Diabetes is a disease characterized by hyperglycemia due to lack of insulin. Animal models are useful to study the pathophysiology and complications of diabetes. The studies shown below provide some characterization parameters on monogenic, multigenic and diabesity models that are critical for choosing the best models.
Goto-Kakizaki rat is an inbred model bred selectively for insulin resistance. As this model is not bred in a classical way of inbreeding, some genetic heterogeneity is expected. We observed variability in hyperglycemia and tested if this is due to genetic heterogeneity by selective improvement of phenotype. We found a significant improvement in the hyperglycemia within a generation (pre-selection vs post-selection glucose levels - 160.0+1.1 vs 174.8+1.6 mg/dl; p<0.001; n=3990). The data suggests that the genetic heterogeneity for hyperglycemia is prevalent in this model and could be exploited for identification of candidate genes for hyperglycemia.
NOD model is also an inbred model to study type I diabetes, it develops diabetes due to insulitis starting at about 8 weeks of age. There are many gene-environment interactions influencing the penetrance of diabetic phenotype in this model. We assessed whether environmental variation due to change in health status can alter the penetrance of Diabetes in NOD/MrkTac model. Our data shows that the health status variation may not be an influencing factor for the disease as the colonies show no variability in diabetic prevalence in 2 different health statuses.
Diet induced obesity (DIO) in C57BL/6NTac strain is being used for testing many drugs against diabesity and associated complications. This model have functional nicotinamide nucleotide transhydrogenase (Nnt) gene that is absent in the “J” strain. NNT is a major source of mitochondrial NADPH and its functional loss results in mitochondrial redox abnormalities. Our phenotypic study shows that DIO Tac model is heavier, have higher cholesterol and are more insulin resistant than age matched DIO Jax model.
Leptin receptor deficiency in C57BLKS genetic background is an inbred monogenic model, which shows sustained rise in blood sugar as the animal ages ( 200 mg/dl at 4 weeks to 500 mg/ dl at 9 weeks of age) due to depletion of beta cells.
We will present data that will compare and contrast the use of these models and their parameters that need to be considered when breeding these for studies. Ideally, diversity seen in human patients can be studied using more than one model.