The Pre-Stroke Induction and Normalization of Insulin Resistance Respectively Worsens and Improves Functional Recovery

Abstract

Type 2 diabetes (T2D) impairs post-stroke recovery, and the underlying mechanisms are unknown. Insulin resistance (IR), a T2D hallmark that is also closely linked to aging, has been associated with impaired post-stroke recovery. However, whether IR worsens stroke recovery is unknown. We addressed this question in mouse models where early IR, with or without hyperglycemia, was induced by chronic high-fat diet feeding or sucrose supplementation in the drinking water, respectively. Furthermore, we used 10-month-old mice, spontaneously developing IR but not hyperglycemia, where IR was normalized pharmacologically pre-stroke with Rosiglitazone. Stroke was induced by transient middle cerebral artery occlusion and recovery was assessed by sensorimotor tests. Neuronal survival, neuroinflammation and the density of striatal cholinergic interneurons were also assessed by immunohistochemistry/quantitative microscopy. Pre-stroke induction and normalization of IR, respectively, worsened and improved post-stroke neurological recovery. Moreover, our data indicate a potential association of this impaired recovery with exacerbated neuroinflammation and a decreased density of striatal cholinergic interneurons. The global diabetes epidemic and population aging are dramatically increasing the percentage of people in need of post-stroke treatment/care. Our results suggest that future clinical studies should target pre-stroke IR to reduce stroke sequelae in both diabetics and elderly people with prediabetes.