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Time Trends and Risk Factors for Diabetes Mellitus in Dogs: Analysis of Veterinary Medical Data Base Records (1970–1999)
The Veterinary Journal 2003, 165, 240–247 doi:10.1016/S1090-0233(02)00242-3
Time Trends and Risk Factors for Diabetes Mellitus in Dogs: Analysis of Veterinary Medical Data Base Records (1970–1999) L. GUPTILL , L. GLICKMANà and N. GLICKMAN§
Department of Veterinary Clinical Sciences, Purdue University, West Lafayette, IN 47907, USA, Department of Veterinary Pathobiology, Purdue University, West Lafayette, IN 47907, USA, §The Center for Human–Animal Interaction, Purdue University, West Lafayette, IN 47907, USA à
SUMMARY The objectives of the study were to identify recent trends in the prevalence of diabetes mellitus (DM) in dogs and to identify host risk factors. Veterinary Medical Data Base (VMDB) electronic records of 6860 dogs with a diagnosis of DM (VMDB code 870178500) between 1970 and 1999 were evaluated to determine time trends. Records of 6707 dogs with DM and 6707 frequency matched dogs with any diagnosis other than DM from the same teaching hospitals in the same year, selected as controls, were evaluated for risk factor analysis. The prevalence of DM in dogs presented to veterinary teaching hospitals increased from 19 cases per 10,000 admissions per year in 1970 to 64 cases per 10,000 in 1999, while the case-fatality rate decreased from 37% to 5%. The hospital prevalence of DM was consistently greater over time in older compared with younger dogs with the highest prevalence occurring in dogs 10–15 years of age. Dogs weighing <22:7 kg had a significantly (P < 0:001) greater risk of DM compared with heavier dogs. Female dogs had an increased risk of DM compared with males (P < 0:001). Ó 2002 Elsevier Science Ltd. All rights reserved.
KEYWORDS: Diabetes mellitus; epidemiology; dog; endocrinology.
INTRODUCTION Spontaneous diabetes mellitus (DM) is reported in most dog breeds and in mixed breed dogs (Feldman & Nelson, 1996). Canine DM is generally classified as insulin dependent or non-insulin dependent. However, whether dogs have type I or type II DM as described in human beings is rarely determined (Feldman & Nelson, 1996). Type I DM is characterized by insulin deficiency resulting from destruction or loss of b cells of the islets of Langerhans and type II DM by insulin resistance and/or inadequate insulin production or secretion by b cells (Feldman & Nelson, 1996). Most diabetic dogs are thought to have a disease most like human type I DM and are insulin dependent (Feldman & Nelson,
Correspondence to: L. Guptill, Department of Veterinary Clinical Sciences, 1248 Lynn Hall, Purdue University, West Lafayette, IN 47907, USA. Tel.: 1-765-496-3881; fax: 1-765-4949830; E-mail: [email protected]
1996). Unlike human type I DM, however, DM in dogs is more likely to occur later in life. It has been proposed (Kaneko et al., 1977, Feldman & Nelson, 1996) that DM in adult dogs progresses through several stages beginning with impaired glucose tolerance, followed by non-insulin dependent stages resembling type II DM of human beings, and finally an insulin dependent disease comparable to type I insulin dependent DM of human beings. The aetiology of DM in dogs is probably multifactorial. Factors including obesity, diet, exposure to toxic chemicals or drugs that cause insulin resistance, immune-mediated destruction of islet cells, and destruction of islet cells secondary to pancreatitis may all play a role. While genetic factors probably influence susceptibility, specific genes and inheritance patterns have not been identified in most dog breeds. Multiple genetic and environmental factors have been implicated in the pathogenesis of types I and II DM in human beings, yet modes of inheritance and interaction of
1090-0233/02/$ - see front matter Ó 2002 Elsevier Science Ltd. All rights reserved.
EPIDEMIOLOGY OF DIABETES MELLITUS IN DOGS
genetic and environmental factors in that species are still not completely understood (Unger & Foster, 1998). Previous epidemiological studies (Feldman & Nelson, 1996; Marmor et al., 1982) have reported that most diabetic dogs are between four and 14 years of age, and that females are at increased risk compared with males. Breeds previously reported to have a higher risk for developing DM include Keeshond, Alaskan Malamute, Puli, Cairn Terrier, Fox Terrier, Manchester Terrier, Miniature Pinscher, Toy and Miniature Poodle, Finnish Spitz, Schipperke, and Miniature Schnauzer. Pekingese, German Shepherds, Collies, and Boxers are reportedly at decreased risk (Marmor et al., 1982; Feldman & Nelson, 1996; Hess et al., 2000). The purpose of the study reported here was to identify temporal trends in the hospital prevalence of DM in dogs using the Veterinary Medical Data Base (VMDB), and to further characterize host risk factors using a large sample size. The VMDB, established in 1964 by the National Cancer Institute, is comprised of abstracted medical records from 24 participating veterinary teaching hospitals in the United States and Canada.
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tical significance for the decrease in case-fatality percentage. Seasonal occurrence was evaluated by grouping dogs with DM seen at the participating institutions during the four seasons of the year as follows: Spring ¼ March–May; Summer ¼ June–August; Autumn ¼ September–November; Winter ¼ December–February. Age-specific hospital prevalence was determined by calculating the prevalence of DM in each age group of dogs. The number of dogs with DM in each age group was divided by the total number of dogs in that age group. Potential risk factors including breed, gender, neuter status, and weight were calculated using univariate and multivariate logistic regression (SAS, Cary, NC). Weight is included in VMDB records only as a categorical variable; actual dog weight is not available. An odds ratio and 95% confidence limits for each potential risk factor were determined (SAS, Cary, NC). A P value <0.05 was considered significant. The individual breed risks of DM were calculated for breeds having a minimum of 25 cases or controls using univariate logistic regression. RESULTS
MATERIALS AND METHODS The VMDB was searched for records of first hospital visits of dogs with DM (VMDB code 870178500) for the period from January 1, 1970 to December 31, 1999 (the last year for which data entry from participating institutions was thought to be complete). Control records for risk factor analysis were selected from first hospital visits of dogs with any diagnosis other than DM. Controls were frequency matched to cases by year, institution, and age group. Age is included in VMDB records only as a categorical variable; actual dog age is not available. Records of all diabetic dogs seen over the 30 year period were used to calculate the hospital prevalence of DM (number of cases per 10,000 total dogs seen per year), the age-specific hospital prevalence of DM, the case-fatality percentage, and the seasonal occurrence of DM. Statistical significance of time trends was evaluated using a v2 test for linear trend (SAS, Cary, NC). The case-fatality per cent was calculated by dividing the total number of dogs with DM that died or were euthanased in a given year by the total number of dogs with DM in that year multiplied by 100. A v2 test for linear trend was applied to the total number of deceased DM cases to determine statis-
Diabetes mellitus was diagnosed in 6860 dogs of the 1,847,786 dogs whose VMDB records were available for the 30-year period between January 1, 1970 and December 31, 1999 (hospital prevalence for the 30year period: 37 cases/10,000 dogs examined; 95% confidence limits (CL) 36–38 cases per 10,000 dogs examined). The age distribution of dogs with DM was as follows: 154 (2.2%) dogs with DM aged <1 year, 46 (0.67%) aged 1–2 years, 195 (2.8%) aged 3–4 years, 1058 (15.4%) aged 5–7 years, 2543 (37.1%) aged 8–10 years, 2690 (39.2%) aged 11–15 years, and 121 (1.8%) over the age of 15 years. There were 53 (0.77%) dogs for which age information was missing. The hospital prevalence of DM in dogs included in the VMDB increased significantly (P < 0:00001) over the 30-year period (Fig. 1), from 19 cases per 10,000 hospital admissions in 1970–1974 (95% CL 17–21 cases per 10,000), to 58 cases per 10,000 in 1995–1999 (95% CL 55–61 cases per 10,000; Fig. 1). The highest prevalence of DM occurred in dogs 10– 15 years of age (Fig. 2). Dogs over 10 years of age comprised a greater proportion of dogs presented to the participating teaching hospitals in 1999 (17.5%) than they did in 1970 (6.25%). The agespecific prevalence of DM increased in most age groups during the study period (Fig. 2).
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Fig. 1. Hospital prevalence of canine diabetes mellitus (DM), VMDB 1970–1999. Prevalence of DM increased over the study period. The number of institutions for which data are recorded is lower from 1995 to 1999 (16 institutions in 1994, 13 in 1995, 12 each in 1996–1997, 11 each in 1998–1999), therefore the number of cases per year is lower in these years.
Fig. 2. Age-specific hospital prevalence of canine diabetes mellitus (DM), VMDB 1970–1999. The highest prevalence of DM was in the 10–15 year age group. Diabetes mellitus prevalence increased in most age groups.
There was a steady and significant decrease (P < 0:00001) in the case-fatality per cent over time (Fig. 3). There was no apparent seasonal pattern in the prevalence of DM in dogs (data not shown). The records of 6807 diabetic dogs of known age and 6807 frequency matched controls were used to conduct risk factor analyses. Significant risk factors in univariate analysis included being a mixed versus pure breed, female versus male, neutered versus intact male, and weight being <22.7 kg. All potential
Fig. 3. Case-fatality percentage for canine diabetes mellitus (DM), VMDB 1970–1999. The case-fatality per cent for dogs with DM decreased steadily between 1970 and 1999.
risk factors were included in the multivariate model. Odds ratios did not change substantially between the univariate and multivariate analyses, indicating that there was not confounding between the variables. Multivariate analysis (Table I) showed that pure-bred dogs as a group were at a decreased risk of DM compared with mixed breed dogs (P ¼ 0:002), although the risk of DM was decreased for some breeds and increased for others (Table II). The breed at highest
EPIDEMIOLOGY OF DIABETES MELLITUS IN DOGS
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Table I Summary of potential risk factors for diabetes mellitus (DM), multivariate analysis by logistic regression (Veterinary Medical Data Base, 1970–1999) DM cases Breed Pure breed Mixed breed Gendera Female Male Neuter statusb Female neutered Female intact Male neutered Male intact Weight (kg)c 1–6.8 6.8–13.6 13.6–22.7 22.7–34.1 34.1–45.4 >45.4
Controls
Odds ratio
95% confidence limits
P value
4947 1860
5198 1609
0.86 1.00
0.78, 0.94 Reference group
0.002
4229 2553
3524 3238
1.37 1.00
1.27, 1.49 Reference group
<0.001
3000 1227 1271 1282
2498 1023 1094 2144
0.99 1.00 1.91 1.00
0.89, 1.12 Reference group 1.68, 2.17 Reference group
0.98
1336 2031 884 720 308 98
955 1212 960 1287 651 206
2.62 3.15 1.67 1.05 0.93 1.00
2.03, 3.39 2.45, 4.06 1.28, 2.17 0.81, 1.36 0.71, 1.24 Reference group
<0.001
<0.001 <0.001 <0.001 0.69 0.66
Records of 6707 cases and 6707 controls were evaluated. Controls are dogs presented to the same teaching hospitals in the same year as cases, for any condition other than DM. a Gender information missing for 25 cases and 45 controls. b Neuter status missing for two female cases and three female controls. c Weight information missing for 1430 cases and 1536 controls.
risk of DM was the Australian Terrier (odds ratio ¼ 32.1) while the Boxer breed had the lowest risk (odds ratio ¼ 0.07). Female dogs were at an increased risk compared with male dogs (P < 0:001). Neutered male dogs were at a significantly greater risk than intact male dogs (P < 0:001), but there was no significant difference in risk between neutered and intact females (P ¼ 0:98). Dogs weighing <22:7 kg were at an increased risk of DM compared with dogs weighing >45:4 kg (P < 0:001). DISCUSSION The findings of this study indicate that the hospital prevalence of DM in dogs presented to veterinary teaching hospitals in North America has increased since 1970 despite the fact that diagnostic methods and clinical and laboratory criteria for DM have not changed appreciably over this time period. This suggests that the increased hospital prevalence is not a result of changes in clinical practice, but rather reflects a true increase in the incidence of DM in the owned dog population. The dogs in the
VMDB are mostly referred from private veterinary hospitals. There may have been changes in referral patterns not discernible from these data that could further explain the increased hospital prevalence. It is unlikely that there were decreases in prevalence of enough other illnesses seen at participating hospitals to alter the proportional morbidity of DM; records do not indicate a decrease in other common illnesses such as renal failure, hypothyroidism, or hyperadrenocorticism (unpublished data). The decreasing case-fatality per cent over time suggests that owners and veterinarians are now more willing than previously to undertake long-term management of diabetic dogs. Recent advances in nutritional management of diabetes mellitus in dogs (Nelson et al., 1998; Fleeman & Rand, 2001) and increased availability of client education materials have probably contributed to the apparent increased willingness of both owners and veterinarians to manage this chronic disease in pet dogs. Increased awareness by veterinarians of the importance of managing concurrent problems such as urinary tract infections and dental disease also
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Table II Breeds with a significantly (P < 0:05) decreased or increased risk of diabetes mellitus (Veterinary Medical Data Base, 1970–1999) Breed
DM cases
Australian Terrier 37 Standard Schnauzer 105 Samoyed 175 Miniature Schnauzer 624 Fox Terrier 91 Keeshond 57 Bichon Frise 50 Finnish Spitz 35 Cairn Terrier 67 Miniature Poodle 737 Siberian Husky 80 Toy Poodle 208 Mixed breed 1860 Beagle 73 English Setter 30 Labrador Retriever 246 Basset Hound 33 Dalmatian 28 Doberman Pinscher 109 Irish Setter 68 Boston Terrier 31 Shih Tzu 31 Brittany Spaniel 28 Old English Sheepdog 14 Norwegian Elkhound 10 Golden Retriever 108 English Pointer 11 Cocker Spaniel 90 Great Dane 15 Bulldog 7 Shetland Sheepdog 29 Collie 25 Pekingese 14 German Shepherd 70 Airedale Terrier 8 German Short-Hair Pointer 6 Boxer 7
Controls 1 19 45 172 26 20 18 13 28 356 45 139 1609 94 42 364 50 45 182 121 68 69 64 35 26 294 36 307 54 26 107 109 66 365 45 37 82
Odds ratio 32.10 4.78 3.36 3.13 3.02 2.45 2.40 2.32 2.07 1.79 1.53 1.29 1.00 0.67 0.61 0.58 0.57 0.53 0.51 0.48 0.39 0.38 0.37 0.35 0.33 0.31 0.26 0.25 0.24 0.23 0.23 0.19 0.18 0.16 0.15 0.14 0.07
95% confidence limits 4.36, 233.53 2.91, 7.82 2.40, 4.69 2.61, 3.76 1.94, 4.70 1.47, 4.12 1.39, 4.13 1.22, 4.41 1.32, 3.23 1.55, 2.06 1.06, 2.22 1.03, 1.62 Reference group 0.49, 0.91 0.38, 0:99 0.49, 0.69 0.36, 0.89 0.33, 0.86 0.40, 0.66 0.35, 0.65 0.25, 0.60 0.25, 0.59 0.24, 0.59 0.19, 0.65 0.16, 0.69 0.25, 0.40 0.13, 0.52 0.19, 0.32 0.14, 0.43 0.10, 0.54 0.15, 0.35 0.12, 0.30 0.10, 0.33 0.12, 0.21 0.07, 0.33 0.06, 0.33 0.03, 0.16
P value <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 0.001 0.008 0.001 <0.001 0.02 0.02 0.01 0.04 <0.001 0.01 0.01 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 0.002 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001
Breeds were included in this analysis if there were at least 25 cases or 25 controls. Controls are dogs presented to the same teaching hospitals in the same year as cases, for any condition other than DM. Odds ratios were calculated using univariate logistic regression.
probably contributes to the increased success of long-term management of DM and therefore increased willingness of owners and veterinarians to treat dogs with DM. The lack of an apparent seasonal pattern in the occurrence of DM in dogs is in agreement with a previous report (Marmor et al., 1982) and does not
support an infectious aetiology such as has been proposed for Type I IDDM in human beings (Unger & Foster, 1998). However, the lack of an obvious seasonal pattern in the frequency of DM in dogs in the VMDB may be a result of the referral nature of the practices, in that the month in which a dog with DM is presented to a teaching hospital may be
EPIDEMIOLOGY OF DIABETES MELLITUS IN DOGS
unrelated to when the dog was initially affected with the disorder. Nevertheless, if time between initial diagnosis of DM and presentation of a dog with DM to a referral institution is a random event, then a strong seasonal pattern might have been detected in this large sample of dogs with DM. Many dog breeds reportedly at increased risk of DM in previous studies (Marmor et al., 1982; Hess et al., 2000) were also found to be at increased risk in the study reported here. The current study reports on a larger sample of diabetic dogs, and identified four additional breeds at statistically significantly increased risk of DM (Bichon Frise, Australian Terrier, Siberian Husky, and Standard Schnauzer). Some breeds previously reported to be at increased risk of DM were not found to be at increased risk in this study (Malamute, Schipperke, Puli, Miniature Pinscher, Manchester Terrier). Four Northern (Wilcox & Walkowicz, 1995), or husky-type breeds (Keeshond, Samoyed, Finnish Spitz, and Siberian Husky) were among the 12 breeds identified as being at significantly increased risk of DM. Two Northern breeds, Samoyeds and Alaskan Malamutes, were also found to be at increased risk in another study (Marmor et al., 1982). In contrast, only one Northern breed (Norwegian Elkhound) was among the 24 breeds identified as having a significantly decreased risk of DM. Whether this suggests a genetic predisposition or reflects environmental influences is not known. No single genetic factor responsible for adult-onset DM has been reported in any of these breeds. However, there is one report of apparently familial adult-onset DM in five Samoyed dogs (Kimmel et al., 2000). These five dogs were between 3.5 and 7.8 years of age when DM was diagnosed and three of the dogs were from a single litter. Two other dogs came from another litter not known to be related to the first three dogs. In human beings, the risk of insulindependent DM varies with geographical area (Unger & Foster, 1998), and was higher in Finland compared with Asian countries and one area in the United Stated (Drash, 1990). One animal species (Psammomys obesus; the gerbil) at increased risk for DM is thought to have evolved metabolic mechanisms for maintenance of normoglycaemia when faced with periods of minimal nutrient availability. Similar metabolic mechanisms are thought to exist in certain human populations at increased risk for type II DM (Kalman et al., 2000; Unger & Foster, 1998). It is possible that a similar metabolic mechanism exists in some Northern dog breeds, whose ancestors were bred to
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survive seasonal periods of minimal nutrient availability. Exactly what characterizes the above metabolic genotype in animals or human beings has not been determined, but several candidate genes have been investigated (Unger & Foster, 1998). Interactions of environment and genetic susceptibility are considered likely to result in the development of DM in human beings (Drash, 1990) There may be a single genetic factor responsible for development of congenital DM in some breeds. For example, there are histopathological differences in pancreata of dogs with DM that are less than one year of age, compared with dogs that have adult onset DM. Dogs <1 year of age (presumably congenital DM) had islet cell hypoplasia or aplasia (Kramer et al., 1988, 1980; Atkins et al., 1988; Williams et al., 1981) whereas dogs with adult onset DM had evidence of inflammatory cell infiltration and destruction of islets (Atkins et al., 1988). An autosomally recessively inherited islet hypoplasia is reported in Keeshond (Kramer et al., 1988). The mode of inheritance for islet cell hypoplasia in other breeds has not been established (Kramer et al., 1980; Williams et al., 1981). Female dogs were found be at greater risk of DM than male dogs, as other investigators have also reported (Marmor et al., 1982). Neutered male dogs were found to be at increased risk of DM compared with intact male dogs. Records in VMDB do not specify actual dog age, whether dogs were neutered before or after the diagnosis of DM was made, or the age at which a dog was neutered. Therefore, it cannot be determined for certain whether there is a true increased risk for neutered males, or whether the increased risk occurred because males were neutered later in life, when DM is most likely to occur. An increased risk of DM for neutered males was also identified in a previous study using VMDB records (Marmor et al., 1982). Neutered dogs may be at an increased risk for obesity (Edney & Smith, 1986), and this may to some extent explain their increased risk for development of DM. Obesity was identified as the most important factor influencing glucose tolerance and insulin response in both healthy and diabetic dogs (Mattheeuws et al., 1984). Investigation of glucose tolerance and insulin response in obese and nonobese neutered dogs compared with obese and nonobese intact dogs may help to determine whether neuter status has an effect on glucose and insulin homeostasis independent of obesity. Information concerning diet is not included in the VMDB, nor is actual dog weight, precluding evaluation of the body condition of dogs in this study.
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Prospective studies are required specifically to evaluate the role of diet and obesity in the development of canine DM. The association of an increased risk of DM with smaller body size may reflect as yet unidentified genetic factors, or it may reflect the diets of these dogs. The results of one study show that pet dogs have a relatively increased consumption of canned dog food and table foods as body size decreases, and that these diets are associated with a higher proportion of calories derived from fat and a lower proportion from carbohydrate (Glickman et al., 1995). It is possible that factors such as a high fat/low carbohydrate diet predispose smaller dogs, regardless of their breed, to DM, and that diet may be as or more important than genetics in the development of DM in some breeds. In one study, dogs fed high fat diets had decreased insulin sensitivity and decreased glucose tolerance (Kaiyala et al., 1999). Controlled studies are also needed to determine whether insulin response and glucose tolerance are affected by breed, adult body size, diet, obesity, age and neuter status. Also, the prevalence of DM or impaired glucose tolerance should be measured in a representative sample of pet dogs. With continued investigation of the canine genome (Breen et al., 2001), it may soon be possible to determine whether dog breeds at increased risk of DM share genetic determinants implicated in increased risk of DM in other species, such as those identified as candidates for conveying metabolic mechanisms for maintaining normoglycaemia during periods of minimal nutrient availability in human beings. ACKNOWLEDGEMENTS We thank Ms. Yun Shen and the VMDB staff for their assistance. REFERENCES ATKINS, C. E., LECOMPTE, P. M., CHIN, H. P., HILL, J. R., OWNBY, C. L. & BROWNFIELD, M. S. (1988). Morphologic and immunocytochemical study of young dogs with diabetes mellitus associated with pancreatic islet hypoplasia. American Journal of Veterinary Research 49, 1577– 81. BREEN, M., JOUQUAND, S., RENIER, C., MELLERSH, C. S., HITTE, C., GOLMES, N. G., CHE RON, A., SUTER, N., VIGNAUX, F., BRISTOW, A. E., PRIAT, C., MCCANN, E., ANDRE, C., BOUNDY, S., GITSHAM, P., THOMAS, R., BRIDGE, W. L., SPRIGGS, H. F., RYDER, E. J., CURSON, A., SAMPSON, J., OSTRANDER, E. A., BINNS, M. M. & GALIBERT, F. (2001). Chromosome-specific single-locus FISH probes allow anchorage of an 1800-marker
integrated radiation-hybrid/linkage map of the domestic dog genome to all chromosomes. Genome Research 11, 1784–95. DRASH, A. L. (1990). What do epidemiologic observations tell us about the etiology of insulin dependent diabetes mellitus? Schweizerische Medizinische Wochenschrift 120, 39–45. EDNEY, A. T. B. & SMITH, P. M. (1986). Study of obesity in dogs visiting veterinary practices in the United Kingdom. Veterinary Record 118, 391–6. FELDMAN, E. C. & NELSON, R. W. (1996). Diabetes mellitus. In: Canine and Feline Endocrinology and Reproduction, eds. E. C. Feldman, & R. W. Nelson, pp. 339–91. Philadelphia, PA: W.B. Saunders. FLEEMAN, L. M. & RAND, J. S. (2001). Management of diabetes mellitus. Veterinary Clinics of North America, Small Animal Practice 31, 855–80. GLICKMAN, L. T., SONNENSCHEIN, E. G., GLICKMAN, N. W., DONOGHUE, S. & GOLDSCHMIDT, M. H. (1995). Pattern of diet and obesity in female adult pet dogs. Veterinary Clinical Nutrition 2, 6–13. HESS, R. S., KASS, P. H. & WARD, C. R. (2000). Breed distribution of dogs with diabetes mellitus admitted to a tertiary care facility. Journal of the American Veterinary Medical Association 216, 1414–7. KAIYALA, K. J., PRIGION, R. L., KAHN, S. E., WOODS, S. C., PORTE, D., Jr., & SCHWARTZ, M. W. (1999). Reduced bcell function contributes to impaired glucose tolerance in dogs made obese by high-fat feeding. American Journal of Physiology 277, E659–67. KALMAN, P., ZIV, E., SHAFRIR, E., BAR-ON, H. & PEREZ, R. (2000). Psammomys obesus and the albino rat – two different models of nutritional insulin resistance, representing two different types of human populations. Laboratory Animals 35, 346–52. KIMMEL, S., WARD, C., HENTHORN, P. & HESS, R. (2000). Familial insulin-dependent diabetes mellitus in Samoyed dogs. Journal of Veterinary Internal Medicine 13, 270 (Abstract). KRAMER, J. W., KLAASSEN, J. K., BASKIN, D. G., PRIEUR, D. J., RANTANEN, N. W., ROBINETTE, J. D., GRABER, W. R. & RASHTI, L. (1988). Inheritance of diabetes mellitus in Keeshond dogs. American Journal of Veterinary Research 49, 428–31. KRAMER, J. W., NOTTINGHAM, S., ROBINETTE, J., LENZ, G., SYLVESTER, S. & DESSOUKY, M. I. (1980). Inherited, early onset, insulin-requiring diabetes mellitus of Keeshond dogs. Diabetes 29, 558–65. MARMOR, M., WILLEBERG, P., GLICKMAN, L. T., PRIESTER, W. A., CYPESS, R. H. & HURVITZ, A. I. (1982). Epizootiologic patterns of diabetes mellitus in dogs. American Journal of Veterinary Research 43, 465–70. MATTHEEUWS, D. R. G., ROTTIERS, R., KANEKO, J. J. & VERMEULEN, A. (1984). Diabetes mellitus in dogs: relationship of obesity to glucose tolerance and insulin response. American Journal of Veterinary Research 45, 98–103. NELSON, R. W., DUESBERG, C. A., FORD, S. L., FELDMAN, E. C., DAVENPORT, D. J., KIERNAN, C. & NEAL, L. (1998). Effect of dietary insoluble fiber on control of glycemia in dogs with naturally acquired diabetes mellitus. Journal of the American Veterinary Medical Association 212, 380–6. UNGER, R. H. & FOSTER, D. W. (1998). Diabetes mellitus. In: WilliamsÕ Textbook of Endocrinology, eds. J. D. Wilson,
EPIDEMIOLOGY OF DIABETES MELLITUS IN DOGS
D. W. Foster, H. M. Kronenberg, & P. R. Larsen, pp. 973–1060. Philadelphia: W.B. Saunders. WILCOX, B. & WALKOWICZ, C. (1995). The northern breeds. In: The Atlas of Dog Breeds of the World, eds. B. Wilcox, & C. Walkowicz, pp. 52–7. Neptune City, NJ: TFH Publications.
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WILLIAMS, M. D., GREGORY, R., SCHALL, W., BULL, R. & PADGETT, G. (1981). Characterization of naturally occurring diabetes in a colony of Golden Retrievers. Federation Proceedings 40, 740 (Abstract). (Accepted for publication 26 June 2002)
Time Trends and Risk Factors for Diabetes Mellitus in Dogs: Analysis of Veterinary Medical Data Base Records (1970–1999) L. GUPTILL , L. GLICKMANà and N. GLICKMAN§
Department of Veterinary Clinical Sciences, Purdue University, West Lafayette, IN 47907, USA, Department of Veterinary Pathobiology, Purdue University, West Lafayette, IN 47907, USA, §The Center for Human–Animal Interaction, Purdue University, West Lafayette, IN 47907, USA à
SUMMARY The objectives of the study were to identify recent trends in the prevalence of diabetes mellitus (DM) in dogs and to identify host risk factors. Veterinary Medical Data Base (VMDB) electronic records of 6860 dogs with a diagnosis of DM (VMDB code 870178500) between 1970 and 1999 were evaluated to determine time trends. Records of 6707 dogs with DM and 6707 frequency matched dogs with any diagnosis other than DM from the same teaching hospitals in the same year, selected as controls, were evaluated for risk factor analysis. The prevalence of DM in dogs presented to veterinary teaching hospitals increased from 19 cases per 10,000 admissions per year in 1970 to 64 cases per 10,000 in 1999, while the case-fatality rate decreased from 37% to 5%. The hospital prevalence of DM was consistently greater over time in older compared with younger dogs with the highest prevalence occurring in dogs 10–15 years of age. Dogs weighing <22:7 kg had a significantly (P < 0:001) greater risk of DM compared with heavier dogs. Female dogs had an increased risk of DM compared with males (P < 0:001). Ó 2002 Elsevier Science Ltd. All rights reserved.
KEYWORDS: Diabetes mellitus; epidemiology; dog; endocrinology.
INTRODUCTION Spontaneous diabetes mellitus (DM) is reported in most dog breeds and in mixed breed dogs (Feldman & Nelson, 1996). Canine DM is generally classified as insulin dependent or non-insulin dependent. However, whether dogs have type I or type II DM as described in human beings is rarely determined (Feldman & Nelson, 1996). Type I DM is characterized by insulin deficiency resulting from destruction or loss of b cells of the islets of Langerhans and type II DM by insulin resistance and/or inadequate insulin production or secretion by b cells (Feldman & Nelson, 1996). Most diabetic dogs are thought to have a disease most like human type I DM and are insulin dependent (Feldman & Nelson,
Correspondence to: L. Guptill, Department of Veterinary Clinical Sciences, 1248 Lynn Hall, Purdue University, West Lafayette, IN 47907, USA. Tel.: 1-765-496-3881; fax: 1-765-4949830; E-mail: [email protected]
1996). Unlike human type I DM, however, DM in dogs is more likely to occur later in life. It has been proposed (Kaneko et al., 1977, Feldman & Nelson, 1996) that DM in adult dogs progresses through several stages beginning with impaired glucose tolerance, followed by non-insulin dependent stages resembling type II DM of human beings, and finally an insulin dependent disease comparable to type I insulin dependent DM of human beings. The aetiology of DM in dogs is probably multifactorial. Factors including obesity, diet, exposure to toxic chemicals or drugs that cause insulin resistance, immune-mediated destruction of islet cells, and destruction of islet cells secondary to pancreatitis may all play a role. While genetic factors probably influence susceptibility, specific genes and inheritance patterns have not been identified in most dog breeds. Multiple genetic and environmental factors have been implicated in the pathogenesis of types I and II DM in human beings, yet modes of inheritance and interaction of
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EPIDEMIOLOGY OF DIABETES MELLITUS IN DOGS
genetic and environmental factors in that species are still not completely understood (Unger & Foster, 1998). Previous epidemiological studies (Feldman & Nelson, 1996; Marmor et al., 1982) have reported that most diabetic dogs are between four and 14 years of age, and that females are at increased risk compared with males. Breeds previously reported to have a higher risk for developing DM include Keeshond, Alaskan Malamute, Puli, Cairn Terrier, Fox Terrier, Manchester Terrier, Miniature Pinscher, Toy and Miniature Poodle, Finnish Spitz, Schipperke, and Miniature Schnauzer. Pekingese, German Shepherds, Collies, and Boxers are reportedly at decreased risk (Marmor et al., 1982; Feldman & Nelson, 1996; Hess et al., 2000). The purpose of the study reported here was to identify temporal trends in the hospital prevalence of DM in dogs using the Veterinary Medical Data Base (VMDB), and to further characterize host risk factors using a large sample size. The VMDB, established in 1964 by the National Cancer Institute, is comprised of abstracted medical records from 24 participating veterinary teaching hospitals in the United States and Canada.
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tical significance for the decrease in case-fatality percentage. Seasonal occurrence was evaluated by grouping dogs with DM seen at the participating institutions during the four seasons of the year as follows: Spring ¼ March–May; Summer ¼ June–August; Autumn ¼ September–November; Winter ¼ December–February. Age-specific hospital prevalence was determined by calculating the prevalence of DM in each age group of dogs. The number of dogs with DM in each age group was divided by the total number of dogs in that age group. Potential risk factors including breed, gender, neuter status, and weight were calculated using univariate and multivariate logistic regression (SAS, Cary, NC). Weight is included in VMDB records only as a categorical variable; actual dog weight is not available. An odds ratio and 95% confidence limits for each potential risk factor were determined (SAS, Cary, NC). A P value <0.05 was considered significant. The individual breed risks of DM were calculated for breeds having a minimum of 25 cases or controls using univariate logistic regression. RESULTS
MATERIALS AND METHODS The VMDB was searched for records of first hospital visits of dogs with DM (VMDB code 870178500) for the period from January 1, 1970 to December 31, 1999 (the last year for which data entry from participating institutions was thought to be complete). Control records for risk factor analysis were selected from first hospital visits of dogs with any diagnosis other than DM. Controls were frequency matched to cases by year, institution, and age group. Age is included in VMDB records only as a categorical variable; actual dog age is not available. Records of all diabetic dogs seen over the 30 year period were used to calculate the hospital prevalence of DM (number of cases per 10,000 total dogs seen per year), the age-specific hospital prevalence of DM, the case-fatality percentage, and the seasonal occurrence of DM. Statistical significance of time trends was evaluated using a v2 test for linear trend (SAS, Cary, NC). The case-fatality per cent was calculated by dividing the total number of dogs with DM that died or were euthanased in a given year by the total number of dogs with DM in that year multiplied by 100. A v2 test for linear trend was applied to the total number of deceased DM cases to determine statis-
Diabetes mellitus was diagnosed in 6860 dogs of the 1,847,786 dogs whose VMDB records were available for the 30-year period between January 1, 1970 and December 31, 1999 (hospital prevalence for the 30year period: 37 cases/10,000 dogs examined; 95% confidence limits (CL) 36–38 cases per 10,000 dogs examined). The age distribution of dogs with DM was as follows: 154 (2.2%) dogs with DM aged <1 year, 46 (0.67%) aged 1–2 years, 195 (2.8%) aged 3–4 years, 1058 (15.4%) aged 5–7 years, 2543 (37.1%) aged 8–10 years, 2690 (39.2%) aged 11–15 years, and 121 (1.8%) over the age of 15 years. There were 53 (0.77%) dogs for which age information was missing. The hospital prevalence of DM in dogs included in the VMDB increased significantly (P < 0:00001) over the 30-year period (Fig. 1), from 19 cases per 10,000 hospital admissions in 1970–1974 (95% CL 17–21 cases per 10,000), to 58 cases per 10,000 in 1995–1999 (95% CL 55–61 cases per 10,000; Fig. 1). The highest prevalence of DM occurred in dogs 10– 15 years of age (Fig. 2). Dogs over 10 years of age comprised a greater proportion of dogs presented to the participating teaching hospitals in 1999 (17.5%) than they did in 1970 (6.25%). The agespecific prevalence of DM increased in most age groups during the study period (Fig. 2).
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Fig. 1. Hospital prevalence of canine diabetes mellitus (DM), VMDB 1970–1999. Prevalence of DM increased over the study period. The number of institutions for which data are recorded is lower from 1995 to 1999 (16 institutions in 1994, 13 in 1995, 12 each in 1996–1997, 11 each in 1998–1999), therefore the number of cases per year is lower in these years.
Fig. 2. Age-specific hospital prevalence of canine diabetes mellitus (DM), VMDB 1970–1999. The highest prevalence of DM was in the 10–15 year age group. Diabetes mellitus prevalence increased in most age groups.
There was a steady and significant decrease (P < 0:00001) in the case-fatality per cent over time (Fig. 3). There was no apparent seasonal pattern in the prevalence of DM in dogs (data not shown). The records of 6807 diabetic dogs of known age and 6807 frequency matched controls were used to conduct risk factor analyses. Significant risk factors in univariate analysis included being a mixed versus pure breed, female versus male, neutered versus intact male, and weight being <22.7 kg. All potential
Fig. 3. Case-fatality percentage for canine diabetes mellitus (DM), VMDB 1970–1999. The case-fatality per cent for dogs with DM decreased steadily between 1970 and 1999.
risk factors were included in the multivariate model. Odds ratios did not change substantially between the univariate and multivariate analyses, indicating that there was not confounding between the variables. Multivariate analysis (Table I) showed that pure-bred dogs as a group were at a decreased risk of DM compared with mixed breed dogs (P ¼ 0:002), although the risk of DM was decreased for some breeds and increased for others (Table II). The breed at highest
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Table I Summary of potential risk factors for diabetes mellitus (DM), multivariate analysis by logistic regression (Veterinary Medical Data Base, 1970–1999) DM cases Breed Pure breed Mixed breed Gendera Female Male Neuter statusb Female neutered Female intact Male neutered Male intact Weight (kg)c 1–6.8 6.8–13.6 13.6–22.7 22.7–34.1 34.1–45.4 >45.4
Controls
Odds ratio
95% confidence limits
P value
4947 1860
5198 1609
0.86 1.00
0.78, 0.94 Reference group
0.002
4229 2553
3524 3238
1.37 1.00
1.27, 1.49 Reference group
<0.001
3000 1227 1271 1282
2498 1023 1094 2144
0.99 1.00 1.91 1.00
0.89, 1.12 Reference group 1.68, 2.17 Reference group
0.98
1336 2031 884 720 308 98
955 1212 960 1287 651 206
2.62 3.15 1.67 1.05 0.93 1.00
2.03, 3.39 2.45, 4.06 1.28, 2.17 0.81, 1.36 0.71, 1.24 Reference group
<0.001
<0.001 <0.001 <0.001 0.69 0.66
Records of 6707 cases and 6707 controls were evaluated. Controls are dogs presented to the same teaching hospitals in the same year as cases, for any condition other than DM. a Gender information missing for 25 cases and 45 controls. b Neuter status missing for two female cases and three female controls. c Weight information missing for 1430 cases and 1536 controls.
risk of DM was the Australian Terrier (odds ratio ¼ 32.1) while the Boxer breed had the lowest risk (odds ratio ¼ 0.07). Female dogs were at an increased risk compared with male dogs (P < 0:001). Neutered male dogs were at a significantly greater risk than intact male dogs (P < 0:001), but there was no significant difference in risk between neutered and intact females (P ¼ 0:98). Dogs weighing <22:7 kg were at an increased risk of DM compared with dogs weighing >45:4 kg (P < 0:001). DISCUSSION The findings of this study indicate that the hospital prevalence of DM in dogs presented to veterinary teaching hospitals in North America has increased since 1970 despite the fact that diagnostic methods and clinical and laboratory criteria for DM have not changed appreciably over this time period. This suggests that the increased hospital prevalence is not a result of changes in clinical practice, but rather reflects a true increase in the incidence of DM in the owned dog population. The dogs in the
VMDB are mostly referred from private veterinary hospitals. There may have been changes in referral patterns not discernible from these data that could further explain the increased hospital prevalence. It is unlikely that there were decreases in prevalence of enough other illnesses seen at participating hospitals to alter the proportional morbidity of DM; records do not indicate a decrease in other common illnesses such as renal failure, hypothyroidism, or hyperadrenocorticism (unpublished data). The decreasing case-fatality per cent over time suggests that owners and veterinarians are now more willing than previously to undertake long-term management of diabetic dogs. Recent advances in nutritional management of diabetes mellitus in dogs (Nelson et al., 1998; Fleeman & Rand, 2001) and increased availability of client education materials have probably contributed to the apparent increased willingness of both owners and veterinarians to manage this chronic disease in pet dogs. Increased awareness by veterinarians of the importance of managing concurrent problems such as urinary tract infections and dental disease also
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Table II Breeds with a significantly (P < 0:05) decreased or increased risk of diabetes mellitus (Veterinary Medical Data Base, 1970–1999) Breed
DM cases
Australian Terrier 37 Standard Schnauzer 105 Samoyed 175 Miniature Schnauzer 624 Fox Terrier 91 Keeshond 57 Bichon Frise 50 Finnish Spitz 35 Cairn Terrier 67 Miniature Poodle 737 Siberian Husky 80 Toy Poodle 208 Mixed breed 1860 Beagle 73 English Setter 30 Labrador Retriever 246 Basset Hound 33 Dalmatian 28 Doberman Pinscher 109 Irish Setter 68 Boston Terrier 31 Shih Tzu 31 Brittany Spaniel 28 Old English Sheepdog 14 Norwegian Elkhound 10 Golden Retriever 108 English Pointer 11 Cocker Spaniel 90 Great Dane 15 Bulldog 7 Shetland Sheepdog 29 Collie 25 Pekingese 14 German Shepherd 70 Airedale Terrier 8 German Short-Hair Pointer 6 Boxer 7
Controls 1 19 45 172 26 20 18 13 28 356 45 139 1609 94 42 364 50 45 182 121 68 69 64 35 26 294 36 307 54 26 107 109 66 365 45 37 82
Odds ratio 32.10 4.78 3.36 3.13 3.02 2.45 2.40 2.32 2.07 1.79 1.53 1.29 1.00 0.67 0.61 0.58 0.57 0.53 0.51 0.48 0.39 0.38 0.37 0.35 0.33 0.31 0.26 0.25 0.24 0.23 0.23 0.19 0.18 0.16 0.15 0.14 0.07
95% confidence limits 4.36, 233.53 2.91, 7.82 2.40, 4.69 2.61, 3.76 1.94, 4.70 1.47, 4.12 1.39, 4.13 1.22, 4.41 1.32, 3.23 1.55, 2.06 1.06, 2.22 1.03, 1.62 Reference group 0.49, 0.91 0.38, 0:99 0.49, 0.69 0.36, 0.89 0.33, 0.86 0.40, 0.66 0.35, 0.65 0.25, 0.60 0.25, 0.59 0.24, 0.59 0.19, 0.65 0.16, 0.69 0.25, 0.40 0.13, 0.52 0.19, 0.32 0.14, 0.43 0.10, 0.54 0.15, 0.35 0.12, 0.30 0.10, 0.33 0.12, 0.21 0.07, 0.33 0.06, 0.33 0.03, 0.16
P value <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 0.001 0.008 0.001 <0.001 0.02 0.02 0.01 0.04 <0.001 0.01 0.01 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 0.002 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001
Breeds were included in this analysis if there were at least 25 cases or 25 controls. Controls are dogs presented to the same teaching hospitals in the same year as cases, for any condition other than DM. Odds ratios were calculated using univariate logistic regression.
probably contributes to the increased success of long-term management of DM and therefore increased willingness of owners and veterinarians to treat dogs with DM. The lack of an apparent seasonal pattern in the occurrence of DM in dogs is in agreement with a previous report (Marmor et al., 1982) and does not
support an infectious aetiology such as has been proposed for Type I IDDM in human beings (Unger & Foster, 1998). However, the lack of an obvious seasonal pattern in the frequency of DM in dogs in the VMDB may be a result of the referral nature of the practices, in that the month in which a dog with DM is presented to a teaching hospital may be
EPIDEMIOLOGY OF DIABETES MELLITUS IN DOGS
unrelated to when the dog was initially affected with the disorder. Nevertheless, if time between initial diagnosis of DM and presentation of a dog with DM to a referral institution is a random event, then a strong seasonal pattern might have been detected in this large sample of dogs with DM. Many dog breeds reportedly at increased risk of DM in previous studies (Marmor et al., 1982; Hess et al., 2000) were also found to be at increased risk in the study reported here. The current study reports on a larger sample of diabetic dogs, and identified four additional breeds at statistically significantly increased risk of DM (Bichon Frise, Australian Terrier, Siberian Husky, and Standard Schnauzer). Some breeds previously reported to be at increased risk of DM were not found to be at increased risk in this study (Malamute, Schipperke, Puli, Miniature Pinscher, Manchester Terrier). Four Northern (Wilcox & Walkowicz, 1995), or husky-type breeds (Keeshond, Samoyed, Finnish Spitz, and Siberian Husky) were among the 12 breeds identified as being at significantly increased risk of DM. Two Northern breeds, Samoyeds and Alaskan Malamutes, were also found to be at increased risk in another study (Marmor et al., 1982). In contrast, only one Northern breed (Norwegian Elkhound) was among the 24 breeds identified as having a significantly decreased risk of DM. Whether this suggests a genetic predisposition or reflects environmental influences is not known. No single genetic factor responsible for adult-onset DM has been reported in any of these breeds. However, there is one report of apparently familial adult-onset DM in five Samoyed dogs (Kimmel et al., 2000). These five dogs were between 3.5 and 7.8 years of age when DM was diagnosed and three of the dogs were from a single litter. Two other dogs came from another litter not known to be related to the first three dogs. In human beings, the risk of insulindependent DM varies with geographical area (Unger & Foster, 1998), and was higher in Finland compared with Asian countries and one area in the United Stated (Drash, 1990). One animal species (Psammomys obesus; the gerbil) at increased risk for DM is thought to have evolved metabolic mechanisms for maintenance of normoglycaemia when faced with periods of minimal nutrient availability. Similar metabolic mechanisms are thought to exist in certain human populations at increased risk for type II DM (Kalman et al., 2000; Unger & Foster, 1998). It is possible that a similar metabolic mechanism exists in some Northern dog breeds, whose ancestors were bred to
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survive seasonal periods of minimal nutrient availability. Exactly what characterizes the above metabolic genotype in animals or human beings has not been determined, but several candidate genes have been investigated (Unger & Foster, 1998). Interactions of environment and genetic susceptibility are considered likely to result in the development of DM in human beings (Drash, 1990) There may be a single genetic factor responsible for development of congenital DM in some breeds. For example, there are histopathological differences in pancreata of dogs with DM that are less than one year of age, compared with dogs that have adult onset DM. Dogs <1 year of age (presumably congenital DM) had islet cell hypoplasia or aplasia (Kramer et al., 1988, 1980; Atkins et al., 1988; Williams et al., 1981) whereas dogs with adult onset DM had evidence of inflammatory cell infiltration and destruction of islets (Atkins et al., 1988). An autosomally recessively inherited islet hypoplasia is reported in Keeshond (Kramer et al., 1988). The mode of inheritance for islet cell hypoplasia in other breeds has not been established (Kramer et al., 1980; Williams et al., 1981). Female dogs were found be at greater risk of DM than male dogs, as other investigators have also reported (Marmor et al., 1982). Neutered male dogs were found to be at increased risk of DM compared with intact male dogs. Records in VMDB do not specify actual dog age, whether dogs were neutered before or after the diagnosis of DM was made, or the age at which a dog was neutered. Therefore, it cannot be determined for certain whether there is a true increased risk for neutered males, or whether the increased risk occurred because males were neutered later in life, when DM is most likely to occur. An increased risk of DM for neutered males was also identified in a previous study using VMDB records (Marmor et al., 1982). Neutered dogs may be at an increased risk for obesity (Edney & Smith, 1986), and this may to some extent explain their increased risk for development of DM. Obesity was identified as the most important factor influencing glucose tolerance and insulin response in both healthy and diabetic dogs (Mattheeuws et al., 1984). Investigation of glucose tolerance and insulin response in obese and nonobese neutered dogs compared with obese and nonobese intact dogs may help to determine whether neuter status has an effect on glucose and insulin homeostasis independent of obesity. Information concerning diet is not included in the VMDB, nor is actual dog weight, precluding evaluation of the body condition of dogs in this study.
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Prospective studies are required specifically to evaluate the role of diet and obesity in the development of canine DM. The association of an increased risk of DM with smaller body size may reflect as yet unidentified genetic factors, or it may reflect the diets of these dogs. The results of one study show that pet dogs have a relatively increased consumption of canned dog food and table foods as body size decreases, and that these diets are associated with a higher proportion of calories derived from fat and a lower proportion from carbohydrate (Glickman et al., 1995). It is possible that factors such as a high fat/low carbohydrate diet predispose smaller dogs, regardless of their breed, to DM, and that diet may be as or more important than genetics in the development of DM in some breeds. In one study, dogs fed high fat diets had decreased insulin sensitivity and decreased glucose tolerance (Kaiyala et al., 1999). Controlled studies are also needed to determine whether insulin response and glucose tolerance are affected by breed, adult body size, diet, obesity, age and neuter status. Also, the prevalence of DM or impaired glucose tolerance should be measured in a representative sample of pet dogs. With continued investigation of the canine genome (Breen et al., 2001), it may soon be possible to determine whether dog breeds at increased risk of DM share genetic determinants implicated in increased risk of DM in other species, such as those identified as candidates for conveying metabolic mechanisms for maintaining normoglycaemia during periods of minimal nutrient availability in human beings. ACKNOWLEDGEMENTS We thank Ms. Yun Shen and the VMDB staff for their assistance. REFERENCES ATKINS, C. E., LECOMPTE, P. M., CHIN, H. P., HILL, J. R., OWNBY, C. L. & BROWNFIELD, M. S. (1988). Morphologic and immunocytochemical study of young dogs with diabetes mellitus associated with pancreatic islet hypoplasia. American Journal of Veterinary Research 49, 1577– 81. BREEN, M., JOUQUAND, S., RENIER, C., MELLERSH, C. S., HITTE, C., GOLMES, N. G., CHE RON, A., SUTER, N., VIGNAUX, F., BRISTOW, A. E., PRIAT, C., MCCANN, E., ANDRE, C., BOUNDY, S., GITSHAM, P., THOMAS, R., BRIDGE, W. L., SPRIGGS, H. F., RYDER, E. J., CURSON, A., SAMPSON, J., OSTRANDER, E. A., BINNS, M. M. & GALIBERT, F. (2001). Chromosome-specific single-locus FISH probes allow anchorage of an 1800-marker
integrated radiation-hybrid/linkage map of the domestic dog genome to all chromosomes. Genome Research 11, 1784–95. DRASH, A. L. (1990). What do epidemiologic observations tell us about the etiology of insulin dependent diabetes mellitus? Schweizerische Medizinische Wochenschrift 120, 39–45. EDNEY, A. T. B. & SMITH, P. M. (1986). Study of obesity in dogs visiting veterinary practices in the United Kingdom. Veterinary Record 118, 391–6. FELDMAN, E. C. & NELSON, R. W. (1996). Diabetes mellitus. In: Canine and Feline Endocrinology and Reproduction, eds. E. C. Feldman, & R. W. Nelson, pp. 339–91. Philadelphia, PA: W.B. Saunders. FLEEMAN, L. M. & RAND, J. S. (2001). Management of diabetes mellitus. Veterinary Clinics of North America, Small Animal Practice 31, 855–80. GLICKMAN, L. T., SONNENSCHEIN, E. G., GLICKMAN, N. W., DONOGHUE, S. & GOLDSCHMIDT, M. H. (1995). Pattern of diet and obesity in female adult pet dogs. Veterinary Clinical Nutrition 2, 6–13. HESS, R. S., KASS, P. H. & WARD, C. R. (2000). Breed distribution of dogs with diabetes mellitus admitted to a tertiary care facility. Journal of the American Veterinary Medical Association 216, 1414–7. KAIYALA, K. J., PRIGION, R. L., KAHN, S. E., WOODS, S. C., PORTE, D., Jr., & SCHWARTZ, M. W. (1999). Reduced bcell function contributes to impaired glucose tolerance in dogs made obese by high-fat feeding. American Journal of Physiology 277, E659–67. KALMAN, P., ZIV, E., SHAFRIR, E., BAR-ON, H. & PEREZ, R. (2000). Psammomys obesus and the albino rat – two different models of nutritional insulin resistance, representing two different types of human populations. Laboratory Animals 35, 346–52. KIMMEL, S., WARD, C., HENTHORN, P. & HESS, R. (2000). Familial insulin-dependent diabetes mellitus in Samoyed dogs. Journal of Veterinary Internal Medicine 13, 270 (Abstract). KRAMER, J. W., KLAASSEN, J. K., BASKIN, D. G., PRIEUR, D. J., RANTANEN, N. W., ROBINETTE, J. D., GRABER, W. R. & RASHTI, L. (1988). Inheritance of diabetes mellitus in Keeshond dogs. American Journal of Veterinary Research 49, 428–31. KRAMER, J. W., NOTTINGHAM, S., ROBINETTE, J., LENZ, G., SYLVESTER, S. & DESSOUKY, M. I. (1980). Inherited, early onset, insulin-requiring diabetes mellitus of Keeshond dogs. Diabetes 29, 558–65. MARMOR, M., WILLEBERG, P., GLICKMAN, L. T., PRIESTER, W. A., CYPESS, R. H. & HURVITZ, A. I. (1982). Epizootiologic patterns of diabetes mellitus in dogs. American Journal of Veterinary Research 43, 465–70. MATTHEEUWS, D. R. G., ROTTIERS, R., KANEKO, J. J. & VERMEULEN, A. (1984). Diabetes mellitus in dogs: relationship of obesity to glucose tolerance and insulin response. American Journal of Veterinary Research 45, 98–103. NELSON, R. W., DUESBERG, C. A., FORD, S. L., FELDMAN, E. C., DAVENPORT, D. J., KIERNAN, C. & NEAL, L. (1998). Effect of dietary insoluble fiber on control of glycemia in dogs with naturally acquired diabetes mellitus. Journal of the American Veterinary Medical Association 212, 380–6. UNGER, R. H. & FOSTER, D. W. (1998). Diabetes mellitus. In: WilliamsÕ Textbook of Endocrinology, eds. J. D. Wilson,
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D. W. Foster, H. M. Kronenberg, & P. R. Larsen, pp. 973–1060. Philadelphia: W.B. Saunders. WILCOX, B. & WALKOWICZ, C. (1995). The northern breeds. In: The Atlas of Dog Breeds of the World, eds. B. Wilcox, & C. Walkowicz, pp. 52–7. Neptune City, NJ: TFH Publications.
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WILLIAMS, M. D., GREGORY, R., SCHALL, W., BULL, R. & PADGETT, G. (1981). Characterization of naturally occurring diabetes in a colony of Golden Retrievers. Federation Proceedings 40, 740 (Abstract). (Accepted for publication 26 June 2002)