Prevention of hyperglycemia and glucotoxic effects on insulin gene expression by troglitazone in ZDF rats

J. S. Harmon, E. A. Oseid, C. E. Gleason, Y. Tanaka, K. K. Hunter-Berger, R. P. Robertson

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Chronic exposure of β-cell lines to supraphysiologic glucose concentrations causes defects in insulin gene expression and insulin secretion. To determine whether these adverse effects occur in vivo in Type II diabetes, we examined β-cell abnormalities in the Zucker diabetic fatty (ZDF) rat. We observed hyperglycemia in 12 and 16 week old ZDF rats that was associated with a decrease in glucose-induced insulin secretion during static incubations of pancreatic islets, a decrease in insulin mRNA, and decreases in STF-1 mRNA and binding to the insulin promoter compared to the age matched Zucker lean control (ZLC) rats, and compared to the 6 week old prediabetic ZDF rats. To determine whether prevention of hyperglycemia would prevent these defects, we treated the rats beginning at 6 weeks of age. Troglitazone prevented the ZDF rats from becoming hyperglycemic and preserved glucose-dose insulin response. Furthermore, ZDF-treated animals compared to untreated animals of the same ages at 12 and 16 weeks had greater levels of insulin mRNA by 262% and 323%, respectively. Similarly, STF-1 mRNA was greater by 349% and 327% and STF-1 protein binding to the insulin promoter was enhanced by 477% and 346%. Body weights in animals treated with troglitazone for 10 weeks were 43% greater and were accompanied by a 31% decrease in plasma triglycerides and a 10% decrease in plasma free fatty acids. Our results indicate that the hyperglycemia that results from in vivo Type II diabetes is associated with a loss of insulin and STF-1 mRNAs, loss of STF-1 transcription factor binding, and loss of glucose stimulated insulin secretion. Prevention of hyperglycemia with troglitazone partially reverses these detrimental effects in 12 and 16 week old ZDF rats.

Original languageEnglish (US)
Pages (from-to)29A
JournalInvestigative Ophthalmology and Visual Science
Issue number3
StatePublished - Feb 15 1996
Externally publishedYes


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