Abstract
Background: Admission hyperglycemia aggravates neurovascular injury and worsens outcome in acute ischemic stroke (AIS). Current stroke guidelines recommend glycemic control as an important therapeutic strategy to prevent cerebrovascular complications. We have previously shown that chronic glucose control with metformin prior to AIS prevents cerebrovascular remodeling, reduces hemorrhagic transformation (HT), and improves neurological outcome. The goal of this study was to test the hypothesis that acute glucose control in diabetes prior to AIS will also provide neurovascular protection and improve functional outcome. Methods: Ten-week-old male control and type 2 diabetic Goto-Kakizaki (GK) rats (n=6-9 each group) were treated with or without metformin (300mg/kg/day in drinking water) for 3 days prior to stroke. Infarct size, edema ratio (% edema/infarct), and HT frequency and severity were evaluated in all groups after 3 hr middle cerebral artery occlusion (MCAO) and 21 hr reperfusion. AMPK activity and lactate levels--biomarkers of ischemic brain metabolism--were also measured. Results: Compared to controls, metformin treatment decreased blood glucose levels in diabetic animals (160.4±36.5 vs. 120.1±31.1 mg/dL, p<0.0001). Metformin treatment decreased edema ratio in GKs (0.90±0.71 vs. 1.55±0.70, p<0.05), but increased infarct size (23.3±17.5 vs. 12.5±9.5%, p<0.05). Untreated diabetic rats had lower composite scores for neurological tests (3.8±2.4 vs. 5.9±1.2, p<0.05), indicating worse outcome. Metformin treatment worsened this deficit in both diabetic and control animals (2.4±1.6 vs. 1.9±1.0, p=0.0008). AMPK activity was increased only in metformin-treated GK rats while lactate levels were increased in both groups (p<0.05). Results are expressed as mean ± SD. Conclusion: Worsening of stroke outcome by acute metformin treatment is associated with increased lactate accumulation in both control and diabetic rats. Increased infarct size in diabetic but not control rats may be due to greater AMPK activation in diabetes. Whether this effect is specific to metformin or general to acute glycemic control needs to be confirmed with other glucose control measures.
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