O'Brien T D
Department of Veterinary Diagnostic Medicine, College of Veterinary Medicine, Veterinary Diagnostic Laboratory, University of Minnesota, 1333 Gortner Avenue, St. Paul, MN 55108, USA.
Mol Cell Endocrinol. 2002 Nov 29;197(1-2):213-9. doi: 10.1016/s0303-7207(02)00265-4.
The common form of spontaneous diabetes mellitus that occurs in domestic cats bears close resemblance clinically and pathologically to human type 2 diabetes mellitus (T2DM). For example, the typical diabetic cat is obese and middle-aged, and has low but detectable circulating insulin levels. However, the most striking similarity is the occurrence of islet amyloidosis (IA) in nearly all diabetic cats and in over 90% of humans with T2DM. IA in both humans and cats is derived from islet amyloid polypeptide (IAPP, or amylin) which is a hormone produced and secreted along with insulin by the pancreatic beta cells. Since all cats and humans normally produce IAPP, additional factors must be invoked in order to explain the development of IA. Several lines of evidence support the concept that IA is caused by chronically increased stimulus for beta cells to secrete IAPP (and insulin). For example, peripheral insulin resistance such as in chronic obesity results in increased IAPP and insulin secretion. A recent study, in which diabetes mellitus was induced in cats, demonstrated that IAPP hypersecretion was induced by treatment with a sulfonylurea drug and resulted in 4/4 cats in this group developing IA. In contrast, cats treated with insulin had low IAPP secretion and minimal IA developed in 1/4 cats. Several human-IAPP transgenic mouse models, in which there is IAPP overexpression, also support the notion that prolonged high expression of IAPP leads to IA. In vitro models of IAPP overexpression also support this mechanism for IA formation and by demonstrating an association between IA formation and beta cell toxicity, suggest a linkage between IA formation and loss of beta cells in T2DM. A recent study has indicated that intermediate-sized IAPP-derived amyloid fibrils can disrupt cell membranes and therefore, may be involved in the destruction of beta cells. Striking parallels between the pathogenesis of IA and beta-amyloid plaque formation in Alzheimer's disease suggest possible parallel pathogenetic mechanisms of cell death and provide potential avenues for future studies into the pathogenesis of IA.
家猫中常见的自发性糖尿病在临床和病理上与人类2型糖尿病（T2DM）极为相似。例如，典型的糖尿病猫肥胖且处于中年，循环胰岛素水平较低但可检测到。然而，最显著的相似之处是几乎所有糖尿病猫以及超过90%的T2DM患者都会出现胰岛淀粉样变（IA）。人类和猫的IA均源自胰岛淀粉样多肽（IAPP，或胰淀素），它是一种由胰腺β细胞与胰岛素一起产生和分泌的激素。由于所有猫和人类通常都会产生IAPP，因此必须引入其他因素来解释IA的发生。多条证据支持IA是由β细胞分泌IAPP（和胰岛素）的慢性刺激增加所致这一概念。例如，慢性肥胖等外周胰岛素抵抗会导致IAPP和胰岛素分泌增加。最近一项在猫身上诱导糖尿病的研究表明，用磺脲类药物治疗可诱导IAPP分泌过多，该组4/4的猫出现了IA。相比之下用胰岛素治疗的猫IAPP分泌较低，1/4的猫出现了轻微的IA。几种IAPP过表达的人源转基因小鼠模型也支持IAPP长期高表达会导致IA这一观点。IAPP过表达的体外模型也支持IA形成的这一机制，并且通过证明IA形成与β细胞毒性之间的关联，提示了IA形成与T2DM中β细胞丢失之间的联系。最近一项研究表明，中等大小的IAPP衍生淀粉样原纤维可破坏细胞膜，因此可能参与β细胞的破坏。IA发病机制与阿尔茨海默病中β淀粉样斑块形成之间的显著相似性提示了可能的细胞死亡平行发病机制，并为未来IA发病机制的研究提供了潜在途径。
