Islet amyloid, islet-amyloid polypeptide, and diabetes mellitus.
Islet amyloid, islet-amyloid polypeptide, and diabetes mellitus.
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DOI：
10.1056/nejm198908243210806
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发表时间：
1989-08
期刊：
影响因子：
--
通讯作者：
K. Johnson;T. O'Brien;C. Betsholtz;P. Westermark
中科院分区：
文献类型：
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作者：
K. Johnson;T. O'Brien;C. Betsholtz;P. Westermark
胰岛淀粉样沉积是II型糖尿病的共同特征，是由一种被认为是IAPP的激素聚合而来的。IAPP是由正常胰岛β细胞合成的，可能与胰岛素共分泌。尽管IAPP的生理功能及其在II型糖尿病发病机制中的作用才刚刚开始被阐明，但IAPP可能通过对抗外周组织中胰岛素的作用而在这种最常见的糖尿病的发生发展中发挥重要作用。IAPP聚合形成细胞外胰岛-淀粉样蛋白沉积，可能通过破坏胰岛细胞并干扰葡萄糖和激素的来往，进一步促进II型糖尿病的发展。大量证据表明，IAPP仅在某些物种(如人类、猫和浣熊)中聚合并形成细胞外淀粉样沉积的倾向与分子中固有的淀粉样变性部分--即IAPP的第20至29位--直接相关。在这些物种中，IAPP固有的淀粉样变性可能通过增加IAPP的β细胞产量而进一步促进，从而导致易于聚合的高局部浓度。支持后一种可能性的研究表明，糖耐量受损的正常血糖猫胰岛β细胞产生IAPP的能力增加。虽然IAPP的产生增加最初可能导致胰岛素抵抗，但长期的IAPP过度产生可能最终通过导致不溶性胰岛淀粉样蛋白的进行性沉积而损害胰岛素的分泌，这一发现在大多数显性糖尿病患者中都很明显。如果正如这些研究表明的那样，IAPP的产生增加与II型糖尿病的发展有关，那么进一步的研究必须解决影响人类和某些动物物种这一重要生物变化的遗传和非遗传因素。
Islet-amyloid deposits, which are a common feature of Type II diabetes mellitus, are derived from the polymerization of a putative hormone identified as IAPP. IAPP is synthesized by normal islet beta cells and probably is cosecreted with insulin. Although the physiologic function of IAPP and its role in the pathogenesis of Type II diabetes mellitus are just beginning to be unraveled, IAPP may play an important part in the development of this most common form of diabetes mellitus by opposing the action of insulin in peripheral tissues. The polymerization of IAPP to form extracellular islet-amyloid deposits may further contribute to the development of Type II diabetes mellitus by destroying islet cells and by disrupting the passage of glucose and hormones to and from them. Substantial evidence indicates that the propensity of IAPP to polymerize and form extracellular amyloid deposits in only certain species (e.g., humans, cats, and raccoons) is directly associated with an intrinsically amyloidogenic part of the molecule--i.e., positions 20 through 29 of IAPP. The inherent amyloidogenicity of IAPP in these species may be further facilitated by increased beta-cell production of IAPP, leading to a high local concentration that predisposes to polymerization. The latter possibility is supported by studies demonstrating that IAPP production by islet beta cells is increased in normoglycemic cats with impaired glucose tolerance. Although increased production of IAPP may initially cause insulin resistance, prolonged overproduction of IAPP may ultimately impair insulin secretion by leading to the progressive deposition of insoluble islet amyloid, a finding apparent in most subjects with overt diabetes. If, as these studies suggest, increased IAPP production is linked to the development of Type II diabetes mellitus, further studies must address the genetic and nongenetic factors that influence this important biologic change in humans and some animal species.