Canine Juvenile-Onset Diabetes Mellitus

1. Paula Krimer and Cathy Brown Canine Juvenile-Onset Diabetes Mellitus Painting by Thomas Earl Presented at SEVPAC 2008 – Permission granted for use on SEVPAC website only

2. Patient History • 14 week old F Clumber spaniel • 6 weeks ago: surgery for ileocolic intussusception and normal bloodwork • 3 weeks ago: dribbling urine & polyuria • Glucose uncontrollable and patient euthanized • Normal size but firm pancreas at necropsy • Littermate also euthanized for uncontrolled hyperglycemia & suspected pancreatitis Presented at SEVPAC 2008 – Permission granted for use on SEVPAC website only

3. Histological Findings • Few normal islets and suspected degenerate islets relative to age-matched control • Some atrophic acini with interstitial fibrosis and lymphoplasmacytic inflammation • Morphological Diagnosis: • 1. Pancreatic islet hypoplasia • 2. Mild chronic lymphocytic interstitial pancreatitis with focal acinar atrophy Presented at SEVPAC 2008 – Permission granted for use on SEVPAC website only

4. Age Matched Control Pancreas Presented at SEVPAC 2008 – Permission granted for use on SEVPAC website only

5. Patient Pancreas Presented at SEVPAC 2008 – Permission granted for use on SEVPAC website only

6. Patient Pancreas Presented at SEVPAC 2008 – Permission granted for use on SEVPAC website only

7. Immunohistochemistry • Canine distemper virus was negative • Lymphocytes were CD3 positive and CD79 negative, consistent with a T-cell infiltrate • Insulin and glucagon had rare positive individual cells and rare islets • Age-matched control had positive-staining insulin and glucagon cells in islets that are similar in frequency to an adult Presented at SEVPAC 2008 – Permission granted for use on SEVPAC website only

8. Lymphocyte Immunohistochemistry CD79 CD3 Presented at SEVPAC 2008 – Permission granted for use on SEVPAC website only

9. Insulin Immunohistochemistry Patient Control Presented at SEVPAC 2008 – Permission granted for use on SEVPAC website only

10. Insulin Immunohistochemistry – Patient Presented at SEVPAC 2008 – Permission granted for use on SEVPAC website only

11. Glucagon Immunohistochemistry Control Patient Presented at SEVPAC 2008 – Permission granted for use on SEVPAC website only

12. Diagnosis • Diagnosis of “canine juvenile-onset diabetes mellitus” • Rare condition (7 main articles in the literature) • Heritable autosomal recessive genotype identified in Keeshond dogs: • pancreas grossly normal in size • few scattered islet alpha cells, no beta cells, and no inflammation • Unaffected carrier Keeshonds had normal islets • Interestingly, ileocecal junctional intussusception was found in one of two necropsied Keeshonds Presented at SEVPAC 2008 – Permission granted for use on SEVPAC website only

13. Additional Information • Most extensive study of 11 unrelated canine cases morphologically subdivided the pancreas into three groups • Based on histological findings, Periodic acid-Schiff (PAS) special stain before and after diastase special stains, and immunocytochemical analysis for insulin, glucagon, somatostatin, and pancreatic polypeptide. • Group 1: No islets, otherwise normal pancreas • Group 2: No islets, vacuolated ducts, atrophic acini • Group 3: Scant islets, lymphoid infiltrates • This dog best fits into group 3 Presented at SEVPAC 2008 – Permission granted for use on SEVPAC website only

14. Pedigree Analysis • First breeding between this male and bitch, with 2/8 pups affected • Pedigree analysis was ambiguous – same sire appeared multiple times in pedigree of each parent • Conversations with breeder & veterinarian breeder indicates heavily used stud dog in small breeding community; problems should be more prevalent if he is the carrier Presented at SEVPAC 2008 – Permission granted for use on SEVPAC website only

15. Human Disease Model? • Normal early bloodwork: suggests lack of trophic factors to maintain islets or islet destruction • Human Type I insulin-dependent diabetes of children has distinct morphological characteristics; atrophic islets with marked beta cell reduction but some alpha and delta cells • With exception of recent solitary case report of possible canine model, canine juvenile-onset diabetes is not an appropriate model for human disease as alpha cells also absent Presented at SEVPAC 2008 – Permission granted for use on SEVPAC website only

16. References • Atkins CE et al. Morphologic and immunocytochemical study of young dogs with diabetes mellitus associated with pancreatic islet hypoplasia. Am J Vet Res. 1988 Sep;49(9):1577-81. • Kramer JW et al, Inherited, early onset, insulin-requiring diabetes mellitus of Keeshond dogs. Diabetes. 1980 Jul;29(7):558-65. • Jouvion G, Abadie J, Bach JM, Roux F, Miclard J, Deschamps JY, Guigand L, Saï P, Wyers M. Lymphocytic insulitis in a juvenile dog with diabetes mellitus. Endocr Pathol. 2006 Fall;17(3):283-90. Presented at SEVPAC 2008 – Permission granted for use on SEVPAC website only

17. Acknowledgments • Dr. Cathy Brown • Histotechnology technicians, especially Tricia Rowe and Abbie Butler • AVDL Pathologists • UGA Department of Pathology Presented at SEVPAC 2008 – Permission granted for use on SEVPAC website only