Unconditioned and conditioned effects of intranasally administered insulin vs placebo in healthy men: a randomised controlled trial

Abstract

Aims/hypothesis In humans, the intranasal route allows insulin to reach the brain while maintaining peripheral euglycaemia. Our aims were to examine acute (unconditioned) effects of central insulin on normal-range blood glucose and hormones in men, and to find out whether the effects of intranasal insulin can be learnt via classical conditioning. Methods In a randomised controlled trial, 32 healthy normalweight men (mean age 24.2 [SEM 0.5], mean BMI 22.4 [0.3]) received a conditioned stimulus (CS) and six administrations of either soluble H-insulin 100 (20 U [0.2 ml]; group 1; n=16) or vehicle (0.2 ml; group 2; n=16) on day 1. The CS was the tarry smell of meta-cresol (used as a stabilising vehicle in many insulin preparations and placebos). On day 2, all participants received the CS and six administrations of placebo. Participants and experimenters were blinded to group assignment. Sixteen individuals were randomised to and analysed in each group. Participants were sequentially numbered for group allocation. The main outcome measures were blood glucose and insulin, expressed as cumulative difference-from-baseline changes.

Nasal insulin changes peripheral insulin sensitivity simultaneously with altered activity in homeostatic and reward-related human brain regions

“…For humans, the issue is not yet clear. Recently, nasal insulin application was demonstrated to influence noradrenaline (norepinephrine) levels, an indicator of sympathetic nervous system activity [47]. However, a smaller study found no effect of intranasal insulin on muscular sympathetic nervous activity [48].…”

Neuro-Bio-Behavioral Mechanisms of Placebo and Nocebo Responses: Implications for Clinical Trials and Clinical Practice

“…The experimental group is then re-exposed to the CS during evocation and alterations in neuroendocrine functions (e.g., concentrations of adrenaline, glucose, cortisol, insulin, norepinephrine, glucagon, vasopressin, ACTH, somatropin) 710 are analyzed, reflecting the conditioned response. Although learned placebo responses in neuroendocrine functions have been demonstrated in experimental animals (Ader, 1976;Buske-Kirschbaum et al, 1996;Janz et al, 1996;Pacheco-Lopez et al, 2004), there are few studies reporting these effects in humans, and those that do mainly employed insulin as a US measuring blood glucose or insulin levels as a conditioned response (Fehm-Wolfsdorf et al, 1993;Stockhorst et al, 1999Stockhorst et al, , 2004Stockhorst et al, , 2011Klosterhalfen et al, 2000;reviewed in Wendt et al, 2014b). Two human studies reported conditioned changes in plasma cortisol concentrations.…”

Conditioning Immune and Endocrine Parameters in Humans: A Systematic Review

“…Concerning the studies on conditioning of immune functions, 5 studies addressed conditioned immunosuppression (31% of all studies) [19][20][21][22][23] , 3 studies addressed conditioned immunostimulation (19%) [24][25][26] , and 3 studies addressed conditioned allergic responses (19%) [9,27,28] . Of the studies on conditioning of endocrine outcomes, 4 (25%) addressed conditioned glycemic responses [29][30][31][32] and the remaining study addressed conditioned cortisol (6%) [33] .…”

“…The participants in 13 studies were healthy volunteers (81%) [19][20][21][22][23][24][25][26][29][30][31][32][33] , whereas 3 studies (19%) included participants who were allergic to either pollen [27] or house dust mites [9,28] .…”

“…Regarding the general conditioning paradigm, all but one [26] of the studies (94%) [9,[19][20][21][22][23][24][25][27][28][29][30][31][32][33] employed a design with an acquisition phase, in which the UCS was repeatedly paired with the CS, and an evocation phase, in which the CS was presented together with a placebo. The remaining study on immunostimulation employed an intermittent treatment schedule in which the CS was consistently paired with the UCS in the first phase of the study (acquisition phase) and was administered intermittently with or without the UCS in the second phase of the study [26] .…”