MemAID: Memory advancement with intranasal insulin vs. placebo in type 2 diabetes and control participants: a randomized clinical trial

Background This study aimed at assessing the long-term effects of intranasal insulin (INI) on cognition and gait in older people with and without type 2 diabetes mellitus (T2DM). Methods Phase 2 randomized, double-blinded trial consisted of 24 week treatment with 40 IU of INI (Novolin ® R, off-label use) or placebo (sterile saline) once daily and 24 week follow-up. Primary outcomes were cognition, normal (NW), and dual-task (DTW) walking speeds. Of 244 randomized, 223 completed baseline (51 DM-INI, 55 DM-Placebo, 58 Control-INI, 59 Control-Placebo; 109 female, 65.8 ± 9.1; 50–85 years old); 174 completed treatment (84 DM, 90 Controls); 156 completed follow-up (69 DM). Results DM-INI had faster NW (~ 7 cm/s; p = 0.025) and DTW on-treatment ( p = 0.007; p = 0.812 adjusted for baseline difference) than DM-Placebo. Control-INI had better executive functioning on-treatment ( p = 0.008) and post-treatment ( p = 0.007) and verbal memory post-treatment ( p = 0.004) than Control-Placebo. DM-INI increased cerebral blood flow in medio-prefrontal cortex ( p < 0.001) on MRI. Better vasoreactivity was associated with faster DTW ( p < 0.008). In DM-INI, plasma insulin ( p = 0.006) and HOMA-IR ( p < 0.013) decreased post-treatment. Overall INI effect demonstrated faster walking ( p = 0.002) and better executive function ( p = 0.002) and verbal memory ( p = 0.02) (combined DM-INI and Control-INI cohort, hemoglobin A1c-adjusted). INI was not associated with serious adverse events, hypoglycemic episodes, or weight gain. Conclusion There is evidence for positive INI effects on cognition and gait. INI-treated T2DM participants walked faster, showed increased cerebral blood flow and decreased plasma insulin, while controls improved executive functioning and verbal memory. The MemAID trial provides proof-of-concept for preliminary safety and efficacy and supports future evaluation of INI role to treat T2DM and age-related functional decline. Graphical abstract