Title: Intranasal insulin increases cerebral vascular reactivity to carbon dioxide in young adults with obesity: a magnetic resonance imaging study

Objective: Obesity, a metabolic disorder affecting one in three U.S. adults, increases risk for stroke and vascular dementia. Cerebral vascular reactivity (CVR) is impaired in adults with obesity, contributing to heightened cerebrovascular disease risk. In addition to impairments in CVR, preclinical studies in obesity demonstrate reduced brain insulin levels, supporting a potential link between impaired CVR and brain insulin signaling. Notably, insulin is vasoactive and may be required for optimal cerebrovascular function. Emerging data support the use of intranasal insulin to increase brain insulin levels. Herein we examined the acute effect of intranasal insulin on CVR to carbon dioxide (CO 2 ) in young adults with normal weight and obesity. We hypothesized intranasal insulin would enhance CVR to CO 2 in both groups. Methods: Twenty young adults [normal weight: n=10 (5F/5M), 25±8 yrs, 23±1 kg/m 2 ; obesity: n=10 (5F/5M), 30±7 yrs, 34±6 kg/m 2 ] underwent magnetic resonance imaging (3 Tesla) with pseudo-continuous arterial spin labeling to quantify regional cerebral blood flow (CBF). Measurements were taken during a 5-min baseline, followed by 5 min of hypercapnia (+7.5±3.4 mmHg). Assessments were conducted before and 20 min after insulin administration (160 IU). Region of interest analysis was performed for the parietal, occipital, temporal, and insular lobes. CVR was assessed as a relative (%) change from baseline with CO 2 . The effect of insulin on CVR was compared between groups (2x2 mixed methods ANOVA, Bonferroni pairwise multiple comparisons). Results: There was no effect of insulin on CVR in the temporal (effect of insulin, p=0.163; interaction of insulin and group, p=0.615) nor insular (effect of insulin, p=0.348; interaction of insulin and group, p=0.093) regions in either group. In the parietal and occipital regions, a group-specific effect of insulin on CVR was observed (interaction of insulin and group, p=0.018 and p=0.002 respectively). Post hoc multiple comparisons uncovered no effect of insulin on CVR in the parietal (14±16 to 9±18%, p=0.363) and occipital (13±18 to 3±15%, p=0.137) regions of normal weight adults, yet an insulin-mediated increase in adults with obesity (1±9 to 17±16%, p=0.013 and -1±12 to 21±17%, p=0.002, respectively). Conclusions: Intranasal insulin had no effect on CVR to CO 2 in normal weight adults. In contrast, intranasal insulin enhanced CVR to CO 2 in select brain regions (e.g., parietal and occipital lobes) of adults with obesity. The potentiating effect of insulin on CVR to CO 2 in the parietal and occipital lobes may reflect improvements in endothelial function and neurovascular coupling in adults with obesity and will be the focus of future investigations to better understand how intranasal insulin impacts cerebrovascular health. Funding: UL1TR002345 (JKL) This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.