Genetics of canine diabetes mellitus: Are the diabetes susceptibility genes identified in humans involved in breed susceptibility to diabetes mellitus in dogs?

Diabetes mellitus is a common endocrinopathy in companion animals, characterised by hyperglycaemia, glycosuria and weight loss, resulting from an absolute or relative deficiency in the pancreatic hormone insulin. There are breed differences in susceptibility to diabetes mellitus in dogs, with the Samoyed breed being overrepresented, while Boxers are relatively absent in the UK population of diabetic dogs, suggesting that genetic factors play an important role in determining susceptibility to the disease. A number of genes, linked with susceptibility to diabetes mellitus in humans, are associated with an increased risk of diabetes mellitus in dogs, some of which appear to be relatively breed-specific. Diabetes mellitus in dogs has been associated with major histocompatibility complex (MHC) class II genes (dog leucocyte antigen; DLA), with similar haplotypes and genotypes being identified in the most susceptible breeds. A region containing a variable number of tandem repeats (VNTR) and several polymorphisms have been identified in the canine insulin gene, with some alleles associated with susceptibility or resistance to diabetes mellitus in a breed-specific manner. Polymorphisms in the canine CTLA4 promoter and in other immune response genes are associated with susceptibility to diabetes mellitus in a number of pedigree breeds. Genome wide association studies are currently underway that should shed further light on the genetic factors responsible for the breed profile seen in the diabetic dog population.     

Survival of a dog with pneumonia caused by Mycobacterium fortuitum

Pneumonia caused by Mycobacterium fortuitum was diagnosed in the left lung lobes of a 3-year-old male Samoyed. Unilateral pneumonectomy and antibiotic treatment (primarily amoxicillin trihydrate-clavulanate potassium and kanamycin) were associated with resolution of the pneumonia. In dogs, M fortuitum causes pulmonary disease that radiographically resembles bacterial pneumonia. Therefore, M fortuitum infection should be considered in dogs with radiographic signs of bronchopneumonia that worsen despite antibiotic treatment.     

Study of 253 dogs in the United Kingdom with diabetes mellitus

Clinical information and blood samples were collected from 253 dogs with naturally occurring diabetes mellitus. Over half of them were labrador retrievers, collies, Yorkshire terriers or crossbred dogs, and approximately 80 per cent of them were diagnosed between the ages of five and 12 years. The majority of the dogs were receiving insulin therapy once a day, but in the dogs receiving insulin injections twice a day there was a trend for lower serum fructosamine concentrations, suggesting better glycaemic control. The proportion of female dogs with diabetes was lower than in previous surveys. The disease was diagnosed more commonly in the winter months, a seasonal pattern also observed in human beings with diabetes, suggesting that similar environmental factors might be involved in the disease.     

Short-limbed dwarfism and ocular defects in the Samoyed dog

A syndrome of short-limbed dwarfism and ocular defects was found in Samoyed dogs. The most prominent abnormalities were small stature and valgus deformity of the carpi. Radiographic evidence of retarded growth at the distal ulnar physis was apparent by 12 weeks of age. Ocular defects included cataracts and retinal detachment. Family studies and limited breeding experiments were consistent with an autosomal recessive mode of inheritance.     

Fat absorption in dogs with diabetes mellitus or hypothyroidism

Quantitative fat absorption was studied in normal dogs and in dogs with hypothyroidism and diabetes mellitus. The serum triglyceride concentrations of diabetic and hypothyroid dogs were significantly higher at each sampling time than those of normal dogs. The fat absorption curve of hypothyroid dogs peaked at 180 minutes and though significantly raised was parallel to that of normal dogs whereas the fat absorption curve of diabetic dogs continued to rise up to 240 minutes. These results provide evidence for impaired plasma clearance of triglyceride in canine diabetes mellitus and hypothyroidism.     

EMPHYSEMATOUS CHOLECYSTITIS IN THE NONDIABETIC DOG: THREE CASE HISTORIES

Emphysematous cholecystitis not associated with diabetes mellitus was diagnosed in three dogs. All three dogs were examined because of vomiting. Neutrophilia, elevated serum alkaline phosphatase, and normal serum glucose were present in each animal. A gas-filled gallbladder and pericholecystic gas were seen radiographically in all three dogs; a cholecystolith was present in one dog. A cholecystectomy was performed on two dogs. Cultures of bacteria from these two bladders revealed Clostridium sp. One of these dogs was euthanized because of acute renal tubular necrosis that was diagnosed after ten days of treatment with gentamicin. The second dog recovered without incident. The third dog was treated successfully with antibiotics.     

犬细小病毒病的病理学观察

对2例萨摩耶犬的犬细小病毒自然感染病例进行了临床观察、病理剖检及病理组织学观察,结果显示2病例均以犬细小病毒肠炎综合征为主要特征。表现为食欲废绝,排番茄酱样粪便,肠道黏膜坏死,覆以红黄色黏糊状物;镜检肠绒毛缩短,肠黏膜上皮细胞坏死或脱落,肠腺萎缩,肠腺细胞核内可见包涵体,胞浆呈玻璃样变;心肌纤维萎缩,粗细不均,肌纤维间较松散,有少量出血,炎症变化不明显。     

Gentamicin pharmacokinetics in diabetic dogs

Reduction of the prolonged terminal elimination phase of gentamicin may be caused by diabetes mellitus, irrespective of the model of diabetes. To test this hypothesis, five normal dogs, three dogs with alloxan-induced diabetes mellitus, and four dogs with naturally occurring diabetes mellitus (all of which were given exogenous insulin to control hyperglycemia) were given 4.4 mg/kg gentamicin intravenously. Serum pharmacokinetics were analyzed using non-compartmental pharmacokinetics assuming a sum of exponential terms. Gentamicin pharmacokinetics during the first 8 h were the same in normal and diabetic dogs. Over 7 days, MRT in normal dogs (5830 +/- 2970 min, mean +/- SD) was longer (P less than 0.01) than in diabetic dogs (136 +/- 164 min). In diabetic dogs, Cls was greater (3.01 +/- 0.86 ml/min/kg) than in normal dogs (1.45 +/- 0.11 ml/min/kg; P less than 0.01), whereas Vd(ss) was smaller in diabetic dogs (0.405 +/- 0.508 l/kg) than in normal dogs (8.56 +/- 4.48 l/kg; P less than 0.01). Serum gentamicin concentrations were less than 0.020 microgram/ml by 2 days in all of the diabetic dogs, but were 0.048 +/- 0.018 microgram/ml at 7 days in normal dogs. Thus, diabetes mellitus, either induced by alloxan administration or naturally occurring, abolished the terminal elimination phase of gentamicin disposition in a non-rodent species.     

Pregnancy-related diabetes mellitus in two dogs

CASE SUMMARIES: Two cases of diabetes mellitus occurring in bitches in association with pregnancy are reported. In the first case, a bitch with suspected acromegaly developed diabetes mellitus within 2 weeks of the due date. Despite insulin therapy, euglycaemia was not achieved. Tw o live, small pups were delivered by elective Caesarean section but died within 2 days. Signs consistent with acromegaly resolved but diabetes mellitus was permanent in the bitch. In the second case, diabetic ketosis with severe gastrointestinal disease was diagnosed 2 days after Caesarean section was performed due to dystocia. The pups delivered all died within 5 days. The bitch recovered fully from diabetes mellitus within 2 weeks and has remained euglycaemic without insulin for a period of at least 18 months.

CLINICAL RELEVANCE: These two cases demonstrate that diabetes mellitus can occur in association with pregnancy in dogs, that diabetic ketosis can occur during transient diabetes mellitus in dogs, and suggest that acromegaly may occur during pregnancy-related dioestrus in dogs. The scarcity of previous reports of this nature, however, suggests that such cases are unusual.

Lack of prompt resolution of hyperglycaemia may result in secondary diabetes mellitus becoming permanent. Management should focus on immediate insulin therapy or ovariohysterectomy to minimise this risk. Even mild hyperglycaemia should not be ignored during pregnancy. The insulin antagonistic effects of pregnancy, stressful illness, surgery and dystocia can be enough to result in diabetic ketosis in the absence of permanent insulin deficiency. Maternal hyperglycaemia may contribute to adverse fetal outcomes in dogs but further study is required regarding the nature of the risk.     

A re-examination of islet cell cytoplasmic antibodies in diabetic dogs

Serum samples were obtained from 48 dogs with recently diagnosed untreated diabetes mellitus. Serums were tested for cytoplasmic autoantibodies to normal canine pancreatic islet antigens by indirect immunofluorescence, peroxidase-anti-peroxidase, and avidin-biotin complex, immunohistochemistry. Autoantibodies were not detectable in any of the samples. Serums were also examined from 20 diabetic dogs maintained on exogenous insulin therapy for periods of one month to five years. Positive reactions were seen in 11 dogs. These positive responses were completely absorbed by preincubation of serums with commercial insulin preparations or with purified pork or beef insulin. Newly diagnosed diabetic dogs do not have readily detectable autoantibodies to islet cytoplasmic antigens. Our previous report (Haines and Penhale, 1985) of islet antibody in diabetic dogs with unknown clinical histories was likely demonstrating antibody to insulin in patients treated with exogenous insulin. Antibodies to insulin were detected in approximately half of the insulin treated dogs tested. These antibodies were induced by commercial beef and pork insulin preparations and were found to be broadly cross-reactive recognizing epitopes on canine, bovine and porcine insulins.     

Pregnancy-related diabetes mellitus in two dogs

CASE SUMMARIES: Two cases of diabetes mellitus occurring in bitches in association with pregnancy are reported. In the first case, a bitch with suspected acromegaly developed diabetes mellitus within 2 weeks of the due date. Despite insulin therapy, euglycaemia was not achieved. Two live, small pups were delivered by elective Caesarean section but died within 2 days. Signs consistent with acromegaly resolved but diabetes mellitus was permanent in the bitch. In the second case, diabetic ketosis with severe gastrointestinal disease was diagnosed 2 days after Caesarean section was performed due to dystocia. The pups delivered all died within 5 days. The bitch recovered fully from diabetes mellitus within 2 weeks and has remained euglycaemic without insulin for a period of at least 18 months. CLINICAL RELEVANCE: These two cases demonstrate that diabetes mellitus can occur in association with pregnancy in dogs, that diabetic ketosis can occur during transient diabetes mellitus in dogs, and suggest that acromegaly may occur during pregnancy-related dioestrus in dogs. The scarcity of previous reports of this nature, however, suggests that such cases are unusual. Lack of prompt resolution of hyperglycaemia may result in secondary diabetes mellitus becoming permanent. Management should focus on immediate insulin therapy or ovariohysterectomy to minimise this risk. Even mild hyperglycaemia should not be ignored during pregnancy. The insulin antagonistic effects of pregnancy, stressful illness, surgery and dystocia can be enough to result in diabetic ketosis in the absence of permanent insulin deficiency. Maternal hyperglycaemia may contribute to adverse fetal outcomes in dogs but further study is required regarding the nature of the risk.     

Samoyed hereditary glomerulopathy: serial, clinical and laboratory (urine, serum biochemistry and hematology) studies.

Human hereditary nephritis refers to familial glomerular diseases which may progress to renal failure. Samoyed hereditary glomerulopathy has been shown previously to be a model for hereditary nephritis. Clinical and laboratory studies were performed to follow progression to renal failure in 44 dogs in a family with Samoyed hereditary glomerulopathy. Affected males appeared healthy for their first three months but then became progressively wasted. Proteinuria was detected between two to three months of age; after five months, urine protein electrophoresis showed pre-albumin, albumin and alpha and beta globulin peaks. From three months onward, a reduced glomerular filtration rate was detected. Serum albumin decreased while amylase, urea, creatinine and phosphate increased from four to five months of age. Death from renal failure occurred by 15 months. Carrier females also became thinner and developed proteinuria between two and three months of age, but neither renal failure nor death ensured. Hence, SHG progressed rapidly in affected males but not in carrier females.     

Nondiabetic emphysematous cystitis in two dogs.

Emphysematous cystitis unassociated with diabetes mellitus was diagnosed in two dogs. One dog had chronic recurring urinary tract infection with aerobic and anaerboic bacteria, and the other had urinary tract infection associated with renal glucosuria. In both dogs, the cystitis was resolved with appropriate antibacterial therapy.     

Spontaneously obese dogs exhibit greater postprandial glucose, triglyceride, and insulin concentrations than lean dogs

Dogs do not appear to progress from obesity-induced insulin resistance to type 2 diabetes mellitus. Both postprandial hyperglycemia and postprandial hypertriglyceridemia have been proposed to cause or maintain beta cell failure and progression to type 2 diabetes mellitus in other species. Postprandial glucose, triglyceride, and insulin concentrations have not been compared in lean and obese dogs. We measured serum glucose, triglyceride, and insulin concentrations in nine naturally occurring obese and nine age- and gender-matched lean dogs. After a 24-h fast, dogs were fed half their calculated daily energy requirement of a standardized diet that provided 37% and 40% of metabolizable energy as carbohydrate and fat, respectively. Fasting and postprandial glucose and triglyceride concentrations were greater in the obese dogs (P < 0.001), although the mean insulin concentration for this group was five times greater than that of the lean group (P < 0.001). Most of the 0.6 mM (11 mg/dL) difference in mean postprandial glucose concentrations between lean and obese dogs was attributable to a subset of persistently hyperglycemic obese dogs with mean postprandial glucose concentrations 1.0 mM (18 mg/dL) greater than that in lean dogs. Persistently hyperglycemic obese dogs had lower triglyceride (P = 0.02 to 0.04) and insulin (P < 0.02) concentrations than other obese dogs. None of the dogs developed clinical signs of diabetes mellitus during follow-up for a median of 2.6 yr. We conclude that pancreatic beta cells in dogs are either not sensitive to toxicity because of mild hyperglycemia or lack another component of the pathophysiology of beta cell failure in type 2 diabetes mellitus.     

Endogenous serum insulin concentration in dogs with diabetic ketoacidosis

Objective: To determine endogenous serum insulin concentration in dogs with diabetic ketoacidosis (DKA), and to compare it to endogenous serum insulin concentration in diabetic dogs with ketonuria but no acidosis (KDM), diabetic dogs with uncomplicated diabetes mellitus (DM) that did not have ketonuria or acidosis, and dogs with non‐pancreatic disease (NP). Design: Prospective study. Setting: Veterinary Hospital of the University of Pennsylvania. Animals: Forty‐four client‐owned dogs; 20 dogs with newly diagnosed diabetes mellitus (7 dogs with DKA, 6 dogs with KDM, and 7 dogs with DM) and 24 dogs with non‐pancreatic disease. Interventions: Blood and urine samples were obtained at the time of admission to the hospital. Measurements and main results: Signalment, clinical signs, physical examination findings, and concurrent disease were recorded for all dogs. Blood glucose concentration, venous blood pH, venous blood HCO3^? concentration, urinalysis, and endogenous serum insulin concentration were determined in all dogs. Dogs with DKA have significantly decreased endogenous serum insulin concentrations compared to dogs with DM (P = 0.03) and dogs with non‐pancreatic disease (P = 0.0002), but not compared to dogs with KDM (P = 0.2). Five of 7 dogs with DKA had detectable endogenous serum insulin concentrations, and 2 of these dogs had endogenous serum insulin concentration within the normal range. Conclusions: Diabetic dogs with ketoacidosis have significantly decreased endogenous serum insulin concentration compared to dogs with uncomplicated diabetes mellitus. However, most dogs with DKA have detectable endogenous serum insulin concentrations, and some dogs with DKA have endogenous serum insulin concentrations within the normal range.     

Autoantibodies to pancreatic islet cells in canine diabetes mellitus

Indirect immunofluorescence on normal canine pancreatic tissue fixed in Bouin's solution was used to detect islet cell antibodies in dogs with diabetes mellitus, other endocrine diseases, and pancreatitis. 18 of 25 dogs with diabetes mellitus alone, 2 of 8 dogs with diabetes mellitus and concurrent pancreatitis, and 2 of 2 dogs with diabetes mellitus and concurrent pancreatic exocrine insufficiency were positive for autoantibody. 2 of 12 dogs with hypoadrenocorticism, 3 of 6 dogs with hyperadrenocorticism, 6 of 28 dogs with hypothyroidism and one of 19 dogs with pancreatitis alone were also antibody positive. None of 20 healthy dogs or 20 dogs with disorders other than those of the pancreas or endocrine organs were antibody positive. Islet cell antibodies were demonstrated in dogs with diabetes mellitus and other endocrine disorders. The possibility of autoimmune involvement in the development of diabetes mellitus in the dog should be considered.     

Ocular complications of persistent hyperplastic primary vitreous in three dogs

Persistent hyperplastic primary vitreous (PHPV) syndrome associated with either severe ocular complications or multiple ocular lesions was diagnosed in three young dogs, a Samoyed, a Spanish Pachon, and a mixed breed dog. Due to opacification of the anterior ocular structures, B-mode and color-flow Doppler ultrasonography were performed to aid diagnosis. The Samoyed presented with unilateral hyphema; the Spanish Pachon presented with unilateral secondary glaucoma associated with uveitis and hyphema OD and leucocoria OU; and the mixed breed presented with bilateral leucocoria. B-mode ultrasonography of the Samoyed revealed a subcapsular cataract and a hyperechoic tubular structure attached from the optic disk to the posterior lens capsule. In the Spanish Pachon B-mode ultrasonography of the right eye indicated microphakia, cataract formation, and a retrolental mass with a thin hyperechoic strand stretching from the optic disk to the posterior lens; and for the right eye cataract formation, PHPV, retinal detachment, and vitreous hemorrhage. In the mixed breed dog, B-mode ultrasonography of both eyes indicated microphthalmia, retrolental mass, and hyperechoic lenses. By color-flow Doppler imaging, blood flow was present in the retrolental mass of the right eye suggesting a persistent hyaloid artery.     

Morphologic and immunocytochemical study of young dogs with diabetes mellitus associated with pancreatic islet hypoplasia

In 11 dogs (7 males, 4 females; 10 purebred, 1 mixed breed), diagnosed as having diabetes mellitus before the age of 6 months, the pancreas was evaluated histologically; in 6, the pancreas also was examined by use of electron microscopy and/or immunocytochemical methods. Each dog was placed in 1 of 3 groups (A through C) on the basis of pancreatic histopathologic findings: Group A (n = 3)--no recognizable islets, but the pancreas in 2 dogs contained scattered endocrine cells detectable by use of immunoperoxidase staining or electron microscopy; Group B (n = 4)--no recognizable islets, but the pancreas had severe vacuolation of ducts and acini, as well as acinar atrophy; Group C (n = 4)--scant shrunken islets; 1 pancreas had reduced numbers of recognizable islets, hydropic beta-cell vacuolation attributable to glycogen deposition, and islet and nonislet endocrine cells in expected proportions. Insulitis was not observed in any pancreas, although scattered lymphocytes were seen in the pancreatic interstitial fibrous tissue of 3 dogs. Histologic pancreatic lesions in these young dogs were distinct from those of type-I (insulin-dependent) diabetes mellitus in human beings, as well as from those of diabetes mellitus in aged dogs, but were similar to those described in other young diabetic dogs. This uncommon syndrome is distinct from commonly recognized canine diabetes mellitus, on the basis of age of onset, predisposition for purebred dogs, lack of predisposing endocrinopathies or obesity, and pancreatic histologic features. The cause(s) is unknown, but is related to pancreatic endocrine hypoplasia and not to insulitis or to exocrine pancreatic inflammation. The term pancreatic islet hypoplasia is chosen as best describing this disorder.