A feline model of experimentally induced islet amyloidosis

Abstract

The study of the pathogenesis of islet amyloidosis and its relationship to the development and progression of type 2 diabetes mellitus has been hampered by the lack of an experimentally inducible animal model. The domestic cat, by virtue of the fact that it is one of the few species that spontaneously develop a form of diabetes mellitus that closely resembles human type 2 diabetes, including the formation of amyloid deposits derived from islet amyloid polypeptide (IAPP), was considered to be an excellent candidate species in which to attempt to develop a nontransgenic animal model for this disease process. To develop the model, 8 healthy domestic cats were given a 50% pancreatectomy, which was followed by treatment with growth hormone and dexamethasone. Once a stable diabetic state was established, cats were randomly assigned to groups treated with either glipizide or insulin at doses appropriate to control hyperglycemia. Cats were maintained on this treatment regimen for 18 months and then euthanized. Based on light microscopic examination of Congo red-stained sections of pancreas, all cats were negative for the presence of islet amyloid at the time of pancreatectomy. At the end of the study all 4 glipizide-treated cats had islet amyloid deposits, whereas only 1 of 4 insulin-treated cats had detectable amyloid. In addition, the glipizide treated cats had threefold higher basal and fivefold higher glucose-stimulated plasma IAPP concentrations than insulin-treated cats, suggesting an association between elevated IAPP secretion and islet amyloidosis. Blood-glycosylated hemoglobin concentrations were not significantly different between the two treatment groups. This study documents for the first time an inducible model of islet amyloidosis in a nontransgenic animal.

Figure 1.

Plasma glucose and insulin concentrations in 8 cats after i.v. administration of glucose before partial pancreatectomy and treatment with growth hormone and dexamethasone (mean ± SD).

Figure 2.

Representative examples of sequential changes in glucose and insulin release in one cat during the diabetes induction with growth hormone and dexamethasone. a: Changes in insulin secretion but normal glucose tolerance after 1 month. b: After 2 months, changes in glucose tolerance are present and the changes in insulin secretion are more marked. c: Insulin secretion has markedly decreased after 3 months. There is now marked glucose intolerance and a marked defect in insulin secretion.

Figure 3.

Comparison of IAPP concentrations of 4 cats treated with glipizide with 4 cats treated with insulin. Baseline concentrations and concentrations 15 minutes after i.v. glucose administration are shown (mean ± SD).

Figure 4.

Percentage of islets containing amyloid deposits in glipizide- and insulin-treated cats.

Figure 5.

Congo red-stained sections from glipizide-treated cats demonstrating amyloid deposits. a: Low magnification photomicrograph showing 4 islets exhibiting congophilic amyloid deposits (arrows). Bar, 124 μm. b: High magnification photomicrograph showing congophilic peripheral and central amyloid deposits (arrows) in a pancreatic islet. c: Same section with cross-polarized light demonstrating green birefringence of amyloid (arrows). Bars, 44 μm.

Figure 6.

Immunohistochemical staining for islet amyloid polypeptide (IAPP). a: Pancreatic islet from a cat before diabetes induction (normal islet). Note intense staining for IAPP, which is more intense at one pole of the cells (arrow). Bar, 46 μm. b: Pancreatic islet from a glipizide-treated cat showing strong IAPP immunoreactivity in islet amyloid deposit (wide arrows). Note also the diffuse, intense cytoplasmic IAPP staining in the remaining cells (narrow arrows). Bar, 26 μm. c: Pancreatic islet from an insulin-treated cat showing marked vacuolar change in islet cells (wide arrow), most of which show no IAPP immunoreactivity. Note some residual IAPP immunoreactivity in some islet cells (narrow arrow). Bar, 36 μm.