1. Canine Juvenile-Onset DiabetesMellitus Paula Krimer and Cathy Brown Cathy Brown 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 ParameterValue Reference Interval Glucose (mg/dL) 68160-125 Phosphorous (mg/dL) 11.52.1-6.3 Potassium (mEq/L) 5.94.0-5.6 Urine Glucose (dipstick) 4+ (>2000m g/dL) <1 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 CD3 CD79 Presented at SEVPAC 2008 – Permission granted for use on SEVPAC website only

9. Insulin Immunohistochemistry PatientControl 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 Patient Control 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