Islet amyloid polypeptide: mechanisms of amyloidogenesis in the pancreatic islets and potential roles in diabetes mellitus.
Islet amyloid polypeptide: mechanisms of amyloidogenesis in the pancreatic islets and potential roles in diabetes mellitus.
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发表时间：
1992
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通讯作者：
K. Johnson;T. O’Brien;C. Betsholtz;P. Westermark
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作者：
K. Johnson;T. O’Brien;C. Betsholtz;P. Westermark
淀粉样蛋白沉积特征性地与那些物种的胰岛相关（例如，人、猫和猴），其发展出与年龄相关的糖尿病形式，已经显示代表了先前未知的胰岛衍生蛋白质的浓缩和聚合形式，所述胰岛衍生蛋白质被鉴定为IAPP或胰淀素。IAPP是一种高度保守的、羧基末端酰胺化的37个氨基酸多肽，与CGRP具有约45%的氨基酸序列同一性，由胰岛β细胞产生，并在葡萄糖和其他促分泌素的作用下与胰岛素共同分泌。Prepro-IAPP在β细胞中合成为89至93个氨基酸的分子，成熟IAPP似乎是通过与胰岛素形成中所涉及的酶促加工类似的酶促加工形成的。葡萄糖刺激的IAPP分泌通常与胰岛素的分泌平行，并且在摩尔基础上，IAPP占胰岛素分泌量的约1%。观察到IAPP和胰岛素分泌的显著解离（与IAPP分泌的相对更大的上调相关）响应于显著的高血糖，表明IAPP和胰岛素表达受到差异调节。仅在非常有限数量的物种中IAPP的淀粉样蛋白原性与在来自这些物种的IAPP的20-29区域中固有发现的氨基酸残基重要相关。人和猫IAPP的25-28区域在结构上是相同的，并且似乎是人和猫共有的最重要的淀粉样蛋白形成序列。体外纤维形成研究表明，该区域的氨基酸取代特别影响IAPP的淀粉样蛋白形成。在狗和猫中的研究表明，IAPP的β细胞合成（或加工）的异常可能导致局部环境中IAPP浓度增加，从而为IAPP自我聚集形成胰岛淀粉样蛋白提供了第二个先决条件。IAPP在葡萄糖调节、血液动力学、钙稳态中具有生理作用，并作为厌食剂。目前对IAPP的主要兴趣在于其与葡萄糖代谢和2型糖尿病发展的潜在关系。已经提供的证据表明，IAPP可以抑制β细胞的葡萄糖刺激的胰岛素分泌，并且IAPP还可以通过增加肝脏葡萄糖输出和诱导外周胰岛素抵抗而潜在地促成2型糖尿病的发病机制。（400字处截断摘要）
Amyloid deposits characteristically associated with pancreatic islets of those species (e.g., humans, cats, and monkeys) that develop age-associated forms of diabetes have been shown to represent a concentrated and polymerized form of a previously unknown islet-derived protein identified either as IAPP or amylin. IAPP, a highly conserved and carboxy-terminally amidated 37 amino acid polypeptide with approximately 45% amino acid sequence identity to CGRP, is produced by islet beta cells and is cosecreted with insulin in response to glucose and other secretagogues. Prepro-IAPP is synthesized in beta cells as an 89 to 93 amino acid molecule, and mature IAPP appears to be formed by enzymatic processing similar to that involved in the formation of insulin. Glucose-stimulated IAPP secretion generally parallels that of insulin and, on a molar basis, IAPP represents about 1% of the amount of insulin secreted. A significant dissociation of IAPP and insulin secretion (associated with relatively greater upregulation of IAPP secretion) is observed in response to marked hyperglycemia, suggesting that IAPP and insulin expression are differentially regulated. The amyloidogenicity of IAPP in only a very limited number of species is importantly related to the amino acid residues inherently found in the 20-29 region of IAPP from those species. The 25-28 region of human and cat IAPP is identical in structure and appears to be the most important amyloidogenic sequence common to the human and cat. In vitro fibrillogenesis studies have shown that amino acid substitutions in this region especially affect the amyloidogenicity of IAPP. Studies in dogs and cats suggest that aberrations in beta cell synthesis (or processing) of IAPP may lead to an increased concentration of IAPP in the local milieu, thus providing a second prerequisite for the self aggregation of IAPP to form islet amyloid. IAPP has been implicated to have physiological roles in glucose regulation, hemodynamics, calcium homeostasis, and as an anorectic agent. The major current interest in IAPP concerns its potential relationships to glucose metabolism and the development of type 2 diabetes. Evidence has been provided which indicates that IAPP can inhibit glucose-stimulated insulin secretion by beta cells, and that IAPP can also potentially contribute to the pathogenesis of type 2 diabetes by increasing hepatic glucose output and by inducing peripheral insulin resistance.(ABSTRACT TRUNCATED AT 400 WORDS)