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

Abstract

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. In a randomised controlled trial, 32 healthy normal-weight 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. While maintaining euglycaemia, intranasal insulin induced an increase of peripheral insulin on day 1 (group 1, 17.78 [21.88] pmol/l vs group 2, -10.24 [9.42] pmol/l), and also on day 2 when the CS was given with placebo (group 1, 12.53 [5.57] pmol/l vs group 2, -5.51 [6.16] pmol/l). Moreover, a moderate reduction of blood glucose on day 1 (group 1, -0.54 [0.36] mmol/l vs group 2, 0.58 [0.48] mmol/l) was obtained (all p values < 0.05). There were no adverse side effects. The unconditioned blood glucose decrease on day 1 and the unconditioned and conditioned increases of peripheral insulin are indicative of brain-pancreas cross-talk. The conditionability of the hormonal responses reveals new applications for intranasal insulin. DRKS00000537 http://apps.who.int/trial search/ Deutsche Forschungsgemeinschaft DFG STO 323/1-1 and 1-2.