title: Validity of animal models of type 1 diabetes, and strategies to enhance their utility in translational research.
abstract: Type 1 diabetes currently affects 20-40 million people worldwide. Insulin treatment is standard, but a majority of patients still experience glycemic instability and associated comorbidity: there is an unmet medical need for novel therapeutics. Animal models have been indispensable in testing innovative medicinal approaches since the early testing of insulin in dogs almost a century ago. Models include mainly rodents with spontaneous diabetes, or rodents and nonhuman primates in which diabetes is induced by chemicals that are toxic to insulin-producing pancreatic β-cells, or by pancreatectomy. To a less extent models in pigs are used. Rodent models have shown value in studies on pathogenesis and disease prevention, while models in nonhuman primates have translational value in testing β-cell replacement products and immunosuppressives to prevent rejection. Evidently, for many immunosuppressives this validation follows from the close similarity in immune function. Gene therapy approaches are being tested in both rodents and nonhuman primates. We present an overview of models used to answer various research questions, with particular focus on their translational value. This includes a consideration of divergence between the animal model and the clinical condition, and a consideration of the species and model difference in pathogenesis, especially the induction of the diabetic state. Careful attention should be given to managing diabetic animals: outcome measures in the model are highly stress-sensitive and parameters that have potential for confounding should be addressed, i.e., environment, metabolic management, and handling. This review concludes with a few recommendations on how to make animal models more clinical-like.
authors: University of Minnesota, Department of Surgery, St. Paul, MN, USA; University of Minnesota, Veterinary Population Medicine Department, St. Paul, MN, USA. Electronic address: graha066@umn.edu.
authors: Melanie L
authors: ML
authors: Graham
authors: SchuBiomed Consultancy BV, Utrecht, The Netherlands. Electronic address: Schuurman2@planet.nl.
authors: Henk-Jan
authors: HJ
authors: Schuurman
mesh_terms: D000818:Animals; D017690:Cell Transplantation; D003921:Diabetes Mellitus, Experimental / Q000209:etiology* / Q000276:immunology / Q000517:prevention & control / Q000628:therapy*; D003922:Diabetes Mellitus, Type 1 / Q000209:etiology* / Q000276:immunology / Q000517:prevention & control / Q000628:therapy*; D006801:Humans; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D050417:Insulin-Secreting Cells / Q000637:transplantation; D013045:Species Specificity; D057170:Translational Research, Biomedical / Q000379:methods*
chemical_list: D007166:Immunosuppressive Agents
keywords: Animal models; Cell therapy; Immunosuppressives; Nonhuman primate; Rodent; Type 1 diabetes