Type 1 diabetes is an autoimmune condition that manifests in predisposed, genetically susceptible individuals. It is a disease characterized by the infiltration of leukocytes within pancreatic islets, resulting in the eventual destruction of insulin-producing beta cells. Insilitis may present in Type 1 diabetics for an extended period before beta cells are terminally destroyed.
Susceptible NOD mice begin presenting insilitis at approximately 12-weeks of age. Injecting these animals with cyclophosphamide destroys beta cells causing the mice to become diabetic. The cyclophosphamide-induced beta cell destruction in NOD mice mimics many of the clinical manifestations of final stage type 1 diabetogenesis and is a model that can be used to screen compounds used in treating this disease.
Preclinical Drug Efficacy Studies
Mice (NOD, Female, acquired at 10-weeks, tested at 12-weeks)
Animals arrive at the facility at 10-weeks of age and undergo a 2-week acclimation period. At 12-weeks of age (Study Day 1) body weights and fasting glucose measures are obtained 1X/week. Mice begin receiving injections of cyclophosphamide (300 mpk bw) at study week 2.5. Glucose tolerance (GTT) is measured before and after cyclophosphamide injection. Animals are considered diabetic when their blood glucose reaches a concentration of 250 mg/dL. Damage to pancreatic tissues due to diabetic status is determined through histological examination.
Clinical observations, body weight (1X/week), GTT, histological examination of pancreatic tissue to determine degree of lymphatic infiltration, calculation of insilitis using the Insilitis index (I)
Chaparro RJ, Konigshafer Y, Beilhack GF, Shizuru JT, McDevitt HO, Chien YH. (2006) Non-obese diabetic mice express aspects of both type 1 and type 2 diabetes. Proc. Natl Acad Sci USA; 103: 12475-80.
Mator M, Park R, Mathis D, Benoist C. (2004) Progression to islet destruction in a cyclophosphamide-induced transgenic model: a microarray overview. Diabetes; 53:2310-21.