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 language||English (US)|
|Journal||Investigative Ophthalmology and Visual Science|
|State||Published - Feb 15 1996|