Interestingly, intranasal insulin, which is under investigation in humans to treat metabolic (Heni et al., 2014; Gancheva et al., 2015) and cognitive decline (Claxton et al., 2015), has shown promise in healthy volunteers, but efficacy appears to wane in obese (Heni et al., 2014) and T2DM (Gancheva et al., 2015) patients, which may be the direct result of acquired central insulin resistance in these subjects. This evidence concerns the gene INS and type 2 diabetes mellitus.