Abstract WP341: Recurrent hypoglycemia exposure increases post-ischemic hypoperfusion in female insulin-treated diabetic rats.

Cerebral ischemia is a serious complication of diabetes. Treatment of diabetes increases the risk of recurrent hypoglycemia (RH). RH exposure leads to severe post-ischemic hypoperfusion at least up to 80 minutes and increases the extent of ischemic brain injury in insulin-treated diabetic (ITD) rats. Since the total duration for which these perfusion deficits last is unknown, we evaluated cerebral blood flow (CBF) up to 5 days post-ischemia in RH-exposed ITD rats using laser speckle imaging. We observed that post-ischemic hypoperfusion lasts for up to 24 hours in male ITD rats. Since response to glucose counterregulation is different between women and men, we tested the hypothesis that RH exposure results in sustained severe post-ischemic hypoperfusion in RH-exposed female ITD rats and leads to an increased ischemic brain injury. Streptozotocin diabetic rats were treated with insulin, were randomly assigned to euglycemia control or hypoglycemia groups. Rats were subjected to global cerebral ischemia and CBF was quantified using laser speckle imaging at baseline (pre-ischemia), 1h, 24h, 3d, and 5d post-ischemia. We previously showed that RH-exposed male ITD rats (n=7) display a significant decrease in CBF as compared to the control rats (n=7) when quantified 1 hour (23%, p<0.01) and 1 day (17%, p<0.05) post-ischemia (Figure A, B). In the present study, our data shows that RH-exposed young female ITD rats (n=5) display a significantly lower CBF when compared to the control rats (n=5) 1 day (27%, p<0.05) post-cerebral ischemia. The changes were not significantly different from the control group at remaining time points (Figure C, D). The CBF at 1-hour (17%; p<0.05) and 1-day (19%; p<0.001) post-ischemia was significantly lower while at 3-, and 5-days was not different from the baseline values in the RH-exposed rats. While the CBF at 1-, and 3-days post-ischemia in control rats was not different from the baseline, the CBF 1-hour (15%, p<0.05), and 5-days (23%, p<0.05) post-ischemia was significantly lower and higher than the baseline, respectively. Our data demonstrate that RH exposure induces severe post-ischemic hypoperfusion for at least ≈24 hours post-ischemia in young male and female ITD rats. Next, we aim to study the underlying mechanism causing the pronounced hypoperfusion in RH exposed ITD rats and the pathways causing hypoperfusion induced increase in ischemic brain injury in the animal model of diabetes.