Abstract
Introduction
Amyloidosis consists of heterogeneous disease processes due to the extracellular deposition of a homogeneous glycoproteic material called amyloid in one or more tissues. Amyloid differs from other hyaline materials in that it stains positively with Congo red, and induces green birefringence under polarized light. The distribution of amyloid in tissues and its association with specific diseases aid in the diagnosis.
Insular amyloidosis (IA) is associated with type II diabetes in humans and animals. IA has been described mostly in humans, domestic cats, degus (Octodon degus) and nonhuman primates.1-4,7,12,14-16,18-20 In nondomestic felids, IA has only been documented in cougars (Felis concolor).8 The amyloid precursor deposited in the islets of Langerhans of IA patients is called amylin or insular amyloid polypeptide (IAPP), and is a normal secretion product of β-cells in the islets as insulin. In addition, IAPP is produced by δ-cells in the islets and endocrine cells in the gastrointestinal tract.5,9,14,16 Although IAPP is involved in IA and amyloidosis associated with some neoplastic diseases (e.g., insulinoma), there is evidence that IAPP is an active islet hormone involved in the control of glucose metabolism together with insulin and glucagon. Specifically, IAPP inhibits gastric emptying, glycogen synthesis in skeletal muscle, as well as insulin and glucagon secretion, and stimulates hepatic gluconeogenesis.9 IAPP is a 37-aminoacid molecule with a critical amyloidogenic sequence highly preserved in the different species studied. This sequence is located between residues 20 to 29 and is identical in humans, macaques, dogs, cats, and cougars except for the amino acid at position 25 (alanine in humans, threonine in the other species).14
There is controversy regarding the role of IA in type II diabetes. Although most humans, cats and macaques with type II diabetes have concurrent IA, IAPP deposits are also found in nondiabetic humans and animals, however, the number of islets affected and the severity of IA are considerably reduced as compared to age-matched diabetic patients.1,14,18 Furthermore, insulin resistance, a key factor in the development of type II diabetes, is accompanied by an overproduction of IAPP6,10 but it is not sufficient to induce IA and thus some other additional mechanisms may be involved in the deposition of IAPP in the islets of Langerhans17,20. Interestingly, IAPP amyloid fibrils are toxic to β-cells and, therefore, IA can contribute to the progression of type II diabetes.11 In conclusion, although IA and type II diabetes are highly correlated, the exact pathogenesis of IAPP deposition and its relationship with insulin resistance and type II diabetes are not fully understood.
The importance of IA in the domestic cat and the diagnosis of IA cases in nondomestic felids at the authors’ institutions led us to conduct a retrospective study of IA in these species and to document, whenever possible, the glycemic control of the IA cases identified in this survey at or close to the time of diagnosis.
Materials and Methods
A retrospective review of the medical and pathology records of nondomestic felids at the institutions involved in this study (Africam Safari, Puebla, México; Smithsonian National Zoological Park, Washington, DC; Northwest ZooPath, Snohomish, WA; Department of Veterinary Diagnostic Medicine, University of Minnesota, St. Paul, MN) was performed. All clinical histories, clinical pathology data (with special reference to serum glucose and urinalysis), and paraffin blocks or histologic sections containing pancreas from all IA cases identified were obtained and reviewed. The pancreas of all felids previously unprocessed for histology was routinely embedded in paraffin and stained with hematoxylin and eosin for microscopic examination. Pancreas from all IA cases was processed for IAPP and insulin detection by immunohistochemistry as previously described.13
Results and Discussion
Twelve cases of IA were identified in this preliminary survey. Clouded leopards (Neofelis nebulosa) accounted for eight of these cases; the other animals were two tigers (Panthera tigris), a Mexican bobcat (Felis rufus escuinapae), and a snow leopard (Panthera uncia). All these felids were above 10-years old; six were males (all clouded leopards) and five were females. Nine were euthanatized mostly due to osteoarticular or neoplastic diseases. None of these felids was reported to exhibit clinical signs of diabetes, however, three clouded leopards and one of the tigers were hyperglycemic at or close to the time of death. The snow leopard had slightly elevated glucose levels. All animals with urinalysis available were negative for glucosuria. Three cases had hypercholesterolemia or hypertriglyceridemia in the absence of hyperglycemia. Serum insulin-like immunoreactivity as well as IAPP and insulin immunohistochemical studies are in progress at the time of writing of this manuscript.
The results of this retrospective study suggest that IA may be a common pathologic finding in clouded leopards. In this species, IA may be frequently associated with hyperglycemia. Captive clouded leopards should be monitored for their endocrine pancreatic function on a regular basis.
Acknowledgments
The authors thank The Audubon Park Zoo, Minnesota Zoological Gardens, Oregon Zoo and Santa Barbara Zoo for the contribution of four of the cases included in this study and all their clinical information. This work is funded by the Departamento de Investigación, Conservación y Alcance, Africam Safari (Puebla, México) and Department of Veterinary Diagnostic Medicine, University of Minnesota (St. Paul, MN).
Literature Cited
1. Clark A, Saad MF, Nezzer T, Uren C, Knowler WC, Bennett PH, Turner RC. Islet amyloid polypeptide in diabetic and non-diabetic Pima Indians. Diabetologia. 1990;33:285–289.
2. Clark A, de Koning EJ, Hattersley AT, Hansen BC, Yajnik CS, Poulton J. Pancreatic pathology in non-insulin dependent diabetes (NIDDM). Diabetes Res Clin Pract. 1995;28(Suppl):S39–47.
3. Cromeens DM, Stephens LC. Insular amyloidosis and diabetes mellitus in a crab-eating macaque (Macaca fascicularis). Lab Anim Sci. 1985;35:642–645.
4. Davis KJ, Bell RC, Wilhelmsen CL, Langford MJ, Montali RJ. Immunohistochemical analysis of spontaneous pancreatic islet amyloid deposits in nonhuman primates. Vet Pathol. 1994;31:479–480.
5. Deste L, Wimalawansa SJ, Renda TG. Amylin-immunoreactivity is co-stored in a serotonin cell subpopulation of the vertebrate stomach and duodenum. Arch Histol Cytol. 1995;58:537–547.
6. Höppener JW, Oosterwijk C, Nieuwenhuis MG, Posthuma G, Thijssen JH, Vroom TM, et al. Extensive islet amyloid formation is induced by development of type II diabetes mellitus and contributes to its progression: pathogenesis of diabetes in a mouse model. Diabetologia. 1999;42:427–434.
7. Howard CF Jr, Fang T-Y, Southwick C, Erwin J, Sugardjito J, Supriatna J, et al. Islet cell antibodies in Sulawesi macaques. Am J Primatol. 1999;47:223–229.
8. Johnson KH, Wernstedt C, Obrien TD, Westermark P. Amyloid in the pancreatic islets of the cougar (Felis concolor) is derived from islet amyloid polypeptide (IAPP). Comp. Biochem Physiol B. 1991;98:115–119.
9. Karlsson E. IAPP as a regulator of glucose homeostasis and pancreatic hormone secretion. Int J Mol Med. 1999;3:577–584.
10. Leckström A, Lundquist I, Ma Z, Westermark P. Islet amyloid polypeptide and insulin relationship in a longitudinal study of the genetically obese (ob/ob) mouse. Pancreas. 1999;18:266–273.
11. Lorenzo A, Razzaboni B, Weir GC, Yankner BA. Pancreatic islet cell toxicity of amylin associated with type-2 diabetes mellitus. Nature. 1994;368:756–760.
12. Murphy JC, Crowell TP, Hewes KM, Fox JG, Shalev M. Spontaneous lesions in the degu. In: Montali RJ, Migaki G, eds. The Comparative Pathology of Zoo Animals. Washington, DC: Smithsonian Institution Press; 1980:437–444.
13. O’Brien T, Butler AE, Johnson KH, Roche PC, Butler PC. Islet amyloid polypeptide (IAPP) in human insulinomas: evidence for intracellular amyloidogenesis. Diabetes. 1994;43:329–336.
14. O’Brien T, Wagner JD, Litwak KN, Carlson CS, Cefalu WT, Jordan K, et al. Islet amyloid and islet amyloid polypeptide in cynomolgus macaques (Macaca fascicularis): an animal model of human non-insulin-dependent diabetes mellitus. Vet Pathol. 1996;33:479–485.
15. Stokes WS. Spontaneous diabetes mellitus in a baboon (Papio cynocephalus anubis). Lab Anim Sci. 1986;36:529–533.
16. Toshimori H, Narita R, Nakazato M, Asai J, Mitsukawa T, Kangawa K, et al. Islet amyloid polypeptide in insulinoma and in the islets of the pancreas of non-diabetic and diabetic subjects. Virchows Arch A Pathol Anat Histopathol. 1991;418:411–417.
17. Verchere CB, D’Alessio DA, Wang S, Andrikopoulos S, Kahn SE. Transgenic overproduction of islet amyloid polypeptide (amylin) is not sufficient for islet amyloid formation. Horm Metab Res. 1997;29:311–316.
18. Yano BL, Hayden DW, Johnson KH. Feline insular amyloid: incidence in adult cats with no clinicopathologic evidence of overt diabetes mellitus. Vet Pathol. 1981;18:310–315.
19. Yano BL, Hayden DW, Johnson KH. Feline insular amyloid: association with diabetes mellitus. Vet Pathol. 1981;18:621–627.
20. Westermark P. Islet pathology of non-insulin-dependent diabetes mellitus (NIDDM). Diabet Med. 1996;13(Suppl. 6):S46–48.