WALTHAM International Science Symposium:

Nature, Nurture, and the Case for Nutrition

Canine and Feline Diabetes Mellitus: Nature or Nurture?1

Jacquie S. Rand,2 Linda M. Fleeman, Heidi A. Farrow, Delisa J. Appleton, and
Rose Lederer
Centre for Companion Animal Health, School of Veterinary Science, The University of Queensland,
Brisbane 4072, Australia

ABSTRACT There is evidence for the role of genetic and environmental factors in feline and canine diabetes. Type
2 diabetes is the most common form of diabetes in cats. Evidence for genetic factors in feline diabetes includes the
overrepresentation of Burmese cats with diabetes. Environmental risk factors in domestic or Burmese cats include
advancing age, obesity, male gender, neutering, drug treatment, physical inactivity, and indoor confinement. High-
carbohydrate diets increase blood glucose and insulin levels and may predispose cats to obesity and diabetes. Low-
carbohydrate, high-protein diets may help prevent diabetes in cats at risk such as obese cats or lean cats with
underlying low insulin sensitivity. Evidence exists for a genetic basis and altered immune response in the
pathogenesis of canine diabetes. Seasonal effects on the incidence of diagnosis indicate that there are
environmental influences on disease progression. At least 50% of diabetic dogs have type 1 diabetes based on
present evidence of immune destruction of b-cells. Epidemiological factors closely match those of the latent
autoimmune diabetes of adults form of human type 1 diabetes. Extensive pancreatic damage, likely from chronic
pancreatitis, causes ;28% of canine diabetes cases. Environmental factors such as feeding of high-fat diets are
potentially associated with pancreatitis and likely play a role in the development of pancreatitis in diabetic dogs.
There are no published data showing that overt type 2 diabetes occurs in dogs or that obesity is a risk factor for
canine diabetes. Diabetes diagnosed in a bitch during either pregnancy or diestrus is comparable to human
gestational diabetes. J. Nutr. 134: 2072S–2080S, 2004.

KEY WORDS:  diabetes  dogs  cats  genetic  environmental influences

Introduction Feline diabetes: nature or nurture?

Diabetes mellitus is one of the most frequently diagnosed The incidence of diabetes in cats ranges from 1 in 50 to 1 in
endocrinopathies in cats and dogs. The present classification 400 depending on the population studied (2,3). Recent
system divides diabetes into four categories (1). The most evidence suggests that the incidence is increasing because of
common form of diabetes in companion animals varies with an increase in the frequency of predisposing factors such as
the species. Type 1 diabetes mellitus, previously called insulin- obesity and physical inactivity (4). Although the incidence in
dependent diabetes, is most common in dogs, whereas type 2, cats is substantially lower than in humans, it is hypothesized to
previously called non-insulin–dependent or adult-onset di- be much higher if the same diagnostic criteria were applied to
abetes, appears to be the most common form of diabetes in cats (5). In human diabetics, diagnosis is based on fasting
cats. Other specific types of diabetes account for a smaller blood-glucose concentration values of $7 mmol/L, whereas in
proportion of cases in each species. Gestational diabetes has cats, it is usually diagnosed once clinical signs are evident (1).
not been reported in cats, but dogs appear to develop an This occurs when blood glucose concentration exceeds the
equivalent form during diestrus. The genetic and environ- renal threshold, which is ;16 mmol/L in healthy cats (6).
mental influences vary with species and the type of diabetes; Based on histological findings and clinical characteristics,
therefore, the case for nature or nurture is presented sep- type 2 diabetes accounts for 80–95% of feline diabetes (7).
arately for dogs and cats. Other specific types of diabetes account for ;15–20% of cases
1
(8,9) and are caused by a variety of diseases that either decrease
Presented as part of the WALTHAM International Science Symposium: b-cell numbers or cause marked insulin resistance. The most
Nature, Nurture, and the Case for Nutrition held in Bangkok, Thailand, October
28–31, 2003. This symposium and the publication of the symposium proceedings common diseases that produce diabetes by decreasing b-cell
were sponsored by the WALTHAM Centre for Pet Nutrition, a division of Mars, numbers are pancreatic adenocarcinoma and pancreatitis (10).
Inc. Symposium proceedings were published as a supplement to The Journal of Diseases that produce marked insulin resistance include acrome-
Nutrition. Guest editors for this supplement were D’Ann Finley, James G. Morris,
and Quinton R. Rogers, University of California, Davis. galy (growth hormone excess), and more moderate insulin
2
To whom correspondence should be addressed. E-mail: j.rand@uq.edu.au. resistance results from hyperadrenocorticism and hyperthyroid-

0022-3166/04 $8.00 Ó 2004 American Society for Nutritional Sciences.

2072S

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 NATURE OR NURTURE? 2073S

ism. Little is known about the environmental or genetic causes of particularly obesity and physical inactivity. Data largely from
diseases that produce other specific types of diabetes in cats. domestic short- and long-hair cats in North America and
Burmese cats in Australia identified obesity, advancing age,
Cause of type 2 diabetes male gender, being neutered, and drug treatment as risk factors
(3,19,20).
Type 2 diabetes has a complex etiology and is caused by a
combination of genetic factors and environmental interactions, Role of insulin resistance in type 2 diabetes
and risk increases with aging (11,12).
Type 2 diabetes results from impaired insulin secretion
Genetic factors in type 2 diabetes combined with impaired insulin action, which is also referred to
as decreased insulin sensitivity or insulin resistance (21).
The susceptibility to type 2 diabetes in humans, monkeys, Insulin sensitivity is defined as the decrease in glucose for a
and rodents is inherited, and preliminary data support a genetic given amount of insulin. Insulin resistance refers to markedly
influence in cats (12). Diabetes is most common in domestic decreased insulin sensitivity (21).
long- and short-hair cats. Burmese cats are overrepresented, The ability of insulin-resistant individuals to compensate for
and many other pure breeds are underrepresented, compared reduced insulin sensitivity by increasing insulin secretion
to the incidence in domestic cats. The Burmese breed is largely determines the degree to which their glucose tolerance
overrepresented in Australia, New Zealand (13,14), and the can be prevented from deteriorating (22). In individuals where
UK (personal communication, D. Gunn-Moore, 2002). The this balance cannot be maintained, impaired glucose tolerance
frequency of diabetes in the Burmese breed is approximately and overt diabetes ensues.
four times the rate in domestic cats in Australia, with 1 in 50 Overt diabetes is the result of b-cell failure. It is
Burmese affected compared with ,1 in 200 domestic cats (2). hypothesized that the major cause of b-cell failure is a prolonged
In some Burmese families, .10% of the offspring are affected and increased demand on the b-cell to secrete insulin
(14). The genetic factors that predispose cats to diabetes are secondarily to insulin resistance (21,23). This leads to b-cell
unknown. In Burmese cats, the inheritance is not sex linked or damage, in part mediated by oxidant damage, that triggers
dominant (14). Preliminary results of histological examination apoptosis or programmed cell death. Other factors that ad-
of pancreatic tissue show a similar range of islet pathology in versely affect b-cell numbers and function include islet amyloid
diabetic Burmese and diabetic domestic cats, which suggests deposition (24), glucose toxicity (25), pancreatitis (8), and certain
that the mutation does not directly result in excessive dietary influences (26).
deposition of islet amyloid polypeptide or another metabolic Because insulin resistance requires increased insulin secre-
product causing destruction of b-cells (personal communica- tion to maintain euglycemia, which over time also leads to
tion, R. Lederer, 2003). Limited data available suggest the b-cell failure, it is a core abnormality in type 2 diabetes. Many
genes involved may influence insulin sensitivity (unpublished factors contribute to insulin resistance including genotype,
data, J. Rand, 2003). obesity, physical inactivity, drugs, illness, hyperglycemia, and
Ethnicity is a risk factor in humans, and a very high gender.
prevalence of type 2 diabetes occurs in some indigenous
populations such as American Indians, Australian Aboriginals, Genetic influences on insulin sensitivity
and Pacific Islanders. This genetic predisposition of some ethnic
groups is most apparent when combined with a Western In cats, we have shown (27) that with an average of 44%
lifestyle (15). Underlying insulin resistance (low insulin sen- body weight gain, nearly 50% of healthy cats develop impaired
sitivity) is thought to be associated with a ‘‘thrifty gene’’(16), glucose tolerance. Interestingly, lean cats that developed
which once enabled hunter-gatherers to utilize food efficiently, impaired glucose tolerance with weight gain already had on
but is disadvantageous when combined with an affluent life- average 35% lower insulin sensitivity than cats that maintained
style. Cats have undergone similar lifestyle changes to the ethnic normal glucose tolerance after gaining weight. In fact, having
groups predisposed to diabetes, as they have evolved from an insulin sensitivity index below the reference-range median
hunters to suburban indoor cats and are no longer dependent on resulted in a threefold increased risk of developing impaired
hunting to supply their nutritional needs. glucose tolerance with weight gain. These results indicate that
normal-weight cats with underlying low insulin sensitivity are at
Age and type 2 diabetes greater risk of developing impaired glucose tolerance if they
become overweight or obese. Human patients with impaired
Increasing age in domestic and Burmese cats is a risk factor glucose tolerance progress to type 2 diabetes at a rate of up to
for type 2 diabetes, and most cats are .8 y of age with a peak 6% per year (28). It is interesting to speculate whether the
incidence between 10 and 13 y of age (2,3). Although 1 in 50 underlying low insulin sensitivity in our lean cats, which
Burmese cats has diabetes, the incidence increases to 1 in 10 for increased their risk of impaired glucose tolerance with obesity,
Burmese cats $8 y of age (2). Type 2 diabetes also occurs most was genetically determined as it is in people. In human patients,
commonly in older human patients. As b-cell function declines insulin resistance is largely the result of genotype but is
with age, the risk of overt disease increases (17). Because of the worsened by environmental factors such as obesity (21,29). In
marked increase in obesity and physical inactivity in children fact, insulin resistance is present in ;25% of nonobese people
(18), 30% of new cases of human type 2 diabetes now occur in with normal glucose tolerance (30). If these individuals gain
people ,20 y of age. weight, some will no longer be able to secrete enough insulin to
compensate for the additional deterioration in insulin re-
Environmental factors predisposing to type 2 diabetes sistance that accompanies weight gain. In this situation, de-
compensation of glucose metabolism occurs, and impaired
Environmental factors are important in increasing the risk of glucose tolerance develops.
feline diabetes. They are also very important in the de- Importantly, our results suggest that some cats have an
velopment of human type 2 diabetes and relate to lifestyle, underlying predisposition to develop glucose intolerance, and if

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 2074S SUPPLEMENT

these cats become obese, they may be at greater risk of insulinemia in lean cats was the greatest single risk factor for
developing overt type 2 diabetes over time. Preventative the development of impaired glucose tolerance with obesity.
programs aimed at reducing body weight and improving insulin The pattern of fat deposition in obese individuals also
sensitivity would be most effective if directed at cats with un- influences the severity of insulin resistance. In general, central
derlying low insulin sensitivity. obesity (abdominal obesity) in humans is associated with
greater insulin resistance and risk of diabetes than peripheral
Insulin resistance, evolution, and diet obesity (38). Interestingly, overweight Burmese cats typically
develop abdominal fat rather than the subcutaneous inguinal
Insulin resistance is frequent in indigenous populations that fat found in overweight domestic cats (unpublished observa-
have a high incidence of diabetes. This raises the question tion, J. Rand, 2003).
whether insulin resistance has an evolutionary advantage. Two
theories have been proposed to explain the high frequency of Physical inactivity and insulin resistance
insulin resistance and diabetes in these populations. The
‘‘thrifty gene’’ theory proposes that selective resistance to the Physical inactivity increases the risk of human type 2
glucose lowering but not the fat forming effects of insulin diabetes both directly by decreasing insulin sensitivity and
facilitated the efficient conversion of energy to fat when food indirectly by an effect on body weight (39,40). Inactive dogs are
was plentiful. When food was scarce, the fat store was utilized also insulin resistant. In Burmese cats, being confined indoors
and insulin resistance maintained glucose levels (16). and having a low physical activity score were significant risk
The ‘‘carnivore connection’’ theory proposes that resistance factors for diabetes (20). If the modern lifestyle of an urban cat
to the glucose-lowering effects of insulin evolved during the Ice is compared with a feral cat that hunts to obtain all its food,
Age to maintain euglycemia on a high-protein, low-carbohy- urban cats, especially cats confined indoors, are very physically
drate diet (26). Inherited insulin resistance in conjunction with inactive. They no longer hunt for food or fight and are therefore
environmental risk factors such as physical inactivity, obesity, also likely to be insulin resistant. Increasing physical activity in
and consumption of excessive amounts of highly refined, easily cats by 10 min of daily play produced as much weight loss as
digestible carbohydrates places a large, prolonged demand on calorie restriction (41).
the b-cells for excessive insulin secretion, which eventually
results in b-cell exhaustion and diabetes. Drugs and insulin resistance
Recent evolutionary history of cats parallels that of modern
human populations, particularly the recently urbanized in- Veterinarians can contribute to loss of insulin sensitivity by
digenous populations that have very high incidences of insulin prescribing drugs that cause insulin resistance, especially if
resistance and diabetes. Although cats evolved as strict these medications are used long term or if long-acting forms are
carnivores, many commercial diets are moderate to high in chosen. A wide variety of pharmacological agents such as
carbohydrates (.50% of calories). This change from a low- corticosteroids are known to be diabetogenic in people. Corti-
carbohydrate, high-protein diet typical of feral cats to a high- costeroids and progestins (42) are the most commonly used
carbohydrate diet has only become widespread in the last 20–30 drugs in cats that cause insulin resistance. Two or more treat-
y and may be partially responsible for the recent increase in ments with corticosteroids in the 2 y preceding diagnosis of
incidence of diabetes in domestic cats. This change in diet has diabetes were a significant risk factor for diabetes in Burmese
also been accompanied by a shift from an outdoor environment cats (20) and are reported as a risk factor in domestic cats
to indoor confinement and decreased physical activity, because (43,44). A trend for diabetic Burmese cats to have been treated
cats no longer need to hunt to obtain nutrition. If these theories with megestrol acetate approached significance.
were true for cats, possessing the thrifty genotype would confer
a survival advantage in times of inconsistent or limited food Illness and insulin resistance
supply but would be disadvantageous when there is a consistent
supply of highly palatable, energy-dense food. Dental disease was a significant risk factor for diabetes in
Burmese cats as were chronic or recurring medical problems
Obesity and insulin resistance (20). Anecdotally, treatment for periodontal disease is often
associated with improved glycemic control in diabetic cats and
The major acquired risk factor for type 2 diabetes in other sometimes a reduction in insulin dose. Inflammation may also
species is insulin resistance associated with obesity. Even small play a pathogenic role in human type 2 diabetes(45–47), and
increases in body-mass index and fat-cells sizes have been periodontal disease and diabetes tend to promote one another
associated with a significant increase in the risk of developing (48). It is thought that illness decreases insulin sensitivity, and
diabetes (31). Obesity is also a significant risk factor for diabetes evidence suggests that insulin therapy is helpful in maintaining
in cats (3,19,32). This increased risk is the result of obesity- euglycemia even in nondiabetic patients (49).
induced insulin resistance and hyperinsulinemia (21,27). In
a recent study (27), free access to a highly palatable, energy- Gender and insulin resistance
dense diet over ;10 mo resulted in cats increasing their
bodyweight by a mean of 1.9 kg or 44.2%. Insulin sensitivity was Male cats have a greater risk for developing diabetes than
reduced by more than half with weight gain in these cats. In female cats (3,13,32). The reason for this increased risk may be
fact, in two thirds of the cats, insulin sensitivity fell below the related to two factors. The first is the tendency of male cats to
range previously reported for normal cats (33). These results have lower insulin sensitivity values (37% lower) than females
concur with studies on human patients, which report a decrease when they are lean, which deteriorates further with weight gain
in insulin sensitivity of between 44 and 72% in obese subjects (27). Similarly, when obese, male cats also tend to have lower
compared with normal-weight control subjects (34–37). insulin sensitivity than female cats. Interestingly, only male cats
Importantly, after weight gain, 25% of the cats in our study had significantly increased basal insulin concentrations after
had an insulin sensitivity value that lay within the range weight gain, and the absolute concentrations tended to be
previously reported for diabetic cats (33). Fasting hyper- higher than in obese female cats. Data for other species suggests

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 NATURE OR NURTURE? 2075S

that low insulin sensitivity contributes to obesity by shifting sources (sorghum and corn vs. rice). When compared with the
energy metabolism from muscle to fat as hypothesized by the sorghum/corn-based diet, cats fed the rice-based diet consumed
thrifty gene theory (16). more energy and gained more weight in response to free-access
Second, male cats are predisposed to obesity (50–52). In our feeding. Cats fed the rice-based diet also tended to have higher
study (27), cats were allowed free access to food over ;10 mo. blood glucose concentrations and insulin secretion in response
Male cats gained more weight (54 vs. 39% body weight) and to a glucose load or a test meal.
were significantly heavier after weight gain than female cats Foods that produce relatively rapid and high postprandial
(7.26 vs. 5.69 kg), although their initial body weights were not glucose and insulin responses (high glycemic index foods) have
significantly different (4.78 vs. 4.12 kg) (27). Male cats also had been associated with lessened satiety and greater subsequent
a significantly higher fat mass (3.2 vs. 2.3 kg) and lean body food intake in people (58–60). Thus, consumption of high
mass (4.1 vs. 3.4 kg) compared with female cats, which glycemic index foods may lead to increased hunger and
reflected their higher weight gain. Our study also showed that promote overeating and weight gain. As carnivores, feral cats
the greater the fat mass, the less effective insulin was in consume high levels of dietary protein and are not naturally
reducing plasma glucose. These findings of lower insulin adapted to eating large quantities of dietary carbohydrate (61).
sensitivities and higher insulin concentrations in male cats It could be theorized that feeding cats a high-carbohydrate diet,
may explain why male cats have a greater risk of developing particularly if it is sourced from rice, may result in increased
obesity and diabetes than female cats (3). Excess energy intake, insulin secretion and lead to reduced satiety and increased food
obesity, and inactivity may contribute to or interact with these intake. When fed over the long term, such a diet could be
underlying defects in male cats and ultimately lead to the considered a factor in the etiology of feline obesity and may
development of diabetes. contribute to the maintenance of excess body weight in
overweight cats. In some cats, particularly those with un-
Diet and development of type 2 diabetes derlying low insulin sensitivity, life-long consumption of a high
glycemic index diet (such as a rice-based diet) may also
Traditionally, human diets recommended for the prevention contribute to premature b-cell ‘‘burnout’’ and diabetes by in-
of obesity and diabetes were rich in readily digestible creasing the animals’ overall demand for insulin secretion.
carbohydrates and fiber and low in fat (53). Recently, this Feeding a diet with a low glycemic load may exert a protective
recommendation has been questioned. It is hypothesized that role against the development of obesity, impaired glucose
chronic ingestion of a high-carbohydrate diet promotes obe- tolerance, and diabetes, and may prove beneficial for managing
sity and increases the demand on b-cells for insulin secretion, feline obesity and diabetes.
thereby predisposing individuals to hyperinsulinemia, apo-
ptosis, b-cell failure, and development of type 2 diabetes (21).
The effects of dietary macronutrients were recently eval- Dietary supplements and development of
uated in healthy cats (54). Three test diets were used that were diabetes: chromium
high in protein (46% of energy), fat (47% of energy), or car-
bohydrate (46% of energy). The two lesser macronutrients Chromium is an essential trace element that is required for
contributed approximately equally to energy. Cats fed the high- normal carbohydrate and lipid metabolism (62). It is thought
carbohydrate diet had significantly higher mean and peak (23– (63) that chromium improves glucose tolerance by increasing
32%) glucose concentrations and tended to have higher insulin insulin sensitivity: with greater insulin effectiveness, blood
concentrations than cats fed either the high-protein or the glucose concentrations decrease.
high-fat diet (54). Consequently, feeding a high-protein, low- We recently investigated (64) the effect of dietary chro-
carbohydrate, moderate-fat diet to cats at risk of diabetes may mium supplementation on glucose and insulin metabolism in
be beneficial. Feeding diabetic cats a very low-carbohydrate, healthy, nonobese cats. Results demonstrated that the incor-
high-protein diet improved hyperglycemia, reduced insulin poration of chromium tripicolinate at 300 and 600 parts per
dosage, and increased the rate of diabetic remission (55). billion in the ration of healthy cats produced small but signif-
Although diet was not found to be a significant risk factor icant improvements in glucose tolerance as measured by glucose
in the study of 66 Burmese cats, diets supplemented with half-life, area under the glucose curve, and absolute glucose
high-protein, low-carbohydrate foods such as meat or fish concentrations.
approached significance in protecting against diabetes (20). Based on the understanding that chromium is an essential
There was a trend in Burmese cats for diabetes to be associated nutrient and not a therapeutic drug, only individuals with
with treatment for renal disease, which typically includes suboptimal chromium nutrition would be expected to respond
a restricted-protein, high-carbohydrate diet. Owners of diabetic to chromium supplementation (65). However, .90% of typical
Burmese cats also tended to describe the cat as a ‘‘greedy eater.’’ diets consumed by people in the USA contain daily chromium
A direct nutritional role in human type 2 diabetes is evident concentrations below the recommended minimum daily intake
from large epidemiologic studies and it is important in primate for dietary chromium level (66). Presently, there are no
and rodent models of the disease (56). guidelines for recommended daily chromium intake in cats
(67). Before and during the trial, cats in our study consumed
Carbohydrate source and diabetes complete and balanced diets that met the Association of
American Feed Control Officials standards for adult mainte-
Ingestion of different sources of carbohydrate (such as rice) nance, and were expected to contain adequate chromium
has been shown to increase the demand for insulin in cats and levels. However, the response in our study suggests that cats
could potentially contribute to b-cell failure in susceptible cats that consume such diets may still have marginal chromium
when fed long term. The impact of the dietary carbohydrate intake and may benefit from supplementation.
source on food intake, glucose and insulin concentrations, and Because of its trend to improve glucose tolerance, cats most
insulin sensitivity in overweight cats with reduced insulin likely to benefit from chromium supplementation are those
sensitivity was assessed (57) using two diets formulated to with glucose intolerance and insulin resistance from lack of
contain similar starch content (33%) from different cereal exercise, obesity, and old age; cats with underlying low insulin

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sensitivity; or cats that are genetically at risk of diabetes (e.g., The etiology of b-cell destruction in diabetic dogs is often
Burmese cats) (13,14). unknown, although there is evidence that it is frequently
caused by immune-mediated processes similar to human type 1
Conclusion diabetes (70–72,82–84). Inflammatory cell infiltration of
pancreatic islets occurs in 46% of diabetic dogs (83), and
Strong evidence exists in cats to suggest that diabetes is the ;50% of diabetic dogs have circulating antibodies against
result of a combination of genetic and environmental factors. b-cells (70–72). These antibodies target insulin or an antigen in
Obesity, physical inactivity, diet, concurrent illness, and drug the b-cell membrane and may be either a cause or
intake appear to be the most common predisposing factors. a consequence of b-cell destruction. Recently, a radioimmuno-
Genetic factors play a role in feline diabetes, but the genes precipitation assay was developed to detect antibodies to
involved are still to be elucidated. It is likely that the genes will recombinant canine glutamic acid decarboxylase and insuli-
be first identified in Burmese cats based on evidence of their noma antigen-2 (84,85). This assay has the potential to provide
genetic predisposition. evidence for true ‘‘autoimmunity’’ in canine diabetes.
Autoantibodies to both pancreatic antigens have been
Canine diabetes: nature or nurture? identified in a proportion of canine diabetic patients (84) and
the prevalence, kinetics, and significance of these antibodies
Diabetes mellitus is one of the most frequent endocrine are being established.
diseases affecting middle-aged and older dogs, and the
prevalence is increasing. Thirty years ago, 19 in 10,000 dogs
visiting veterinary hospitals were diagnosed with diabetes Genetic factors in type 1 diabetes
(68,69). By 1999, the prevalence in the same veterinary
Human type 1 diabetes is principally a disease of Caucasians,
hospitals had increased threefold to 58 per 10,000 dogs (69). At
and the major genetic susceptibility is linked to the major
present, there are no internationally accepted criteria for the
histocompatibility complex alleles on the leukocyte antigen
classification of canine diabetes. No laboratory test is readily
gene on chromosome 6p, although many other genes contribute
available to identify the underlying cause of diabetes in dogs,
(74). Evidence is mounting for a similar genetic basis for canine
and diagnosis is generally made late in the disease course. If the
diabetes. Breed predisposition exists (68,69,86), and familial
criteria established for human diabetes are applied to dogs, at
predisposition is reported in Samoyed dogs (87) and Miniature
least 50% of diabetic dogs would be classified as type 1, because
Poodles (88) and is documented by the authors in Rottweiler
this proportion has been shown to have antibodies against
dogs. Preliminary sequence analysis of the dog leukocyte
b-cells (70–72). The remainder probably has ‘‘other specific
antigen (DLA) gene in a heterogeneous population of canine
types of diabetes’’ that result from pancreatic destruction or
diabetics revealed that one haplotype is overrepresented
chronic insulin resistance, or they have diestrus-induced
(84,89). This haplotype has sequence similarities to human
diabetes.
major histocompatibility complex alleles associated with
susceptibility to type 1 diabetes (89). Dogs with this one
Cause of type 1 diabetes DLA haplotype are three times more likely to develop diabetes
than dogs with other haplotypes. The association between
Type 1 diabetes appears to be the most common form of
canine diabetes and the major histocompatibility complex in
diabetes in dogs, and is characterized by pancreatic b-cell
a heterogeneous population strongly suggests that both
destruction that leads to absolute insulin deficiency. In people,
a genetic predisposition and the immune response have roles
this usually occurs via cell-mediated autoimmune processes and
in the pathogenesis of diabetes in dogs (84).
is associated with multiple genetic predispositions and poorly
defined environmental factors (1). Similar to canine diabetes,
the incidence rate of type 1 diabetes in people is rising (73), Environmental factors in type 1 diabetes
a trend that has been explained on the basis of increased
contacts with adverse environmental factors acting on Although genetic susceptibility appears to be a prerequisite
a background of complex genetic factors (74). The rate of in type 1 diabetics, multiple environmental factors likely
progression to absolute insulin deficiency is quite variable in initiate b-cell autoimmunity, which, once begun, proceeds by
humans. It can be rapid in young children and much slower in common pathogenic pathways (74). b-Cell autoimmunity
middle-aged and older people. This latter group has the latent probably propagates continuing destruction of b-cells and
autoimmune diabetes of adults (LADA) form of type 1 prevents islet cell regeneration after injury (90). Although the
diabetes, which is characterized by gradual b-cell destruction rate of progression is irregular, accelerated b-cell destruction
over months or years and is not associated with obesity (75). may occur just before diagnosis (74). This may be due to
Distinct autoantibody patterns are recognized in the acute environmental influences, because human type 1 diabetes is
onset and slowly progressive (LADA) forms of human type 1 diagnosed more frequently in autumn and winter (91,92).
diabetes (75,76), which indicates a different pathogenesis for Interestingly, a highly significant seasonal incidence of di-
the two forms of the disease. The majority of diabetic dogs have agnosis of canine diabetes also exists and the incidence peaks in
absolute insulin deficiency (77–80). The rate of progression to winter (93).
absolute insulin deficiency has not been studied in dogs, but Specific environmental risk factors have not yet been
epidemiological factors closely match those of human patients evaluated in diabetic dogs, and prospective epidemiological
with the LADA form of type 1 diabetes, who are usually not investigation of affected animals and age-matched nondiabetic
obese and tend to be middle aged and older. Most affected dogs controls is indicated. The association between canine diabetes
are .7 y of age, and the onset of clinical signs is typically and pancreatitis warrants particular attention, because b-cell
insidious, ranging from weeks to months in duration (81). This autoimmunity, pancreatic inflammation, and regulation of gut
prompted speculation that there may also be similarities immunity may be linked in disease pathogenesis. The gut
between the pathogenesis of canine diabetes and human immune system likely plays a central role in the pathogenesis of
LADA. type 1 diabetes, because accumulating evidence suggests that

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affected people have aberrant regulation of gut immunity Obesity-induced insulin resistance in dogs
(94,95). The gut and the pancreas are probably immunolog-
ically as well as anatomically linked and influenced by There are no well-documented studies that convincingly
environmental factors such as intestinal microflora, infections, demonstrate that type 2 diabetes is a significant disease entity
and dietary factors (94). Two environmental risk factors that in dogs.
are frequently implicated in type 1 diabetes, enteroviral Although obesity causes insulin resistance in dogs, there are
infections and exposure to cow’s milk proteins, both trigger no published data that clearly indicate obesity is a risk factor for
the gut immune system (95). canine diabetes. No epidemiological data examining the
relationship between canine diabetes and obesity have been
published since 1960 (113), and an association between obesity
and diabetes in dogs is not presently recognized. Obesity is
Association between diabetes and pancreatitis in dogs a well-established risk factor for type 2 diabetes in cats and
people. In contrast, dogs are not reported to develop a form of
Extensive pancreatic damage, which likely results from chronic diabetes analogous to type 2 diabetes. In dogs, obesity causes
pancreatitis, is responsible for the development of diabetes insulin resistance (114–116), which leads to hyperinsulinemia
in ;28% of diabetic dogs (83). Chronic pancreatitis is recog- and impaired glucose tolerance (117,118). These effects are
nized as a distinct cause of diabetes in people, because affected particularly pronounced when obesity is induced by feeding
insulin-dependent individuals do not have the immunolo- a diet high in saturated fat (119). Dogs fed a high-fat diet
gical phenomena or the association with leukocyte antigen develop insulin resistance that is not compensated for by in-
alleles that characterize type 1 diabetes (96). Lack of humoral creased insulin secretion, resulting in more severe glucose
immunity may contribute to the slower rate of destruction intolerance (120). Despite the evidence that obesity causes
of b-cells in people with chronic pancreatitis compared with impaired glucose tolerance, it appears that very few dogs
those with type 1 diabetes (97). The rate of progression of develop overt diabetes as a consequence of obesity-induced
b-cell loss is being investigated in dogs with chronic pan- insulin resistance.
creatitis using sequential glucagon-stimulation tests (84). There are no published studies investigating whether obesity
Preliminary findings indicate that some dogs with chronic is a risk factor for dogs with absolute insulin deficiency, which
pancreatitis have reduced b-cell function and appear to be represent the majority of diabetic dogs. The only study to
prediabetic. examine the effects of obesity in diabetic dogs used animals
Although extensive pancreatic damage is responsible for the with relative insulin deficiency (117). Unfortunately, the study
development of diabetes in 28% of diabetic dogs, evidence of used mostly intact bitches. Because 13 of the 15 diabetic dogs
acute or chronic pancreatitis is found in a larger proportion with residual b-cell function were female and most if not all
(;40%) of diabetic dogs (81,98–104). It is possible that were intact females, they most likely had diestrus-induced
pancreatitis plays a role in the development of b-cell diabetes rather than type 2 diabetes (117,121). The study
autoimmunity in genetically susceptible dogs or, alternatively, reported that obesity caused insulin resistance that resulted in
the diabetic state may be a risk factor for pancreatitis. hyperinsulinemia and glucose intolerance, but these findings
Hypertriglyceridemia was proposed as a possible inciting cause were confounded by the insulin resistance associated with
of canine pancreatitis (105) and is commonly seen in diabetic elevated progesterone and growth hormone concentrations
dogs (81). Comparison of the incidence of pancreatitis in that occurs in intact bitches. Therefore, the effect of obesity-
diabetic dogs with that of age-matched nondiabetic dogs would induced insulin resistance cannot be separated from diestrus-
help to clarify its role in the pathogenesis of canine diabetes. induced insulin resistance in this study. Investigation of the role
Obesity affects one quarter to one third of dogs presented to of obesity in diabetic dogs with no underlying diestrus- or
veterinary practices (106–108) and is associated with an in- hyperadrenocorticism-associated insulin resistance still needs
creased risk of pancreatitis (104). As pancreatitis appears to be to be performed.
a common cause of diabetes in dogs (83), this relationship
between obesity and pancreatitis in dogs has relevance to the
pathogenesis of canine diabetes. Environmental factors such as Diestrus- and gestation-associated diabetes
the feeding of high-fat diets that result in lipemia and
Gestational diabetes is another classification of diabetes
disturbances in lipid metabolism are implicated as potential
recognized in humans. In women, it is defined as any degree of
etiological factors in dogs with obesity-associated pancreatitis
glucose intolerance with onset or first recognition during
(109) and likely play a role in the development of pancreatitis
pregnancy (1). If overt diabetes persists after the pregnancy
in diabetic dogs.
ends, then it is reclassified as type 1, type 2, or another specific
type of diabetes. Reduced insulin sensitivity occurs in healthy
bitches by d 30–35 of gestation (122) and becomes more severe
Role of insulin resistance in canine diabetes during late pregnancy (123). The diestrus phase of the
nonpregnant cycle of the bitch is similar in duration to the 9
Diabetes induced by insulin-resistance states are less wk of pregnancy, and it is generally agreed that the hormone
common ‘‘other specific types’’ of canine diabetes. Disease profiles during diestrus and pregnancy are essentially identical
conditions such as hyperadrenocorticism (110) and acromegaly (123–125). However, the reduction in insulin sensitivity is
(111) result in insulin resistance and may induce diabetes in more pronounced during pregnancy than during diestrus (122),
dogs. Iatrogenic causes of insulin resistance that may lead to and the alteration in the metabolic control of growth hormone
induced diabetes include chronic corticosteroid therapy (112). during gestation may in some way be pregnancy-specific in dogs
As most dogs do not develop overt diabetes with chronic cor- (123). Nevertheless, progesterone elevation does cause glucose
ticosteroid therapy or spontaneous hyperadrenocorticism, for intolerance and overt diabetes during diestrus in bitches
overt diabetes to develop may require underlying reduced (126,127). Progesterone also stimulates the mammary gland
b-cell function that results from immunological processes or of bitches to produce growth hormone, which is a potent
chronic pancreatitis. inducer of insulin resistance (111). Consequently, if diabetes is

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diagnosed in a bitch during either pregnancy or diestrus, it autoimmunity, pancreatic inflammation, and regulation of gut
probably should be classified as being comparable to human immunity may be linked in disease pathogenesis.
gestational diabetes. If diabetes persists after the pregnancy or
diestrus ends, then it should be reclassified as type 1 or another
specific type of diabetes. The periodic influence of diestrus- Conclusion
associated insulin resistance may contribute to the increased
risk for developing diabetes in female compared with male dogs In conclusion, genetic and environmental factors play a role
(68,69) and highlights the role that environmental influences in both canine and feline diabetes. In cats particularly,
may play in the pathogenesis of canine diabetes. preventative programs aimed at promoting physical activity
and ideal body condition are likely beneficial in reducing the
risk of diabetes.
Juvenile-onset diabetes in dogs
An inherited early-onset form of diabetes characterized by
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