Modeling long-term diabetes and related complications in rats

Introduction: Accurate preclinical modeling of diabetic complications such as retinopathy, nephropathy and neuropathy is crucial to enable the development of novel preventative therapies. The aims of this study were to establish a model of long-term diabetes with sustained medium scale hyperglycemia and characterize the pathological changes detectable after 4 months, with particular respect to dependence on the degree of hyperglycemia. Methods: Streptozotocin-induced diabetic CFY rats were subjected to four different insulin substitution protocols to achieve different levels of glycemic control (Diabetic 1-4 groups). Eyes were investigated by ophthalmoscopy, kidney function by urine analysis, and neuropathy by functional tests. Retinal and renal morphological evaluations were performed by histology, immuno-histochemistry and electron microscopy. Results: Rats of the Diabetic 3 group showed massive hyperglycemia-dependent anterior segment neovascularization, enhanced total retinal score and retinal apoptotic cell number, degeneration of dopaminergic amacrine cells, increased glomerular PAS-positivity, altered excreted total protein/creatinine ratio and cold allodynia, parallel with medium scale hyperglycemia (blood glucose level between 22 and 25 mmol/L) and satisfying state of health. Discussion: We established a treatment protocol in rats enabling complex investigation of diabetic retinopathy, nephropathy and neuropathy on a long-termperiod. Clearly hyperglycemic dependent parameters of these complications serve as good outcome measures for preclinical trials. Our results provide a useful basis for designing studies for testing preventative treatments as well as other translational medical research in this field. (C) 2015 Elsevier Inc. All rights reserved.