The pre-stroke induction and normalization of insulin resistance respectively worsens and improves functional recovery

Background: Type 2 diabetes (T2D) impairs post-stroke functional recovery, and the underlying mechanisms are mostly unknown. Insulin resistance (IR), which is a hallmark of T2D, also afflicts up to 50% of the elderly without T2D. IR has been associated with impaired recovery after stroke. However, the causative role of IR in impaired stroke recovery has not been demonstrated. By using different mouse models of early IR, we investigated the potential crosstalk between IR and stroke recovery as well as some of the cellular mechanisms possibly involved. Methods: We used three different models of IR. Early IR with or without fasting hyperglycaemia was respectively induced by 4 months of high fat diet or by 30% sucrose supplementation in the drinking water. In addition, we used 10-month-old mice that spontaneously develop IR, but not hyperglycaemia, and where IR was targeted pharmacologically pre-stroke with 10 mg/kg/day Rosiglitazone. Stroke was induced by transient middle cerebral artery occlusion and post-stroke recovery was assessed by sensorimotor tests. Neuronal survival, neuroinflammation and neuroplasticity mediated by cholinergic interneurons were assessed by immunohistochemistry/quantitative microscopy. Results: The induction of IR before stroke, with or without hyperglycaemia, impaired post-stroke neurological recovery. Moreover, the results indicate the involvement of increased neuroinflammation and decreased cholinergic interneuron-mediated neuroplasticity in the recorded effects. Importantly, the pharmacological normalization of IR, significantly improved post-stroke neurological recovery. Conclusion: The global diabetes epidemic and world population aging are dramatically increasing the percentage of people in need of post-stroke treatment and care. Targeting hyperglycaemia acutely post-stroke has so far provided negative results to improve stroke outcome and new targets are highly needed. The results of our study suggest that future clinical studies should focus on the specific targeting of pre-stroke IR to reduce the sequelae of stroke in both diabetic patients and the elderly suffering from prediabetes.