Studies on human ialet amyloid polypeptide gene expression and non-insulin-dependent diabetes

胰岛淀粉样蛋白是人类非胰岛素依赖型糖尿病（NIDDM）最重要的病理发现，而胰岛淀粉样蛋白多肽(IAPP) /胰淀素是淀粉样蛋白的主要组成部分。我们提出解决IAPP基因表达与NIDDM.1发病或进展之间的关系。我们建立了表达人IAPP的转基因小鼠。在转基因小鼠胰腺β细胞的分泌颗粒中形成淀粉样原纤维，提示iapp衍生的淀粉样原纤维在分泌颗粒中形成，释放并聚集成人类NIDDM的淀粉样沉积物。转基因小鼠的糖耐量正常。长期饲喂蔗糖或高脂饮食后，糖耐量保持正常，提示糖尿病的发生并非仅由人类IAPP表达引起。我们尝试用转染法将人IAPP cDNA导入转化后的小鼠胰腺β细胞中，成功培育出表达人IAPP的胰腺β细胞系。虽然胰岛素合成不受IAPP表达的影响，但葡萄糖诱导的胰岛素分泌明显下降。根据这些结果，我们推断IAPP的过表达可能会损害NIDDM患者的胰岛素分泌。本研究有助于了解IAPP基因表达、胰岛淀粉样蛋白沉积与NIDDM发病或进展之间的关系。

Islet amyloid the most significant pathological finding in human non-insulin-dependent diabetes mellitus (NIDDM) and islet amyloid polypeptide (IAPP) /amylin is a major component of the amyloid. We proposed to resolve the relationship between IAPP gene expression and onset or progression of NIDDM.1. We had developed transgenic mouse expressing human IAPP.In the transgenic mice, amyloid-like fibrils were formed in secretory granules of pancreatic Beta-cells, suggesting that IAPP-derived amyloid fibrils are formed in secretory granules, released and aggregated into amyloid deposits in human NIDDM.Glucose tolerance was normal in the transgenic mice. After long-term feeding with sucrose or high fat diet, glucose tolerance remained to be normal, suggesting that onset of diabets mellitus is not induced only by human IAPP expression.2. We tried to introduce human IAPP cDNA in transfomed mouse pancreatic Beta-cells by transfection method and succeeded in the development of pancreatic Beta-cell line expressing human IAPP.Although insulin synthesis was not influenced by human IAPP expression, glucose-induced insulin secretion was markedly depressed. From these results, we conclude that overexpression of IAPP might impaire insulin secretion in NIDDM.The present studies are useful to understand a relationship among IAPP gene expression, islet amyloid deposition and onset or progression of NIDDM.