LAUSR

Abstract Introduction: Copeptin is a surrogate biomarker of vasopressin (AVP) and a well established stress marker in different acute clinical scenarios. Copeptin stimulation by acute hypoglycemia has been shown in the adult population and accurately identifies patients with posterior pituitary dysfunction. The role of AVP in the acute stress response remains to be defined and an interaction between AVP secretion and hypothalamic-pituitary-adrenal (HPA) axis activation in response to hypoglycemia has been suggested, requiring further confirmation. Objectives: The aims of this study were to evaluate copeptin response to acute hypoglycemia in children and adolescents and to assess its potential association with other parameters of the counter-regulatory and inflammatory responses. Methods: This is a prospective single-center study involving 77 children and adolescents (mean age; 11.2 ± 3.1years; 58 males/19 females) undergoing insulin-tolerance test. Results: Baseline plasma copeptin levels (median: 5.2pmol/L, IQR: 3.9-7.7pmol/L) increased significantly after hypoglycemia (median: 9.7pmol/L, IQR: 5.8-14.3pmol/L) (P<0.0001). Counter-regulatory hormones - ACTH, cortisol, growth hormone, prolactin, adrenaline and noradrenaline - and inflammatory markers - IL-1β, IL-6 and TNF - also significantly increased after hypoglycemia (P<0.0001 for all measurements). Copeptin increment correlated significantly with the maximal increases of ACTH (rs:0.30; P: 0.010), cortisol (rs:0.33; P:0.003), prolactin (rs:0.25; P:0.03) and IL-6 (rs:0.35; P:0.008), and with BMI-SDS (rs:-0.28, P:0.01). In stepwise multivariate regression analysis, prolactin was the only independent variable that correlated with copeptin increment (P:0.009). Conclusion: Acute hypoglycemia elicits a significant copeptin response in children and adolescents, confirming the role of copeptin as an acute stress marker in the pediatric population. Interactions between stress-induced AVP/copeptin activation and the HPA axis, IL-6 inflammatory response and BMI were suggested by univariate analyses, although not confirmed by the multivariate analysis. Nevertheless, our data indicate that AVP/copeptin secretion during hypoglycemic stress may be linked to prolactin co-activation as prolactin maximal increase was the only variable independently related to copeptin response, reinforcing the concept that AVP/copeptin might act as a prolactin releasing factor in humans.