Cortisol response to individualised graded insulin infusions: A reproducible biomarker for CNS compounds inhibiting HPA activation

Abstract

AIM: To determine the potential of cortisol secretion, in response to a physiological stressor, as a biomarker for centrally active compounds targeting the hypothalamic-pituitary-adrenocortical (HPA) axis. METHODS: Cortisol response to hypoglycaemia was measured in 26 healthy males in two stages: firstly to derive an algorithm for individualized, graded insulin infusion rates to achieve defined hypoglycaemic targets over 3 h and secondly to determine the inter- and intra-subject variability of cortisol response to hypoglycaemia over two identical periods by measuring the maximum (tmax), time to maximum (Cmax) response and cortisol area under the response curve (AUC). RESULTS: Hypoglycaemia induced a consistent cortisol response starting at approximately 1 h, corresponding to blood glucose concentrations of approximately 3.3 mmol l-1, and peaking approximately 3 h after the start of infusion. The inter- and intra-subject coefficients of variation (CVs) of cortisol response were approximately 19 and 19% (AUC), 15 and 19 % (Cmax) and 10 and 14% (tmax), respectively. The intra-subject CVs for the ratio of maximum cortisol response to baseline concentration and rate of initial cortisol response between study days were more variable (32.8% and 59.0%, respectively). The blood glucose-cortisol response model derived from the study was predictive of the individual observed cortisol responses, and estimated a blood glucose EC50 associated with onset of the cortisol response of 3.3 mmol l-1. CONCLUSIONS: Gradual hypoglycaemia is an effective, reproducible and well-tolerated method of stimulating a cortisol response and may therefore be useful in assessing the neuroendocrine response to HPA axis inhibitors, such as corticotropin-releasing hormone-1 (CRH-1) antagonists. © 2010 The Authors. British Journal of Clinical Pharmacology © 2010 The British Pharmacological Society.