Canine Juvenile-Onset DiabetesMellitus

Canine Juvenile-Onset Canine Juvenile-Onset DiabetesDiabetesMellitusMellitus

Paula Krimer Paula Krimer andand

Cathy BrownCathy Brown

Painting by Thomas EarlPresented at SEVPAC 2008 – Presented at SEVPAC 2008 –

Permission granted for use on SEVPAC Permission granted for use on SEVPAC website onlywebsite only

Patient HistoryPatient History

14 week old F Clumber spaniel14 week old F Clumber spaniel6 weeks ago: surgery for 6 weeks ago: surgery for ileocolic intussusception and ileocolic intussusception and normal bloodworknormal bloodwork3 weeks ago: dribbling urine & 3 weeks ago: dribbling urine & polyuriapolyuriaGlucose uncontrollable and Glucose uncontrollable and patient euthanizedpatient euthanizedNormal size but firm pancreas Normal size but firm pancreas at necropsyat necropsyLittermate also euthanized for Littermate also euthanized for uncontrolled hyperglycemia & uncontrolled hyperglycemia & suspected pancreatitissuspected pancreatitis

ParameterParameter ValueValue Reference Reference IntervalInterval

Glucose Glucose (mg/dL)(mg/dL)

681681 60-12560-125

Phosphorous Phosphorous (mg/dL)(mg/dL)

11.511.5 2.1-6.32.1-6.3

Potassium Potassium (mEq/L)(mEq/L)

5.95.9 4.0-5.64.0-5.6

Urine Urine Glucose Glucose (dipstick)(dipstick)

4+ 4+ (>2000m(>2000m

g/dL)g/dL)

<1<1

Presented at SEVPAC 2008 – Presented at SEVPAC 2008 – Permission granted for use on SEVPAC Permission granted for use on SEVPAC

website onlywebsite only

Histological FindingsHistological Findings

Few normal islets and suspected Few normal islets and suspected degenerate islets relative to age-matched degenerate islets relative to age-matched controlcontrolSome atrophic acini with interstitial fibrosis Some atrophic acini with interstitial fibrosis and lymphoplasmacytic inflammationand lymphoplasmacytic inflammationMorphological Diagnosis:Morphological Diagnosis:

1. Pancreatic islet hypoplasia1. Pancreatic islet hypoplasia2. Mild chronic lymphocytic interstitial 2. Mild chronic lymphocytic interstitial pancreatitis with focal acinar atrophypancreatitis with focal acinar atrophy



Age Matched Control PancreasAge Matched Control Pancreas



Patient PancreasPatient Pancreas



Patient PancreasPatient Pancreas



ImmunohistochemistryImmunohistochemistry

Canine distemper virus was negativeCanine distemper virus was negativeLymphocytes were CD3 positive and Lymphocytes were CD3 positive and CD79 negative, consistent with a T-cell CD79 negative, consistent with a T-cell infiltrateinfiltrateInsulin and glucagon had rare positive Insulin and glucagon had rare positive individual cells and rare isletsindividual cells and rare isletsAge-matched control had positive-staining Age-matched control had positive-staining insulin and glucagon cells in islets that are insulin and glucagon cells in islets that are similar in frequency to an adultsimilar in frequency to an adult



Lymphocyte ImmunohistochemistryLymphocyte Immunohistochemistry

CD3

CD79Presented at SEVPAC 2008 – Presented at SEVPAC 2008 –


Insulin ImmunohistochemistryInsulin Immunohistochemistry

Patient ControlPresented at SEVPAC 2008 – Presented at SEVPAC 2008 –


Insulin Immunohistochemistry – Insulin Immunohistochemistry – PatientPatient



Glucagon ImmunohistochemistryGlucagon Immunohistochemistry

Patient

Control



DiagnosisDiagnosis

Diagnosis of “canine juvenile-onset diabetes Diagnosis of “canine juvenile-onset diabetes mellitus”mellitus”Rare condition (7 main articles in the literature)Rare condition (7 main articles in the literature)Heritable autosomal recessive genotype Heritable autosomal recessive genotype identified in Keeshond dogs: identified in Keeshond dogs:

pancreas grossly normal in sizepancreas grossly normal in sizefew scattered islet alpha cells, no beta cells, and no few scattered islet alpha cells, no beta cells, and no inflammationinflammation

Unaffected carrier Keeshonds had normal isletsUnaffected carrier Keeshonds had normal isletsInterestingly, ileocecal junctional intussusception Interestingly, ileocecal junctional intussusception was found in one of two necropsied Keeshondswas found in one of two necropsied Keeshonds



Additional InformationAdditional Information

Most extensive study of 11 unrelated canine Most extensive study of 11 unrelated canine cases morphologically subdivided the pancreas cases morphologically subdivided the pancreas into three groupsinto three groups

Based on histological findings, Periodic acid-Schiff Based on histological findings, Periodic acid-Schiff (PAS) special stain before and after diastase special (PAS) special stain before and after diastase special stains, and immunocytochemical analysis for insulin, stains, and immunocytochemical analysis for insulin, glucagon, somatostatin, and pancreatic polypeptide. glucagon, somatostatin, and pancreatic polypeptide. Group 1: No islets, otherwise normal pancreasGroup 1: No islets, otherwise normal pancreasGroup 2: No islets, vacuolated ducts, atrophic aciniGroup 2: No islets, vacuolated ducts, atrophic aciniGroup 3: Scant islets, lymphoid infiltratesGroup 3: Scant islets, lymphoid infiltrates

This dog best fits into group 3This dog best fits into group 3Presented at SEVPAC 2008 – Presented at SEVPAC 2008 –


Pedigree AnalysisPedigree Analysis

First breeding between this male and bitch, with First breeding between this male and bitch, with 2/8 pups affected2/8 pups affected

Pedigree analysis was ambiguous – same sire Pedigree analysis was ambiguous – same sire appeared multiple times in pedigree of each appeared multiple times in pedigree of each parentparent

Conversations with breeder & veterinarian Conversations with breeder & veterinarian breeder indicates heavily used stud dog in small breeder indicates heavily used stud dog in small breeding community; problems should be more breeding community; problems should be more prevalent if he is the carrierprevalent if he is the carrier



Human Disease Model?Human Disease Model?

Normal early bloodwork: suggests lack of trophic Normal early bloodwork: suggests lack of trophic factors to maintain islets or islet destructionfactors to maintain islets or islet destructionHuman Type I insulin-dependent diabetes of Human Type I insulin-dependent diabetes of children has distinct morphological children has distinct morphological characteristics; atrophic islets with marked beta characteristics; atrophic islets with marked beta cell reduction but some alpha and delta cellscell reduction but some alpha and delta cellsWith exception of recent solitary case report of With exception of recent solitary case report of possible canine model, canine juvenile-onset possible canine model, canine juvenile-onset diabetes is not an appropriate model for human diabetes is not an appropriate model for human disease as alpha cells also absentdisease as alpha cells also absent



ReferencesReferences

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



AcknowledgmentsAcknowledgments

Dr. Cathy BrownDr. Cathy Brown

Histotechnology technicians, especially Histotechnology technicians, especially Tricia Rowe and Abbie ButlerTricia Rowe and Abbie Butler

AVDL PathologistsAVDL Pathologists

UGA Department of PathologyUGA Department of Pathology



Canine Juvenile-Onset DiabetesMellitus

Documents

sevpac website onlypresented

normal bloodwork3 weeks

cd3 positive

rare isletsagematched

rare positive individual

glucagon cells

positivestaining insulin

interstitial fibrosis