Reversibility of hyperglycaemia and islet abnormalities in the high fat-fed female ZDF rat model of type 2 diabetes.
BACKGROUND
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.


CONCLUSIONS
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.
Teague
Joanne
J
CVGI Discovery, AstraZeneca, Alderley Park, Macclesfield, Cheshire, UK.
Gyte
Amie
A
Peel
Joanne E
JE
Young
Kimberley C
KC
Loxham
Susan J G
SJ
Mayers
Rachel M
RM
Poucher
Simon M
SM
D000818:Animals; D001774:Blood Chemical Analysis; D001786:Blood Glucose / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000178:diet therapy / Q000378:metabolism / Q000473:pathology; D004041:Dietary Fats / Q000008:administration & dosage; D004195:Disease Models, Animal; D018450:Disease Progression; D005260:Female; D006943:Hyperglycemia / Q000178:diet therapy*; D007328:Insulin / Q000097:blood; D007515:Islets of Langerhans / Q000378:metabolism / Q000473:pathology; D009765:Obesity; D051381:Rats; D011924:Rats, Zucker
D001786:Blood Glucose; D004041:Dietary Fats; D007328:Insulin