The endocrine system is vital for normal body function, with dysfunction potentially leading to severe clinical implications [1]. Endocrinopathies diverge in severity depending on the affected gland, but most of these diseases are chronic and require lasting treatment [2, 3]. Canine endocrinopathies can therefore affect the quality of life for both the dog and the owner. In several canine endocrinopathies the immune system play an important role in the aetiology [4] and are commonly referred to as autoimmune endocrinopathies.
In canines, two of the most commonly occurring endocrinopathies are DM and hypothyroidism. Diabetes mellitus is a disease characterized by persistent hyperglycemia due to impaired response to insulin, or impaired ability to produce insulin. The persistent hyperglycemia leads to increased formation of fructosamine (1-amino-1-deoxy-d-fructose), a glycated protein formed by the non-enzymatic, irreversible Amadori-rearrangement between glucose and the amino group of proteins, a compound that is utilized for diagnosis and monitoring of DM in dogs [2]. Accumulation of glycated proteins (Advanced Glycation End products, AGEs) affect nearly every type of cell and molecule in the body and might cause severe damage to the cardiovascular system, eyes, kidneys, and nerves [5]. In canines, DM can present with a variety of clinical signs, however, the clinical signs most commonly recognized are related to impaired metabolism, such as polyuria, polydipsia, polyphagia, and weight loss [2, 4].
The classification of canine DM has been discussed and changed over the last decades. Previously, the terms insulin-dependent DM (IDDM) and non-insulin-dependent DM (NIDDM) were commonly used [1]. In dogs, IDDM resembles type 1A DM (T1ADM) diagnosed in humans, where the body causes autoimmune destruction of the insulin-producing β-cells in the pancreas [6]. Evidence of a serological autoantibody reaction to pancreatic β-cell proteins has been reported in dogs as well [7,8,9,10]. In contrast to T1ADM in humans that mainly occur during childhood, the disease has a later onset in dogs, with a peak prevalence between 7 and 10 years [4, 11]. The aetiologic classification into insulin deficient DM and insulin resistant DM made by ESVE (European Society of Veterinary Endocrinology) is considered the preferred classification system today [12]. Compared to the old IDDM classification, the new classification with type 1B (insulin deficient DM) is more accurate in canines.
Hypothyroidism is caused by insufficient production or antibody inactivation of thyroid hormones [13]. In dogs, this is most often the result of an autoimmune response on the thyroid gland with lymphoid infiltration into the gland, also called lymphocytic thyroiditis categorized as primary hypothyroidism [4]. This will cause an irreversible loss of thyroid tissue, and the dog will need enduring thyroid hormone replacement therapy. Hypothyroidism can also be caused by a pituitary neoplasia resulting in inadequate thyrotropin (TSH)-production and hence, an underactive and histologically atrophic thyroid gland. This is categorized as central or secondary hypothyroidism. Clinical signs of hypothyroidism are non-specific and may be subtle, such as tiredness, alopecia, weight gain, and cold intolerance. These clinical signs reflect the functions of the thyroid hormones as a metabolic actor [14, 15]. In clinical hypothyroidism, the disease is characterized by elevated serum TSH-concentrations and decreased concentrations of free thyroxine (FT4) and total thyroxine (TT4). As in humans, there is probably subclinical hypothyroidism also in dogs, characterized by only elevated TSH-concentrations or thyroglobulin autoantibodies (TgAA) in serum [15,16,17].
Both DM and hypothyroidism are assumed to be complex (multifactorial) diseases caused by genetic, epigenetic and environmental factors in dogs [18, 19]. Several studies have indicated that some canine breeds have a genetic predisposition for the diseases [20,21,22], and many possible aetiological risk factors have been investigated [22, 23]. Sex, weight, and age are acknowledged factors that may influence risk for DM [23, 24]. The prevalence of DM is reported to be significantly higher for female dogs in countries where elective spaying is not allowed [6]. Progesterone stimulates local canine mammary growth hormone production which contributes to systemically clinically overt insulin resistance during metoestrus in some dogs [4, 25]. In a study from the UK where spaying is elective, no significant sex-predisposition was discovered [19], and the annual prevalence is estimated to be around 0.3% (1 of 300 dogs) in the UK [11, 19, 26]. In an epidemiological study from Australia, the prevalence of DM in dogs was reported to be 0.36% per year [27]. For several decades the predisposition of some breeds to canine DM has been investigated and reported. Especially Samoyed and Australian terrier have frequently been reported at high risk of development [18, 19, 21, 22, 27,28,29] and the German Shepherd and Boxer at low risk [11, 18, 22, 26,27,28,29,30]. Other studies have indicated that other breeds are at high risk in some countries, e.g. the Irish Setter and English Setter in Italy [30]. These differences could be due to demographic differences in environment or allele frequencies between breeds in different countries.
For hypothyroidism, no sex-predisposition has been shown, although this has been a topic for discussion in many epidemiologic studies [4, 31, 32]. The influence of risk factors in the development of canine hypothyroidism is sparsely known [17]. Unfortunately, the diagnostic criteria have varied between studies for canine hypothyroidism, making it difficult to conclude on breed distribution. However, several studies have indicated that English Setter, Doberman, Rhodesian Ridgeback, Gordon Setter, and Giant Schnauzer are at higher risk of developing lymphocytic thyroiditis and hence, hypothyroidism [33, 34].
Autoimmune diseases are assumed to originate from defects in certain antigen-presenting genes. Both canine DM and hypothyroidism have been associated with the MHC class II region [10, 15, 20, 21, 34,35,36,37], but other candidate genes have also been investigated [14, 38]. Certain haplotypes of the MHC class II region have been connected to protection and susceptibility for DM in several breeds [10, 20, 21]. In canine hypothyroidism, especially the DLA-DQA1*001:01 allele has been associated with risk of the disease in some breeds [15, 34, 37]. The two diseases are both commonly diagnosed in dogs and can occur in the same individual dog [39,40,41].
The present study aimed to provide more information concerning breed predispositions of canine DM and hypothyroidism based on data from the Norwegian canine population. The objective of the study was to describe relative differences in breed prevalence for canine DM and hypothyroidism to substantiate potential genetic influence in the aetiology of these diseases. The null hypothesis was therefore that there are no differences in breed prevalence for DM and hypothyroidism, and the alternative hypothesis being that there are differences in prevalence for breeds in the two diseases.
