DIABETES MELLITUS AND ISLET AMYLOID IN ADULT FELINES

成年猫科动物的糖尿病和胰岛淀粉样蛋白

• 批准号: 3235226
• 负责人: KENNETH H JOHNSON
• 金额: $ 5.52万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 1986
• 资助国家: 美国
• 起止时间: 1986-02-01 至 1989-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3235226
• 关键词: amyloid proteins; amyloidosis; cats; diabetes mellitus; disease /disorder model; immunochemistry; insulin; insulin sensitivity /resistance; nucleic acid sequence; protein sequence

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.

胰岛淀粉样蛋白 (IA) 是一种重要且一致的形态学标志物 用于人类和猫的成人发病糖尿病 (DM)，并且 当血糖正常时，与糖耐量受损有关 猫。 IA的常见发生及其与抗血清的免疫反应 胰岛素 B 链，以及淀粉样蛋白的证明 与 B 细胞相邻的相同免疫组织化学特征 糖尿病猫的胰腺神经节和神经，支持重要的 DM 和 IA 之间的病因病理关系。 这种常见现象的发生 IA 合并成人发病的 DM（考虑到 潜在胰岛和胰岛外缺陷的复杂性和异质性 有助于这种形式的 DM 的发展）提供了一个 有机会利用来自糖尿病猫的分离/纯化的 IA 和胰岛素 作为分析原发性或继发性 B 细胞缺陷的双探针 发生于成人发病的糖尿病。 利用自发猫模型 我们的实验方案与人类 2 型糖尿病非常相似 旨在阐明 IA 与 DM 的致病关系，并且 确定可能与 B 细胞相关的 IA 形成机制 分泌或降解缺陷。 这将通过以下方式实现：1) 确认 IA 的化学性质（即胰岛素相关性） 通过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（之前未进行）为 比较中可能存在的氨基酸取代的基础 从糖尿病猫中分离出的胰岛素或胰岛素相关 IA；和 3) 确定 IA 是否为异常（即纤维状）积累 正常胰岛素，或者如果 IA 代表胰岛​​素质量异常或 胰岛素相关产品。 分离胰岛素 IA 序列比较 从 IA 阴性猫与 IA 阳性猫的胰腺中进行比较将提供进一步的信息 确认胰岛素序列变异的机会 淀粉样蛋白生成，与独立或同时相关的变异 改变胰岛素功能和糖尿病。