Canine diabetes mellitus: from phenotype to genotype

Abstract

Breed differences in susceptibility to diabetes mellitus in dogs suggest an underlying genetic component to the pathogenesis of the disease. There is little evidence for an equivalent of human type 2 diabetes in dogs, and it has been proposed that canine diabetes is more comparable to the type 1 form of the disease. Certain immune response genes, particularly those encoding major histocompatibility complex molecules involved in antigen presentation, are important in determining susceptibility to human type 1 diabetes. We tested the hypothesis that canine major histocompatibility complex genes (known as the dog leucocyte antigen) are associated with diabetes in dogs. A total of 530 diabetic dogs and more than 1000 controls were typed for dog leucocyte antigen, and associations were found with three specific haplotypes. The DLA-DRB1*009/DQA1*001/DQB1*008 haplotype shows the strongest association with diabetes in the UK dog population. This haplotype is common in diabetes-prone breeds (Samoyed, cairn terrier and Tibetan terrier) but rare in diabetesresistant breeds (boxer, German shepherd dog and golden retriever), which could explain differences in the prevalence of diabetes in these different breeds. There is evidence that the DLA-DQA1*001 allele is also associated with hypothyroidism, suggesting that this could represent a common susceptibility allele for canine immunemediated endocrinopathies.

Breed differences in development of anti-insulin antibodies in diabetic dogs and investigation of the role of dog leukocyte antigen (DLA) genes

“…Porcine insulin was selected as the antigen for use in ELISA as it had been shown previously that there was a high correlation between AIA reactivity measured against bovine or porcine insulin and that there was antibody cross-reactivity between these two insulin types (Davison et al, 2003) Control dogs demonstrated negligible AIA reactivity, which might be expected since they have not been exposed to the antigen, over and above that present physiologically. However, a previous study reported AIA in 4 of 120 control dogs (Davison et al, 2008). This latter finding might represent false positives in the insulin ELISA, or might be due to the presence of insulin autoantibodies in dogs that were potentially in a pre-diabetic state.…”

“…It has been proposed that there are several potential underlying causes of diabetes in dogs, including immune mediated destruction of the beta cells of the pancreas, chronic pancreatitis and insulin resistance due to hormonal antagonism (Hoenig, 2002;Rand et al, 2004). Certain breeds of dog are predisposed to developing diabetes, which strongly suggests that there is a genetic component to disease susceptibility (Catchpole et al, 2008). Breeds such as the Samoyed, Tibetan terrier and Cairn terrier have an increased risk of developing diabetes, whereas other breeds, such as the Boxer and German Shepherd Dog have a reduced risk .…”

“…Measurement of AIA in diabetic and control serum samples was performed by indirect ELISA, as described previously (Davison et al, 2008). Briefly, flat bottomed 96 well microtitre plates (Maxisorp, Nunc) were coated with porcine insulin (Sigma-Aldrich) at 10 µg/mL in 0.05 M carbonate/ bicarbonate buffer, pH 9.6 (Sigma-Aldrich) overnight at 4 °C.…”

“…A previous study showed that around 60% of dogs treated with Insuvet lente (Intervet / Pfizer Animal Health), a bovine insulin preparation, developed AIA, whereas only around 10% of dogs treated with Caninsulin (MSD Animal Health), a porcine insulin preparation, developed AIA (Davison et al, 2008). This suggests that bovine insulin is more immunogenic than porcine insulin, which is likely due to variation of the insulin sequence between species (Fineberg et al, 2007); the amino acid sequence is the same comparing porcine and canine insulin, but bovine insulin differs from canine insulin by two amino acids in the A chain (Davison et al, 2003).…”

“…Breeds such as the Samoyed, Tibetan terrier and Cairn terrier have an increased risk of developing diabetes, whereas other breeds, such as the Boxer and German Shepherd Dog have a reduced risk . Dog leukocyte antigen (DLA) genes, which encode MHC class II molecules, demonstrate considerable inter-breed variability (Kennedy et al, 2002) and have been linked with susceptibility to diabetes mellitus (Catchpole et al, 2008;Kennedy et al, 2006). Three DLA haplotypes in particular, DLA-DRB1*009--DQA1*001--DQB1*008, DRB1*015--DQA1*006--DQB1*023 and DRB1*002--DQA1*009--DQB1*001, have been shown to be associated with susceptibility to diabetes and are prevalent in the Samoyed, Tibetan terrier and Cairn terrier breeds.…”