Abstract:
INTRODUCTION:We characterised the development of Type 2 diabetes and associated changes in islet appearance in female ZDF rats and explored its suitability for studies with novel therapeutic agents. METHODS:Female ZDF rats were either chow or high fat (60%) fed for up to 36 days and blood glucose and plasma insulin concentration measured. Additionally, we restored two groups of rats back to chow diet after ten and nineteen days of high fat feeding to determine the reversibility. Finally, two other groups of high fat-fed animals were dosed either orally with drug vehicle or had a minipump implanted subcutaneously to determine the effect of dosing method upon the progression of this disease model. The beta cell mass and morphology were assessed by immunohistochemistry for insulin. RESULTS:High fat feeding elevated blood glucose compared to chow-fed controls which peaked by 15 days, and maintained throughout the study. Plasma insulin reached a maximum after 8 days, but declined over the remaining 4 weeks. Assessment of islets revealed marked disruption, dispersion and weaker insulin staining. The area and percentage β-cells were higher in high fat-fed animals. High fat diet treatment reversal when animals were moderately hyperglycaemic, when plasma insulin was still elevated, reversed the hyperglycaemia and maintained islet morphology similar to that of chow-fed animals. In contrast, dietary reversal when plasma insulin was declining, did not prevent continual decline in plasma insulin, β-cell mass or islet disruption. Oral dosing tended to increase blood glucose and decrease plasma insulin whereas administration by minipump lowered blood glucose. DISCUSSION:The obese female ZDF rat offers the opportunity for preclinical evaluation of novel therapies directed towards improving pancreatic function, provided treatment is initiated prior to the precipitous decline in insulin production. Caution should be exercised in comparison of compounds administered by different dosing routes however.
journal_name
J Pharmacol Toxicol Methodsjournal_title
Journal of pharmacological and toxicological methodsauthors
Teague J,Gyte A,Peel JE,Young KC,Loxham SJ,Mayers RM,Poucher SMdoi
10.1016/j.vascn.2010.04.001subject
Has Abstractpub_date
2011-01-01 00:00:00pages
15-23issue
1eissn
1056-8719issn
1873-488Xpii
S1056-8719(10)00049-3journal_volume
63pub_type
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