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)最重要的病理改变，胰岛淀粉样多肽(IAPP)/淀粉是淀粉样蛋白的主要成分。我们建议解决IAPP基因表达与NIDDM1发病或进展的关系。我们已经建立了表达人IAPP的转基因小鼠。在转基因小鼠中，在胰岛β细胞的分泌颗粒中形成了淀粉样纤维，这表明IAPP衍生的淀粉样纤维在分泌颗粒中形成，在人NIDDM中释放并聚集成淀粉样沉积。转基因小鼠的葡萄糖耐量正常。结论：1.长期饲喂蔗糖或高脂饲料后，糖耐量仍保持正常，提示糖尿病的发生并非仅由人IAPP表达所致。我们尝试用基因转染法将人IAPP基因导入小鼠胰岛β细胞，成功地建立了表达人IAPP的胰岛β细胞系，虽然人IAPP的表达不影响胰岛素的合成，但葡萄糖诱导的胰岛素分泌明显受到抑制。这些结果表明，IAPP的过度表达可能会损害NIDDM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的发生发展之间的关系。

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.