Exploring Human/Animal Intersections: Converging Lines of Evidence in Comparative Models of Aging

At a symposium convened on March 8, 2007 by the Institute on Aging at the University of Pennsylvania, researchers from the University’s Schools of Medicine and Veterinary Medicine explored the convergence of aging research emerging from the two schools. Studies in human patients, animal models, and companion animals have revealed different but complementary aspects of the aging process, ranging from fundamental biologic aspects of aging to the treatment of age-related diseases, both experimentally and in clinical practice. Participants concluded that neither animal nor human research alone will provide answers to most questions about the aging process. Instead, an optimal translational research model supports a bidirectional flow of information from animal models to clinical research

Development of a requirement for exogenous insulin treatment in dogs with hyperglycemia

Abstract Background It has been suggested that overt diabetes mellitus in dogs be defined based on a persistent fasting blood glucose concentration (BGC) >144 mg/dL. Objective Determine the number of dogs with randomly identified hyperglycemia without insulin‐treated diabetes mellitus (ITDM) that later develop a need for exogenous insulin treatment. Animals A total of 1318 dogs examined at a university teaching hospital without ITDM and with randomly identified hyperglycemia. Methods Retrospective longitudinal study. Hyperglycemia was defined as randomly identified BGC above >112 mg/dL, moderate hyperglycemia as BGC >144 mg/dL but <200 mg/dL and pronounced hyperglycemia as BGC ≥200 mg/dL. Dogs were defined as having ITDM if they were treated with insulin. Follow‐up was attempted 7 to 12 years after hyperglycemia was documented to determine if over time dogs developed a need for exogenous insulin treatment. Results Twenty‐nine of 824 dogs (3.5%) with hyperglycemia and follow‐up information developed ITDM, including 3/824 dogs (0.4%) with moderate hyperglycemia, and 2/824 dogs (0.2%) with pronounced hyperglycemia. Most dogs with hyperglycemia that developed ITDM (24/29, 83%) had BGC ≤144 mg/dL. Among dogs that eventually developed a need for exogenous insulin treatment, no association was found between the degree of hyperglycemia and the time interval between documentation of hyperglycemia and diagnosis of ITDM. Logistic regression determined that BGC is not significantly associated with ITDM. Conclusions and Clinical Importance Most dogs with randomly identified hyperglycemia did not develop a need for exogenous insulin treatment. Other criteria could be required to augment the definition of overt DM in non‐insulin treated dogs

Heritability and complex segregation analysis of naturally-occurring diabetes in Australian Terrier Dogs.

The Australian Terrier breed is the breed at highest risk for naturally-occurring diabetes mellitus in the United States, where it is 32 times more likely to develop diabetes compared to mixed breed dogs. However, the heritability and mode of inheritance of spontaneous diabetes in Australian Terriers has not been reported. The aim of this study was therefore to investigate the heritability and mode of inheritance of diabetes in Australian Terriers. A cohort of related Australian Terriers including 383 Australian Terriers without diabetes, 86 Australian Terriers with spontaneous diabetes, and 14 Australian Terriers with an unknown phenotype, was analyzed. A logistic regression model including the effects of sex was formulated to evaluate the heritability of diabetes. The inheritance pattern of spontaneous diabetes in Australian Terriers was investigated by use of complex segregation analysis. Six possible inheritance models were studied, and the Akaike Information Criterion was used to determine the best model for diabetes inheritance in Australian Terriers, among the models deemed biologically feasible. Heritability of diabetes in Australian Terriers was estimated at 0.18 (95% confidence interval 0.0-0.67). There was no significant difference in the effect of males and females on disease outcome. Complex segregation analysis suggested that the mode of diabetes inheritance in Australian Terriers is polygenic, with no evidence for a large effect single gene influencing diabetes. It is concluded that in the population of Australian Terriers bred in the United States, a relatively small degree of genetic variation contributes to spontaneous diabetes. A genetic uniformity for diabetes-susceptible genes within the population of Australian Terriers bred in the Unites States could increase the risk of diabetes in this cohort. These findings hold promise for future genetic studies of canine diabetes focused on this particular breed

Effect of sodium‐glucose cotransporter 2 inhibitor canagliflozin on interstitial glucose concentration in insulin‐treated diabetic dogs

Abstract Background The utility of sodium‐glucose cotransporter 2 inhibitors (SGLT2i) has not been reported in insulin‐treated diabetic dogs. Hypothesis Canagliflozin, a PO‐administered SGLT2i, decreases interstitial glucose concentration (IG) in insulin‐treated diabetic dogs. Animals Five insulin‐treated diabetic dogs. Methods Uncontrolled open label longitudinal study. Canagliflozin (2‐4 mg/kg/day PO) was added to an unchanged insulin dose for 7 days. Fractional excretion of glucose was calculated by dividing the product of urine glucose and serum creatinine concentrations by the product of serum glucose and urine creatinine concentrations. Hypoglycemia was defined as IG <60 mg/dL. Results Median IG in 2869 measurements obtained while dogs were treated with insulin and canagliflozin was 87 mg/dL (range, 40‐500 mg/dL) and was significantly lower than median IG in 1426 measurements obtained while dogs were treated with insulin alone (212 mg/dL; range, 41‐500 mg/dL; P < .001). Median fractional excretion of glucose when dogs were treated with insulin and canagliflozin was 1.1% (range, 0.9%‐2.0%), significantly higher than when dogs were treated with insulin alone (0.3%; range, 0.01%‐1.0%; P = .04). The frequency of hypoglycemia was higher in dogs treated with insulin and canagliflozin (544 of 2869 IG measurements, 19%) compared with the frequency of hypoglycemia in dogs treated with insulin alone (52 of 1426 IG measurements, 4%; P < .001). Conclusions and Clinical Importance Canagliflozin may have a role in improving glycemic control in insulin‐treated diabetic dogs, but the dose of insulin should be decreased when adding canagliflozin to insulin treatment

Heritability and complex segregation analysis of diabetes mellitus in American Eskimo Dogs.

BackgroundHeritability and mode of inheritance of spontaneous diabetes mellitus (DM) in American Eskimo Dogs (AED) are unknown.ObjectiveInvestigate the heritability and mode of inheritance of DM in AED.AnimalsAn extended family of AED including 71 AED without DM, 47 AED with an unknown phenotype, and 38 AED with spontaneous DM.MethodsRetrospective evaluation of inheritance. A logistic regression model was formulated to evaluate the heritability of DM, including effects of sex and neuter status. Subsequently, complex segregation analysis was employed to investigate the inheritance pattern of DM in AED. Six plausible models were considered, and the Akaike Information Criterion was used to determine the best of the biologically feasible models of inheritance of DM in AED.ResultsHeritability of DM in AED is estimated at 0.62 (95% posterior interval 0.01-0.99). Predicted DM probabilities for neutered females (NF), intact females (IF), neutered males (NM), and intact males (IM) were 0.76, 0.11, 0.63, and 0.12, respectively. There was no overlap between the 95% posterior intervals of disease probabilities in NF and IF or in NF and IM. Complex segregation analysis suggested that the mode of inheritance of DM in AED is polygenic, with no evidence for a single gene of large effect.Conclusions and clinical importanceThe estimated heritability of DM in AED is high but has low precision. Diabetes mellitus transmission in AED appears to follow a polygenic inheritance. Breeders could successfully implement a breeding program to decrease the incidence of DM in AED