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.

Islet amyloid: a complication of islet dysfunction or an aetiological factor in Type 2 diabetes?

“…increased insulin resistance, sulphonylurea therapy in diabetes would then promote fibril formation. Islet amyloidosis was found to be more extensive in sulphonylurea-treated diabetic cats than those treated with insulin [126] confirming this hypothesis. However, the rate of deposition seems to be very different in human patients suggesting that the process is not be driven continuously from a nucleation point throughout the diabetic period.…”

Spontaneous Diabetes Mellitus in Animals

“…Islet amyloidosis is the dominant feature in non-insulin dependent diabetes mellitus, being diagnosed in more than 80% of affected domestic and wild cats [79,80]. Amyloid deposition is usually detected in healthy cats, the amount increasing with the age.…”

“…The deposits are mainly extracellular, with particular concentration at the periphery of islets and around the capillaries and concurrent with depletion of islet cells ( fig. 3) [79,117]. Hepatocytes and epithelium of bile ducts express also vacuolation of the cytoplasm due to lipid accumulation and glycogen, respectively.…”

Amyloidosis in Domestic Animals: Pathology, Pathogenesis, Gross and Microscopic Lesions and Clinical Findings

“…Deposition of amyloid derived from islet amyloid polypeptide (IAPP), a normal protein secreted by the  cell of the pancreas, is reported in the pancreas of cats, and macaques. The mechanisms by which IAPP, a normal product of pancreatic islet beta cells, undergoes assembly and transformation into deposits of amyloid fibrils are not fully understood Hoenig et al, 2000). However, the islet amyloid deposits in humans and feline and macaque animal models of type 2 diabetes mellitus are associated with significant loss of islet  cells (Hoenig et al, 2000).…”