PANCREATIC EXPRESSION AND SECRETION OF HUMAN ISLET AMYLOID POLYPEPTIDE IN A TRANSGENIC MOUSE
PANCREATIC EXPRESSION AND SECRETION OF HUMAN ISLET AMYLOID POLYPEPTIDE IN A TRANSGENIC MOUSE
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DOI：
10.2337/diabetes.43.12.1457
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发表时间：
1994-12-01
期刊：
影响因子：
7.7
通讯作者：
ENSINCK, JW
中科院分区：
文献类型：
--
作者：
DALESSIO, DA;VERCHERE, CB;ENSINCK, JW
胰岛淀粉样蛋白多肽 (IAPP) 是胰腺 β 细胞的分泌产物，是 II 型糖尿病中形成的胰岛淀粉样蛋白的主要成分。为了研究人类 IAPP (hIAPP) 固有的淀粉样蛋白生成性在胰岛淀粉样蛋白沉积物形成中所起的作用，并研究 LAPP 可能的激素作用，开发了表达 hIAPP 的转基因小鼠。该转基因由与大鼠胰岛素 II 启动子连接的 hIAPP cDNA 片段组成。一组转基因小鼠在其胰岛中表达转基因并合成 hIAPP。与非转基因对照小鼠相比，转基因小鼠的胰腺提取物和血浆中的 IAPP 样免疫反应性高出两到三倍。尽管转基因小鼠和对照小鼠中免疫反应性胰岛素 (IRI) 和葡萄糖的血浆浓度仅相等，但转基因动物的胰腺中 IRI 含量几乎高出两倍，并且胰岛素原 mRNA 显着升高，表明胰岛素生物合成速率增加。从 19 个月大的转基因小鼠身上获得的胰腺样本没有发现胰岛淀粉样蛋白的证据。这些结果表明，淀粉样蛋白生成 hIAPP 合成水平的增加不足以引起胰岛淀粉样蛋白沉积。然而，转基因小鼠胰岛中胰岛素合成和储存的增加与IAPP对β细胞的直接调节作用或通过IAPP诱导的胰岛素抵抗间接刺激胰岛素产生一致。
Islet amyloid polypeptide (IAPP) is a secretory product of the pancreatic beta-cell, which is the primary constituent of the islet amyloid that develops in type II diabetes. To study the role the inherent amyloidogenicity of human IAPP (hIAPP) plays in the formation of islet amyloid deposits and to investigate a possible hormonal role for LAPP, transgenic mice expressing hIAPP were developed. The transgene was composed of a fragment of an hIAPP cDNA linked to the rat insulin II promoter. One line of transgenic mice expressed the transgene and synthesized hIAPP in their pancreatic islets. IAPP-like immunoreactivity in pancreatic extracts and plasma were two- to threefold greater in the transgenic mice compared with nontransgenic control mice. Although plasma concentrations of immunoreactive insulin (IRI) and glucose mere equal in transgenic and control mice, the pancreatic content of IRI was nearly twofold greater in the transgenic animals, and proinsulin mRNA was significantly elevated, suggesting increased rates of insulin biosynthesis. Pancreatic samples obtained from transgenic mice up to 19 months of age had no evidence of islet amyloid. These results indicate that an increased level of synthesis of the amyloidogenic hIAPP is not sufficient to cause islet amyloid deposition. However, the increased synthesis and storage of insulin in the islets of the transgenic mice are consistent with either a direct regulatory effect of IAPP on the beta-cell or indirect stimulation of insulin production through IAPP-induced insulin resistance.