Genetically altered mice are at the center of much of the drug discovery world, and metabolic disease is no exception. The ob/ob, db/db and NOD mouse models are widely used across the field as they offer a defined and robust whole-body phenotype of diabetes, with the ob/ob and db/db specifically adding an obese phenotype to the profile. The ob/ob and db/db strains have deficiencies in the leptin signaling pathway (lacking leptin and lacking the leptin receptor, respectively), which results in an early phenotype of hyperphagia and an ensuing profile of impaired glucose tolerance, reduced insulin sensitivity, hyperglycemia (transient in the ob/ob mouse) and hyperinsulinemia. The db/db mouse is a more aggressive model of type 2 diabetes that will progress to pancreatic failure and frank diabetes.
Development of type-1 diabetes in the NOD mouse model
Blood glucose levels (mmol/l).
Incidence of hyperglycaemia (%) over a 20 week period.
The NOD mouse provides an animal model that is similar to the etiology of type 1 diabetes. The severe combined immunodeficiency (SCID) mutation provides a genetic background for insulitis to develop in the pancreatic beta cell by way of leukocyte infiltration, resulting in a type 1 diabetic-specific phenotype of glycosuria and hyperglycemia.
All these mouse models are well suited for assessment of drug candidates in a chronic (2–4 week studies are common among discovery groups) setting paired with oral glucose tolerance tests and drug target-specific biomarkers, as well as advanced histological endpoints. Whether your group is looking to screen compounds to identify a lead candidate or dive deeper into mechanism-of-action studies to prepare for IND submission, these mouse models are useful tools that our scientists have relied on for years to help clients move towards the clinic.