title: Modeling long-term diabetes and related complications in rats.
abstract: BACKGROUND
  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 4months, 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 25mmol/L) and satisfying state of health.
  
  
  CONCLUSIONS
  We established a treatment protocol in rats enabling complex investigation of diabetic retinopathy, nephropathy and neuropathy on a long-term period. 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.
authors.affiliation: Department of Pharmacology and Pharmacotherapy, Faculty of Medicine, University of Pécs, H-7624, Pécs, Szigeti út 12., Hungary; János Szentágothai Research Centre, University of Pécs, H-7624, Pécs, Ifjúság útja 20., Hungary.
authors.forename: Zsófia
authors.initials: Z
authors.lastname: Hajna
authors.affiliation: János Szentágothai Research Centre, University of Pécs, H-7624, Pécs, Ifjúság útja 20., Hungary; Department of Experimental Zoology and Neurobiology, Faculty of Science, University of Pécs, H-7624, Pécs, Ifjúság útja 6., Hungary.
authors.forename: Krisztina
authors.initials: K
authors.lastname: Szabadfi
authors.affiliation: Department of Ophthalmology, Faculty of Medicine, University of Pécs, H-7624, Pécs, Nyár u. 8., Hungary.
authors.forename: Zsolt
authors.initials: Z
authors.lastname: Balla
authors.affiliation: Department of Ophthalmology, Faculty of Medicine, University of Pécs, H-7624, Pécs, Nyár u. 8., Hungary.
authors.forename: Zsolt
authors.initials: Z
authors.lastname: Biró
authors.affiliation: 2nd Department of Internal Medicine, Faculty of Medicine, University of Pécs, H-7624, Pécs, Pacsirta u. 1., Hungary.
authors.forename: Péter
authors.initials: P
authors.lastname: Degrell
authors.affiliation: 2nd Department of Internal Medicine, Faculty of Medicine, University of Pécs, H-7624, Pécs, Pacsirta u. 1., Hungary.
authors.forename: Gergő A
authors.initials: GA
authors.lastname: Molnár
authors.affiliation: Department of Laboratory Medicine, Faculty of Medicine, University of Pécs, H-7624, Pécs, Ifjúság útja 13., Hungary.
authors.forename: Tamás
authors.initials: T
authors.lastname: Kőszegi
authors.affiliation: Department of Pharmacology and Pharmacotherapy, Faculty of Medicine, University of Pécs, H-7624, Pécs, Szigeti út 12., Hungary; János Szentágothai Research Centre, University of Pécs, H-7624, Pécs, Ifjúság útja 20., Hungary.
authors.forename: Valéria
authors.initials: V
authors.lastname: Tékus
authors.affiliation: Department of Pharmacology and Pharmacotherapy, Faculty of Medicine, University of Pécs, H-7624, Pécs, Szigeti út 12., Hungary; János Szentágothai Research Centre, University of Pécs, H-7624, Pécs, Ifjúság útja 20., Hungary; MTA-PTE NAP B Chronic Pain Research Group, Hungary.
authors.forename: Zsuzsanna
authors.initials: Z
authors.lastname: Helyes
authors.affiliation: "Kiséri" Veterinarian Praxis, H-6600, Szentes, Sáfrán Mihály u. 43., Hungary.
authors.forename: András
authors.initials: A
authors.lastname: Dobos
authors.affiliation: Department of Pharmacology and Pharmacotherapy, Faculty of Medicine, University of Pécs, H-7624, Pécs, Szigeti út 12., Hungary; Gedeon Richter Plc., H-1475, Budapest, X. Gyömrői út 19-21., Hungary.
authors.forename: Sándor
authors.initials: S
authors.lastname: Farkas
authors.affiliation: Gedeon Richter Plc., H-1475, Budapest, X. Gyömrői út 19-21., Hungary.
authors.forename: Gyula
authors.initials: G
authors.lastname: Szűcs
authors.affiliation: János Szentágothai Research Centre, University of Pécs, H-7624, Pécs, Ifjúság útja 20., Hungary; Department of Experimental Zoology and Neurobiology, Faculty of Science, University of Pécs, H-7624, Pécs, Ifjúság útja 6., Hungary.
authors.forename: Róbert
authors.initials: R
authors.lastname: Gábriel
authors.affiliation: Department of Pharmacology and Pharmacotherapy, Faculty of Medicine, University of Pécs, H-7624, Pécs, Szigeti út 12., Hungary; János Szentágothai Research Centre, University of Pécs, H-7624, Pécs, Ifjúság útja 20., Hungary. Electronic address: erika.pinter@aok.pte.hu.
authors.forename: Erika
authors.initials: E
authors.lastname: Pintér
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D001835:Body Weight / Q000502:physiology; D003921:Diabetes Mellitus, Experimental / Q000097:blood / Q000150:complications* / Q000473:pathology*; D003928:Diabetic Nephropathies / Q000097:blood / Q000150:complications* / Q000473:pathology*; D003930:Diabetic Retinopathy / Q000097:blood / Q000150:complications* / Q000473:pathology*; D004195:Disease Models, Animal; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D001786:Blood Glucose
keywords: Anterior segment neovascularization; Chronic model; Cold allodynia; Diabetic nephropathy; Diabetic neuropathy; Diabetic retinopathy; Drug development; Insulin implant; Preclinical model; Streptozotocin