Lee H C, Kim S J, Kim K S, Shin H C, Yoon J W
Department of Internal Medicine, Yonsei University, College of Medicine, Seoul, Korea.
Nature. 2000 Nov 23;408(6811):483-8. doi: 10.1038/35044106.
A cure for diabetes has long been sought using several different approaches, including islet transplantation, regeneration of beta cells and insulin gene therapy. However, permanent remission of type 1 diabetes has not yet been satisfactorily achieved. The development of type 1 diabetes results from the almost total destruction of insulin-producing pancreatic beta cells by autoimmune responses specific to beta cells. Standard insulin therapy may not maintain blood glucose concentrations within the relatively narrow range that occurs in the presence of normal pancreatic beta cells. We used a recombinant adeno-associated virus (rAAV) that expresses a single-chain insulin analogue (SIA), which possesses biologically active insulin activity without enzymatic conversion, under the control of hepatocyte-specific L-type pyruvate kinase (LPK) promoter, which regulates SIA expression in response to blood glucose levels. Here we show that SIA produced from the gene construct rAAV-LPK-SIA caused remission of diabetes in streptozotocin-induced diabetic rats and autoimmune diabetic mice for a prolonged time without any apparent side effects. This new SIA gene therapy may have potential therapeutic value for the cure of autoimmune diabetes in humans.
长期以来，人们一直在寻求通过多种不同方法治愈糖尿病，包括胰岛移植、β细胞再生和胰岛素基因疗法。然而，1型糖尿病的永久性缓解尚未令人满意地实现。1型糖尿病的发展是由于针对β细胞的自身免疫反应几乎完全破坏了产生胰岛素的胰腺β细胞。标准胰岛素疗法可能无法将血糖浓度维持在正常胰腺β细胞存在时出现的相对较窄范围内。我们使用了一种重组腺相关病毒（rAAV），该病毒在肝细胞特异性L型丙酮酸激酶（LPK）启动子的控制下表达单链胰岛素类似物（SIA），该类似物无需酶促转化即具有生物活性胰岛素活性，LPK启动子可根据血糖水平调节SIA表达。在此我们表明，基因构建体rAAV-LPK-SIA产生的SIA可使链脲佐菌素诱导的糖尿病大鼠和自身免疫性糖尿病小鼠长时间缓解糖尿病，且无任何明显副作用。这种新的SIA基因疗法可能对治愈人类自身免疫性糖尿病具有潜在的治疗价值。
