤坏死因子 α、干扰素 γ、白介素 1 β以及一氧化氮等多效应分子导致胰岛B细胞凋亡 ,而通过去除和 (或 )抑制促凋亡因素如诱导免疫耐受、免疫豁免 ,阻断凋亡效应分子作用以及直接干预细胞凋亡过程等均可阻止或延缓胰岛B细胞的凋亡 ,将为临床 1型糖尿病的防治提供新的途径。     

关注1型糖尿病并发症

<正>1型糖尿病是由致病性T细胞介导的免疫反应特异性攻击胰岛β细胞而导致胰岛β细胞破坏,胰岛功能进行性衰竭为特征的自身免疫性疾病。相较于2型糖尿病,1型患者由于胰岛功能差,更易合并糖尿病酮症酸中毒、严重低血糖事件等急性并发症。1型糖尿病常出现的慢性并发症主要为微血管并发症,如糖尿病视网膜病变、肾病、神经病变。此外,1型患者还常合并出现其他自身免疫性疾病,尤其是自身免疫性甲状腺疾病。下文结合2014年ADA1型糖尿病终生管理立场声明,具体分析     

对2型糖尿病β细胞功能衰竭和胰岛素治疗的思考——给2型糖尿病病人一个更为美好的未来

众所周知，无论对于大血管病变还是微血管病变的防治，良好的血糖控制均是非常重要的。然而达到理想的血糖控制是对糖尿病治疗的重大挑战。最近一些资料表明，空腹血糖小于7．8mmo1／L的时候能够有效预防微血管病变，但是空腹血糖小于6．0mmol／L(5．6mmol／L?)的时候才能够预防大血管病变。     

Potential role of stem cell therapy in type 1 diabetes mellitus

Type 1 diabetes mellitus is the result of the autoimmune response against pancreatic beta-cell(s). At the time of clinical diagnosis near 70% of beta-cell mass is been destroyed as a consequence of the auto-destruction that begins months or even years before the clinical diagnosis. Although marked reduction of chronic complications was seen after development and progression of insulin therapy over the years for type 1 diabetic population, associated risks of chronic end-organ damage and hypoglycemia still remain. Besides tight glucose control, beta-cell mass preservation and/or increase are known to be other important targets in management of type 1 diabetes as long as it reduces chronic microvascular complications in the eyes, kidneys and nerves. Moreover, the larger the beta-cell mass, the lower the incidence of hypoglycemic events. In this article, we discuss some insights about beta-cell regeneration, the importance of regulation of the autoimmune process and what is being employed in human type 1 diabetes in regard to stem cell repertoire to promote regeneration and/or preservation of beta-cell mass.     

Cyclosporin and methotrexate therapy induces remission in type 1 diabetes mellitus

Cyclosporin and methotrexate administration induces remission of type 1 diabetes mellitus. Administration of high-dose cyclosporin (cyclo) has been demonstrated to induce remission of type 1 diabetes mellitus (T1D). Its usefulness was limited by its toxicity. Since methotrexate (mtx) and cyclo synergistically inhibit autoimmune processes, we postulated that low doses of cyclo and mtx could safely induce remission of T1D. In a pilot study, insulin dose requirements and glycemic control were compared in 10 new onset T1D control children with seven children who were administered cyclo at 7.5 mg/kg/day for 6 weeks and then 4 mg/kg/day in addition to mtx 5 mg/kg/wk for 1 year. After 6 weeks, cyclo doses were adjusted to maintain blood cyclo levels 110–220 ng/ml. All children were treated with two daily injections of insulin. Clinical and biochemical toxicity of drug therapy was assessed. There were only very minor adverse effects and no drug induced biochemical test abnormalities. Mean HbA1c levels were similar in the experimental and control groups at baseline and at 3, 6, and 9 months but was lower in the cyclo + mtx group at 12 months. Daily insulin requirements of the groups were similar at baseline but lower in the cyclo + mtx group at 3, 6, 9, and 12 months. Although no control subjects became non-insulin requiring, four of seven cyclo + mtx-treated subjects were entirely off insulin therapy for 2.5, 4.5, 8, and 12 months. Low-dose cyclo and mtx treatment of subjects with new onset T1D can safely induce remission of disease and decrease the amount of required insulin.     

Insulin lispro therapy in pregnancies complicated by type 1 diabetes mellitus

OBJECTIVE: To compare the efficacy and safety of preprandial administration of rapid-acting lispro analogue with regular short-acting insulin to pregnant women with type 1 diabetes. STUDY DESIGN: Open randomised multicentre study. Women were treated with multiple insulin injections aiming at normoglycaemia. Blood glucose was determined six times daily, HbA(1c) every 4 weeks. Diurnal profiles of blood glucose were analysed at gestational week 14 and during the study period at weeks 21, 28 and 34. PARTICIPANTS: 33 pregnant women with type 1 DM were randomised to treatment with lispro insulin (n=16) or regular insulin (n=17). RESULTS: Blood glucose was significantly lower (P<0.01) after breakfast in the lispro group, while there were no significant group differences in glycemic control during the rest of the day. Severe hypoglycaemia occurred in two patients in the regular group but biochemical hypoglycaemia (blood glucose <3.0 mmol/l) was more frequent in the lispro than in the regular group (5.5 vs. 3.9%, respectively). HbA(1c) values at inclusion were 6.5 and 6.6% in the lispro and regular group respectively. HbA(1c) values declined during the study period and were similar in both groups. There was no perinatal mortality. Complications during pregnancy, route of delivery and foetal outcome did not differ between the groups. Retinopathy progressed in both groups, one patient in the regular group developed proliferative retinopathy. CONCLUSION: The results suggest that it is possible to achieve at least as adequate glycemic control with lispro as with regular insulin therapy in type 1 diabetic pregnancies.     

Pharmaceutical therapy of diabetes mellitus type 2

The sequelae and complications associated with type 2 diabetes mellitus can be reduced or inhibited by optimal therapy. Currently, a variety of medications are available for differentiated therapy, which should be used according to the German Diabetes Association Guidelines. Changes in lifestyle represent the basic therapeutic principle, and it is mandatory to continuously maintain these measures throughout life. If this is not adequately effective (HBA(1c) <6.5%), treatment with oral antidiabetic drugs (OAD) is necessary. Over time OAD monotherapy frequently fails, so that a combination of several oral antidiabetics is needed. The choice of oral antidiabetics is particularly dependent on the patient's body mass index and associated diseases. If combination therapy with OAD is not successful in achieving HbA1c values <6.5%, insulin therapy is required either in combination with OADs as a bedtime regimen or as intensive insulin therapy using both basal and short-term acting insulins.