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维拉帕米新用途:治疗1型糖尿病

来源:生物谷 2014-11-11 16:23

2014年11月10日讯/生物谷BIOON/研究人员日前宣布,维拉帕米这种治疗高血压、心脏病和偏头痛的常用药有望成为治疗1型糖尿病的新药。科学家们惊奇地发现在小鼠实验中,维拉帕米能够完全治愈1型糖尿病。

糖尿病是美国第七大致死病因,它极大地增加患心脏病、失明、肾脏疾病和截肢的风险。联邦政府最近调查显示近20岁以上人群中有12.3%的糖尿病患者,尽管有些没有被确诊。另外有37%的人群血糖高于正常值,处于糖尿病前期,比十年前增加了十个百分点。此外,每年用于治疗糖尿病的费用巨大,并且还在不断增加,数据显示2013年治疗糖尿病的总费用是2450亿美元。

伯明翰的阿拉巴马大学最近得到一笔为期3年共210万美元的资助,用于开展该药物的人体试验。“我们在早期小鼠模型研究中发现维拉帕米可以预防糖尿病,甚至完全扭转病程,并且还发现它可以减少胰岛B细胞的TXNIP浓度,这表明对人类可能会产生同样的效果。”UAB的综合疾病中心负责人Anath Shalev说道。这项研究将于明年年初开始,主要集中于维拉帕米对1型糖尿病患者胰岛B细胞的治疗作用,前期工作已经在UAB的综合疾病中心进行了十年。1型糖尿病通常发生于儿童和年轻人,也被称为青少年糖尿病。糖尿病患者中仅有5%属于1型,他们自身无法产生胰岛素。当前其他糖尿病的研究都关注怎样促进胰岛B细胞产生胰岛素,而本项研究的思路与它们不同。

UAB的科学家发现,高血糖会诱发身体产生一种名为TXNIP的蛋白,它会在B细胞中增加,用来应对糖尿病,但之前并不清楚该蛋白对B细胞本身的作用。胰岛B细胞中过量的TXNIP会导致细胞死亡,并且阻碍机体产生胰岛素,反而加速了糖尿病的进程。

然而UAB的科研人员发现维拉帕米可以降低B细胞中TXNIP的水平,因此血糖浓度高于3000毫克/升的糖尿病小鼠模型用维拉帕米处理后,病情会得到根除。因此只要降低TXNIP的浓度,即便是情况最糟糕的糖尿病也能得到治疗。1型糖尿病的病因在于胰岛B细胞的缺失,现在研究的目的是增加患者胰岛B细胞的数量和胰岛素的产量。目前还没有针对这一问题的疗法,UAB的工作人员将于2015年开展针对人类的临床研究。科学家们已经知道胰岛B细胞对于1型和2型糖尿病的产生都很重要,在这两种类型的糖尿病中,胰岛B细胞都以程序性死亡的方式逐渐消失,但是诱因还不清楚,也有的说法是胰岛B细胞被自身免疫系统杀灭,但病人的胰岛B细胞还保留了一部分功能,只是不足以产生维持血糖浓度的胰岛素了。

该试验会选取52名在过去三个月中确诊1型糖尿病的患者,在未来一年中随机服用维拉帕米或是安慰剂,与此同时胰岛素泵治疗继续。此外,他们会得到持续的血糖检测系统,以便随时随地检测其血糖水平。(生物谷Bioon.com)

原文地址: Have researchers found a way to REVERSE type 1 diabetes? Common heart drug found to work in mice and set for human trial

相关文献

Minireview: Thioredoxin-interacting protein: regulation and function in the pancreatic β-cell.

doi:10.1210/me.2014-1095.

PMID:24911120  PMCID:PMC4116588

Pancreatic β-cells are responsible for insulin production, and loss of functional β-cell mass is now recognized as a critical step in the pathogenesis of both type 1 and type 2 diabetes. However, the factors controlling the life and death of the pancreatic β-cell have only started to be elucidated. Discovered as the top glucose-induced gene in a human islet microarray study 12 years ago, thioredoxin-interacting protein (TXNIP) has now emerged as such a key player in pancreatic β-cell biology. Since then, β-cell expression of TXNIP has been found to be tightly regulated by multiple factors and to be dramatically increased in diabetic islets. Elevated TXNIP levels induce β-cell apoptosis, whereas TXNIP deficiency protects against type 1 and type 2 diabetes by promoting β-cell survival. TXNIP interacts with and inhibits thioredoxin and thereby controls the cellular redox state, but it also belongs to the α-arrestin family of proteins and regulates a variety of metabolic processes. Most recently, TXNIP has been discovered to control β-cell microRNA expression, β-cell function, and insulin production. In this review, the current state of knowledge regarding regulation and function of TXNIP in the pancreatic β-cell and the implications for drug development are discussed.

Preventing β-cell loss and diabetes with calcium channel blockers.

doi: 10.2337/db11-0955.

Although loss of functional β-cell mass is a hallmark of diabetes, no treatment approaches that halt this process are currently available. We recently identified thioredoxin-interacting protein (TXNIP) as an attractive target in this regard. Glucose and diabetes upregulate β-cell TXNIP expression, and TXNIP overexpression induces β-cell apoptosis. In contrast, genetic ablation of TXNIP promotes endogenous β-cell survival and prevents streptozotocin (STZ)- and obesity-induced diabetes. Finding an oral medication that could inhibit β-cell TXNIP expression would therefore represent a major breakthrough. We were surprised to discover that calcium channel blockers inhibited TXNIP expression in INS-1 cells and human islets and that orally administered verapamil reduced TXNIP expression and β-cell apoptosis, enhanced endogenous insulin levels, and rescued mice from STZ-induced diabetes. Verapamil also promoted β-cell survival and improved glucose homeostasis and insulin sensitivity in BTBR ob/ob mice. Our data further suggest that this verapamil-mediated TXNIP repression is conferred by reduction of intracellular calcium, inhibition of calcineurin signaling, and nuclear exclusion and decreased binding of carbohydrate response element-binding protein to the E-box repeat in the TXNIP promoter. Thus, for the first time, we have identified an oral medication that can inhibit proapoptotic β-cell TXNIP expression, enhance β-cell survival and function, and prevent and even improve overt diabetes.

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