BIOLOGICAL ROLES OF NEW TRANSCRIPTION FACTOR FOR GLUCOSE METABOLISM(ChREBP) IN PANCREATIC ISLET CELLS

糖尿病以糖代谢障碍为特征，但糖尿病发生的相关分子尚不清楚。最近，我们已经确定并表征了葡萄糖代谢，碳水化合物反应元件结合蛋白（ChREBP）的转录因子。ChREBP激活肝型丙酮酸激酶基因的转录。本研究旨在探讨ChREBP在胰岛素靶细胞胰腺β细胞和肝细胞中的生物学作用。利用INS-1细胞研究ChREBP在胰岛素分泌中的作用。将ChREBP基因转染INS-1细胞后，INS-1细胞中ChREBP过表达，培养基中胰岛素水平发生改变。我们还检测了糖尿病患者ChERBP基因的突变。虽然研究了ChREBP的调控位点，但没有发现任何基因突变。此外，我们还研究了肝脏胰岛素抵抗的机制。虽然胰岛素受体没有明显变化，但在HepG2细胞中发现肝胰岛素受体底物1/2（细胞内胰岛素信号级联的中心分子）下调，表现出胰岛素抵抗增加。在这项研究中，我们证明了ChREBP在胰岛素抵抗发生过程中在INS-1细胞中的生物学作用以及肝细胞（胰岛素的靶细胞）的参与。因此，ChREBP和胰岛素受体底物1/2可能是糖尿病发生的重要分子。

Diabetes mellitus is characterized by the impairment of glucose metabolism, however, the responsible molecules for the development of diabetes mellitus remains unclear. Recently, we have identified and characterize a transcription factor for glucose metabolism, carbohydrate responsive element binding protein(ChREBP). ChREBP activates the transcripton of liver-type pyruvate kinase gene. The aim of this study is to investigate the biological roles of ChREBP in pancreatic beta cell and hepatocytes, target cells of insulin.The role of ChREBP in insulin secretion was investigated by using INS-1 cells. By transfection of ChREBP gene into INS-1 cell, ChREBP was overexpressed in INS-1 cell and insulin levels in culture media was altered. We also examined the mutation of ChERBP gene in patients with diabetes mellitus. Although regulation sites of ChREBP were investigated, any mutation of gene was not identified. In addition, we investigated the mechanisms for hepatic insulin resistance. Although there was no significant change in insulin receptor, down-regulation of hepatic insulin receptor substrate 1/2, central molecules for intracellular insulin signaling cascade, was seen in HepG2 cells showing increased insulin resistance.In this study, we demonstrated the biological roles of ChREBP in INS-1 cells and the involvement of hepatocyte, a target cell of insulin, in the development of insulin resistance. Thus, ChREBP and insulin receptor substrate 1/2 may be responsible molecules for the development of diabetes mellitus.