DIABETES MELLITUS AND ISLET AMYLOID IN ADULT FELINES

胰岛淀粉样蛋白(IA)是一种实质而统一的形态标志 用于人类和猫的成人糖尿病(DM)，并且是 血糖正常时与糖耐量受损有关 猫。IA的常见发病及其与抗血清的免疫反应性 结合淀粉样蛋白与胰岛素B链的结合 与B细胞相邻的免疫组织化学特征相同 糖尿病猫的胰神经节和神经，对 糖尿病与IA的病因病理关系。这种常见的 患有成人起病的糖尿病的IA(考虑到 潜在胰岛和胰外缺陷的复杂性和异质性 有助于这种形式的DM的发展)提供了一种 利用分离/纯化的糖尿病猫IA和胰岛素的机会 作为分析原发或继发B细胞缺陷的双探针 发生在成人发病的糖尿病中。利用自发性猫模型 它与人类的2型糖尿病非常相似，我们的实验方案 旨在阐明IA与DM的病因关系，以及 确定可能与B细胞相关的IA形成机制 分泌物或降解缺陷。这将通过以下方式实现：1) 确认IA的化学性质(即与胰岛素有关) 通过对IA的分离纯化和氨基酸序列分析 来自糖尿病猫(使用我们实验室建立的程序)；2) 正常猫胰岛素的氨基酸序列分析(未做过) 中可能存在的氨基酸替换的比较基础 从糖尿病猫中分离出胰岛素或胰岛素相关的IA； 确定IA是否是不寻常的(即，纤维状)积聚 正常胰岛素，或如果IA代表定性异常的胰岛素或 胰岛素相关产品。分离的胰岛素IA序列的比较 IA阴性猫和IA阳性猫的胰腺组织将提供进一步的 确认胰岛素序列变异的机会与 淀粉样变与独立或同时连锁的变异 改善胰岛素功能和糖尿病。

Islet amyloid (IA) represents a substantial and uniform morphologic marker for adult-onset diabetes mellitus (DM) in humans and cats, and is associated with impaired glucose tolerance when present in normoglycemic cats. The common occurrence of IA and its immunoreactivity with antiserum to insulin B-chain, together with the demonstration of amyloid with identical immunohistochemical characteristics adjacent to B-cells within pancreatic ganglia and nerves of diabetic cats, supports a significant etiopathologic relationship between DM and IA. This common occurrence of IA with adult-onset DM (which is especially significant considering the complexity and heterogeneity of potential islet and extraislet defects which contribute to the development of this form of DM) provides an opportunity to utilize isolated/purified IA and insulin from diabetic cats as dual probes for the analysis of primary or secondary B-cell defects occurring in adult-onset diabetes. Utilizing the spontaneous cat model which so closely resembles Type 2 DM in humans, our experimental protocol is designed to elucidate the etiopathogenic relationship of IA to DM, and to determine mechanisms of IA formation that may be linked to B-cell secretion or degradation defects. This will be achieved through: 1) Confirmation of the chemical nature (i.e., insulin-relatedness) of IA through isolation, purification, and amino acid sequence analysis of IA from diabetic cats (using procedures established in our laboratory); 2) Amino acid sequence analysis of normal cat insulin (not previously done) as a base of comparison for possible amino acid substitutions present in insulin or insulin-related IA isolated from diabetic cats; and 3) Determination of whether IA is an unusual (i.e., fibrillar) accumulation of normal insulin, or if IA represents qualitatively abnormal insulin or insulin-related product. Comparison of IA sequences of insulin isolated from pancrease of IA-negative versus IA-positive cats will provide further opportunity to confirm insulin sequence variations linked to amyloidogenesis, versus variations independently or simultaneously linked to modified insulin function and DM.