The effect of chronic dexamethasone-induced hyperglycemia and its acute treatment with insulin on grain glucose and glycogen concentrations in rats

Background: In the rat model of forebrain Ischemia, long-term dexamethasone treatment is reported to cause hyperglycemia and worsen postischemic funct ional and histologic injury. This effect was assumed to result from glucose enhancement of intraischemic lactic acidosis within the brain. Short-term insulin therapy restored normoglycemia but did not return histologic injury completely to baseline values. Using a nonischemic rat model, the current study attempted to identify a metabolic basis for such outcome data. Methods: Fifty-eight halothane-anesthetized (1.3% inspired) Sprague-Dawley rats were assigned randomly to be administered either no treatment (N = 18) or 2 mg/kg intraperitoneal dexamethasone (N = 40). The latter were adminis tered dexamethasone 3 h before the study only (N = 8) or for 3 h before the study plus daily for 1 day (N = 8), 2 days (N = 8), or 4 days (N = 16), Of the rats treated with dexamethasone for 4 days, one half(N = 8) were admin istered an insulin-containing saline infusion subsequently to restore normo glycemia short-term All other rats (N = 50) were administered an infusion o f saline without insulin. Plasma glucose was quantified and brains were exc ised after In situ freezing. Brain glucose and glycogen concentrations were measured using enzymatic fluorometric analyses. Results After 4 days of dexamethasone treatment, plasma glucose was 159% gr eater than in rats administered placebo (i.e., 22.01 +/- 4.66 vs. 8.51 +/- 1.65 mu mol/ml; mean +/- SD; P < 0.0001). Brain glucose concentrations incr eased parallel to plasma glucose, An insulin infusion for 27 +/- 5 min rest ored normoglycemia but resulted In a brain-to-plasma glucose ratio that was 32% greater than baseline values (P < 0.01), Neither dexamethasone nor the combination of dexamethasone plus insulin affected brain glycogen concentr ations. Conclusions In a nonischemic rat model, dexamethasone alone had no Independ ent effect on the brain-to-plasma glucose ratio. However, short-term insuli n therapy caused a dysequilibrium between plasma and brain glucose, resulti ng in an underestimation of brain glucose concentrations when normoglycemia was restored. The dysequilibrium likely was caused by the rapid rate of gl ucose reduction, The magnitude of the effect may account for the failure of insulin to reverse dexamethasone enhancement of neurologic injury complete ly Ln a previous report that used the rat model of forebrain Ischemia.