Intranasal insulin helps overcome brain insulin deficiency and improves survival and post‐stroke cognitive impairment in male mice

Abstract Obesity increases the risk for stroke and is associated with worse post‐stroke outcomes; however, the mechanisms are poorly understood. Diet‐induced obesity leads to insulin resistance and subsequently, brain insulin deficiency. The purpose of this study was to investigate the potential impact of brain insulin deficiency on post‐stroke outcomes. To accomplish this, brain insulin levels were assessed in male C57BL/6J (B6) mice placed on either a standard diet or 54% kcal high‐fat diet, a known model of insulin resistance. Mice were subjected to either a sham surgery (control) or 30‐min middle cerebral artery occlusion to induce an ischemic stroke and administered either intranasal saline (0.9%) or intranasal insulin (1.75 U) twice daily for 5 days beginning on day 1 post‐stroke. High‐fat diet‐induced brain insulin deficiency was associated with increased mortality, neurological and cognitive deficits. On the other hand, increasing brain insulin levels via intranasal insulin improved survival, neurological and cognitive function in high‐fat diet mice. Our data suggests that brain insulin deficiency correlates with worse post‐stroke outcomes in a diet‐induced mouse model of insulin resistance and increasing brain insulin levels may be a therapeutic target to improve stroke recovery.