Familial Insulin-Dependent Diabetes Mellitus in Samoyed Dogs

Case Reports

Pedigree and clinical information from five diabetic Samoyed dogs is described. These dogs represented two family groups, with two siblings in one (Family A) and three siblings in the other (Family B). Both dogs from Family A were castrated males, from a litter of nine dogs. They were the only two dogs from the litter raised in the same environment in which they were whelped. The three siblings from Family B included two spayed females and a castrated male, from a litter of seven dogs, of which one died shortly after birth. All three dogs from Family B were raised in separate households after 8 weeks of age. Age at the time of diagnosis of diabetes mellitus ranged from 3.5 to 7.8 years (mean, 5.2 years). Both dogs from Family A and the male dog from Family B were presented to the Veterinary Hospital of the University of Pennsylvania. Historical and medical record information was gathered from the owners and local veterinarians of the other two affected dogs from Family B [see Table]. Medical information of the other siblings of Family A was unavailable. However, information gathered from the owners and local veterinarians of the surviving three nondiabetic siblings of Family B confirmed the absence of clinical or biochemical features of diabetes mellitus in these dogs.

All five affected Samoyed dogs initially presented with clinical signs of polyuria and polydipsia. Four dogs were reported to be polyphagic, and three of the dogs had documentation of weight loss at the time of initial examination for diabetes mellitus. Previous and concurrent illnesses in these dogs included hypothyroidism, epilepsy, and dermatitis. Two dogs were receiving thyroid hormone supplementation, and one was receiving an anticonvulsant. All five dogs demonstrated fasting hyperglycemia (mean, 524 mg/dL; range, 341 to 711 mg/dL; reference range, 65 to 112 mg/dL) and glucosuria ≥2,000 mg/dL at the time of initial diagnosis. Plasma C-peptide concentrations were determined in three dogs representing both litters. All dogs tested had plasma C-peptide concentrations less than the assay’s lower limit of accuracy of 0.05 pmol/mL (reference range, 0.17±0.01 pmol/mL). Long-term administration of an intermediate-acting insulin resolved clinical signs in all five dogs.

Discussion

Diabetes mellitus is among the most common endocrine disorders of the dog. It is a heterogeneous disease that usually occurs sporadically. The etiology is not known in most cases, although pancreatitis, autoimmune destruction of pancreatic beta cells, pancreatic atrophy, infectious agents, toxins, or hypoplasia of the islets of Langerhans are reported causes.¹ Onset of diabetes is typically late, occurring in older adults, and most dogs are insulinopenic, requiring exogenous insulin therapy.² Insulin-dependent diabetes mellitus has been reported in a variety of different dog breeds.³ However, there is evidence for a genetic contribution and familial or breed disposition to developing the disease. The genetic aspects of inherited IDDM have been previously reported in keeshond dogs with a proposed autosomal recessive inheritance.⁴ In one study, the keeshond, Alaskan malamute, Finnish spitz, and schipperke had the highest relative risks of developing diabetes mellitus, suggesting a breed disposition.⁵ In another study, the Samoyed and miniature schnauzer had the highest relative risks of developing diabetes mellitus.³ Although Samoyed dogs are among the many breeds that develop spontaneous diabetes mellitus of undetermined etiology, a familial or genetic predisposition has not been previously reported.

The presence of clinical signs typical of IDDM, documentation of fasting hyperglycemia and glucosuria, evidence of insulinopenia, and response to insulin therapy supported the diagnoses of IDDM in all five Samoyeds. Although the incidence of diabetes mellitus is greater in Samoyeds compared to all breeds of dogs combined (6% versus 0.5%),³ the prevalence of diabetes mellitus in these families exceeds what would be predicted based on this incidence alone. In addition, the higher incidence in this breed could support the possibility of a genetic predisposition to the development of IDDM in Samoyeds when considered with the finding of multiple affected siblings in Families A and B and of multiple affected ancestors in Family B. However, this report lends support only to the presence of a familial predisposition to diabetes mellitus, and these findings cannot be used to draw any specific conclusions regarding genetic causality.

Common environmental factors that could potentially result in diabetes mellitus in these dogs appear unlikely, as several nonSamoyed dogs raised in the household of Family A have not developed diabetes mellitus, and all three siblings from Family B were raised in different environments. It may be possible that the three Samoyeds from Family B had common exposure to a toxin or an infectious agent in utero or prior to 8 weeks of age, when all dogs shared a common environment. Studies in humans suggest a link between viral infection, especially enteroviruses, and IDDM.^6–8 Infection of puppies with parvovirus could potentially result in pancreatitis, which may then lead to diabetes mellitus. However, evidence of gastrointestinal or other illness did not exist prior to the time of diagnosis with IDDM, and these previous studies in humans suggest that onset of IDDM follows infection within days to months. In addition, a previous study was unsuccessful in inducing diabetes mellitus in young dogs with parvovirus.⁹ Therefore, it appears unlikely that a common viral infection caused diabetes mellitus to occur in these Samoyeds after a period exceeding 3 years from the last potential time of common exposure. In addition, these dogs had no potential for exposure to drugs or toxins, such as alloxan and streptozotocin, which may lead to destruction of pancreatic beta cells with subsequent development of IDDM.

In humans, it is believed that many cases of IDDM are caused by autoimmune destruction of the pancreas in genetically susceptible individuals.¹⁰ It is possible that the development of IDDM in Samoyed dogs occurs similarly; however, based on the information currently available, it is not yet possible to determine the mode of inheritance in this breed. Of the three Samoyeds in Family B with documented IDDM, two were treated for presumptive hypothyroidism. Although these dogs were not available for reevaluation by the authors for more definitive documentation of hypothyroidism (i.e., thyroid stimulating hormone [TSH] stimulation test, serum concentrations of free thyroxine, thyroid autoantibodies, TSH, or a combination of the above), it is possible that a multiglandular autoimmune disorder is present with a genetic predisposition for the disease(s) to occur.

An autosomal-recessive mode of inheritance of the diabetes mellitus trait has been previously reported for juvenile-onset diabetes mellitus in keeshond dogs.² Although an autosomal-recessive mode of inheritance for IDDM in Samoyeds is possible, the disease is late in onset and is therefore unlikely to be mediated by the same genetic abnormality as has been observed in keeshonds. Assuming the ancestors of the propositi of Family B would have developed IDDM by this time, the pedigree of Family B is inconsistent with an X-linked (i.e., sex-linked) recessive mode of inheritance. Mitochondrial disorders leading to diabetes mellitus have been reported in human genetic studies.¹¹ Transmission of these disorders is maternal, with both male and female progeny equally affected. Pedigree information is not consistent with mitochondrial inheritance in Family B, and neurological, cardiac, and other abnormalities that consistently accompany IDDM in humans with this disorder were not evident in these Samoyeds. Lack of penetrance may also occur in certain dogs, further hampering the ability to determine the mode of inheritance. Further evaluation of relatives and ancestors of Samoyed dogs with diabetes mellitus may help to further define a potential mode of inheritance in this breed.

As in humans, the development of IDDM in dogs is likely multifactorial, with genetics, infectious agents, nutrition, autoimmunity, and drug or toxin exposure playing potential roles. Further analysis of pedigree information and long-term evaluation of clinicopathological data, as well as genetic studies of families of Samoyed dogs with diabetes mellitus, will likely be helpful in further characterizing the pathogenesis of late-onset IDDM in these dogs.