Normalization of Insulin Resistance Rather Than Hyperglycemia Before Stroke Improves Functional Outcomes in a Mouse Model of Type 2 Diabetes.

Abstract

Prestroke hyperglycemia and insulin resistance (IR) independently correlate with poor stroke outcomes in type 2 diabetes (T2D), although their causative effect is undetermined. Interestingly, an increasing body of evidence points toward the importance of IR in determining stroke outcomes. Filling this gap is fundamental to identifying effective anti-T2D strategies to improve stroke prognosis in people with T2D. The aim of this study was to determine experimentally whether normalizing IR rather than hyperglycemia before stroke improves stroke outcomes in T2D. To address this research question, hyperglycemia or IR was normalized with intermediate-acting insulin or long-acting selective glucagon receptor agonist (La-GCGRa), respectively, in obese/T2D mice before inducing stroke. Functional recovery (primary outcome) was assessed by neurological testing. Systemic inflammation, infarct size, and neuroinflammation (secondary outcomes) were assessed by ELISA and immunohistochemistry, respectively. The results showed that insulin treatment normalized hyperglycemia without affecting IR and did not improve functional recovery. On the contrary, La-GCGRa normalized IR without affecting hyperglycemia and improved functional recovery. This effect occurred in association with reduced systemic and stroke-induced neuroinflammation. Neither treatment affected infarct size. The data demonstrate that targeting IR in T2D is crucial for improving stroke outcomes and may have significant implications for human therapy. Hyperglycemia and insulin resistance independently correlate with poor stroke outcomes in type 2 diabetes, although their causative role is unclear. The aim of this study was to determine experimentally whether normalizing insulin resistance rather than hyperglycemia before stroke improves stroke outcomes in type 2 diabetes. To answer this question, we specifically normalized either hyperglycemia or insulin resistance in obese, type 2 diabetic mice before inducing stroke. We show that targeting insulin resistance rather than hyperglycemia before stroke in type 2 diabetes is crucial to improving stroke outcomes.