Identification of a novel therapeutic target that produces irreversible diabeticg lucotoxicky

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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.