Identification of a novel therapeutic target that produces irreversible diabeticg lucotoxicky

慢性糖尿病并发症是糖尿病患者发病和死亡的主要原因。我们已经报道了产生胰岛素原（Proins-P）的骨髓源性细胞（BMDC）与神经细胞的融合是啮齿动物糖尿病神经病变的基础。我们还报道了小鼠的糖尿病与肝脏中Proins-P细胞的出现有关。然而，目前尚不清楚这些Proins-P BMDC是否仅通过肝脏转运或与肝细胞融合，这通常是非常罕见的事件。在这项研究中，我们发现，在糖尿病中，肝脏中的BMDC不仅产生Proins，而且还产生TNF-α，这表明糖尿病重新编程BMDC中的基因表达，打开“不合适”的基因。使用遗传标记的供体和受体小鼠的骨髓移植显示Proins-P BMDC和肝细胞之间发生融合。接受雄性骨髓移植细胞的雌性小鼠中Proins-P细胞中存在Y染色体进一步支持细胞融合。形态学上，Proins-P融合细胞是产生白蛋白的肝细胞，其构成糖尿病诱导后5个月的肝截面面积的约2.5%。广泛的搜索未能在非糖尿病小鼠中发现任何融合细胞。因此，糖尿病导致Proins-P BMDC和肝细胞在体内融合，这一观察结果对糖尿病的病理生理学以及异型细胞融合的基础生物学具有影响。为了阐明Proins-P BMDC中TNF-α在糖尿病并发症发病机制中的作用，我们正在制备基因治疗载体以通过RNAi抑制TNF-α表达。目前该实验尚在进行中，但可以证明细胞融合在糖尿病并发症的发病机制中具有重要作用。

Chronic diabetic complications are the major cause of morbidity and mortality among patients with diabetes. We have reported that the fusion of proinsulin-producing (Proins-P) bone-marrow-derived cells (BMDC) with nerve cells underlies diabetic neuropathy in rodents. We also reported that diabetes in mice is associated with the appearance of Proins-P cells in the liver. It was unclear, however, whether these Proins-P BMDC merely transit through the liver or undergo fusion with hepatocytes, normally an extremely rare event. In this study, we found that, in diabetes, BMDC in the liver produce not only Proins but also TNF-a, suggesting that diabetes reprograms gene expression in BMDC, turning on "inappropriate" genes. Bone marrow transplantation using genetically marked donor and recipient mice showed that fusion occurs between Proins-P BMDC and hepatocytes. Cell fusion is further supported by the presence of the Y chromosome in Proins-P cells in female mice that received male bone marrow transplantation cells. Morphologically, Proins-P fusion cells are albumin-producing hepatocytes that constitute 〓2.5% of the liver section area 5 months after diabetes induction. An extensive search failed to reveal any fusion cells in nondiabetic mice. Thus, diabetes causes fusion between Proins-P BMDC and hepatocytes in vivo, an observation that has implications for the pathophysiology of diabetes as well as the fundamental biology of heterotypic cell fusion. To clarify the contribution of TNF-a in Proins-P BMDC on the pathogenesis of diabetic complications, we are generating gene therapeutic vector to suppress TNF-a expression by RNAi. The experiment is ongoing at present, but can show an evidence that the cell fusion have an important roles in the pathogenesis of diabetic complications.