Intranasal insulin attenuates the hypothalamic—pituitary—adrenal axis response to psychosocial stress Andreas Bohringer * , Lars Schwabe, Steffen Richter, Hartmut Schachinger Department of Clinical Physiology, University of Trier, Johanniterufer 15, 54290 Trier, Germany Received 28 May 2008; received in revised form 8 July 2008; accepted 6 August 2008 1. Introduction Activation of the hypothalamic—pituitary—adrenal (HPA) axis is crucial for successful regulation of energy homeostasis during situations of stress (Sapolsky et al., 2000). However, hyperactivity of the HPA system is associated with several wide spread diseases like depression, arterial hypertension, Psychoneuroendocrinology (2008) 33, 1394—1400 KEYWORDS Insulin; Intranasal administration; HPA axis; Cortisol; Psychosocial stress; TSST Summary Previous studies have shown that intranasally administered insulin exerts an inhi- bitory influence on the basal hypothalamic—pituitary—adrenal (HPA) axis activity. To date, however, it remains unclear as to whether intranasal insulin does furthermore affect HPA axis responsiveness in situations of stress. Here, we tested whether intranasally administered insulin attenuates the HPA axis response to psychosocial stress. Fifty minutes before being exposed to the Trier Social Stress Test (TSST), 26 healthy young male participants received a single intranasal dose of human insulin (40 I.U.) or placebo in a placebo controlled, double-blind between-subject design. Plasma cortisol, saliva cortisol, heart rate, and blood pressure were measured at resting baseline and in response to the TSST. Plasma cortisol (P <.001) and saliva cortisol (P <.001) increased in response to stress, as did heart rate (P <.001) and blood pressure (P <.001). Intranasal insulin did not influence plasma or saliva cortisol, heart rate, blood pressure, blood glucose, and plasma insulin levels at baseline. However, intranasal insulin diminished the saliva cortisol (two-way ANOVA; treatment by time interaction: P = .05) and plasma cortisol (two-way ANOVA; treatment by time interaction: P = .05) response to the TSST without affecting heart rate, and blood pressure stress reactivity. Our data show that a single intranasal insulin administration effectively lowers stress-induced HPA axis responsiveness. Intranasal insulin may offer a therapeutic potential to prevent hyper- activity of the HPA system. # 2008 Elsevier Ltd. All rights reserved. * Corresponding author. Tel.: +49 651 201 3697; fax: +49 651 201 3737. E-mail address: boeh1303@uni-trier.de (A. Bohringer). available at www.sciencedirect.com journal homepage: www.elsevier.com/locate/psyneuen 0306-4530/$ — see front matter # 2008 Elsevier Ltd. All rights reserved. doi:10.1016/j.psyneuen.2008.08.002