Clinical and pathological characterization of a novel transgenic animal model of diabetes mellitus expressing a dominant negative glucose-dependent insulinotropic polypeptide receptor (GIPR dn)

Clinical and pathological characterization of a novel transgenic animal model of diabetes mellitus expressing a dominant negative glucose-dependent insulinotropic polypeptide receptor (GIPR dn) Gastrointestinal hormones like glucose-dependent insulinotropic polypeptide have recently been shown to be involved in the pathogenesis of diabetes mellitus in humans and animals models of diabetes mellitus. The aim of this study was to characterize a novel transgenic mouse model expressing a dominant negative glucosedependent insulinotropic polypeptide receptor (GIPRdn) under the control of the rat insulin gene promoter and their non-transgenic counterparts. Detailed analysis of clinical parameters was performed, including urine glucose, blood or serum glucose and serum insulin values. In addition, oral and subcutaneous glucose tolerance tests were performed, and HbA1c levels and various serum parameters were determined. The detection of the daily food and water intake and the daily urine volume was performed in two age groups. Further, body and organ weights were determined. Qualitative and quantitative morphological changes of the pancreas and the kidneys were investigated in several age groups. Some of the parameters were studied in different diet groups, one of them received standard rodent chow, and the other received a carbohydrate-restricted diet until four months of age. All transgenic mice studied exhibited severe glucosuria from 21 days of age onwards. From 30 days of age onwards, GIPRdn transgenic males and females showed severe hyperglycemia and hypoinsulinemia (p<0.05). In male transgenic animals, the fasted body weight was found to be lower than in age-matched male control mice. The daily food and water intake and the 24-hour urine volume were significantly higher in all transgenic animals investigated. Histological and immunohistochemical survey of the pancreas revealed a striking change of the islet cell composition and distribution. Further, quantitative- stereological analysis of the pancreas revealed a significant reduction of the total volumes of pancreatic islets, B-cells in the islets and isolated B-cells in the exocrine pancreas indicating neogenesis of islets. Kidney changes included renal and glomerular hypertrophy, glomerulosclerosis and tubulo-interstitial changes. In conclusion, transgenic mice expressing a dominant negative GIP receptor under the control of the rat insulin gene promoter develop a severe diabetic phenotype and striking 138 histological changes of the endocrine pancreas. Further, advanced diabetesassociated organ lesions, particularly of the kidney were observed and therefore, GIPRdn transgenic mice are considered a valuable model for studying long-term complications of diabetes mellitus.

Level thesis:degree_level

thesis.doctoral

Grantor dc:publisher

Ludwig-Maximilians-Universität

Year

2002

Author dc:creator

• Herbach, Nadja

Repository record source_url

https://edoc.ub.uni-muenchen.de/1008/

OAI identifier oai:identifier

oai:edoc.ub.uni-muenchen.de:1008