title: Cortisol response to individualised graded insulin infusions: a reproducible biomarker for CNS compounds inhibiting HPA activation.
abstract: OBJECTIVE
  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 (t(max) ), time to maximum (C(max) ) 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 % (C(max) ) and 10 and 14% (t(max) ), 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 EC(50) 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.
authors.affiliation: Department of Pharmacology, National University Health System, Singapore, Singapore.
authors.forename: Christopher L H
authors.initials: CL
authors.lastname: Chen
authors.forename: Brian A
authors.initials: BA
authors.lastname: Willis
authors.forename: Louise
authors.initials: L
authors.lastname: Mooney
authors.forename: Guan Koon
authors.initials: GK
authors.lastname: Ong
authors.forename: Chay Ngee
authors.initials: CN
authors.lastname: Lim
authors.forename: Stephen L
authors.initials: SL
authors.lastname: Lowe
authors.forename: Sitra
authors.initials: S
authors.lastname: Tauscher-Wisniewski
authors.forename: Gordon B
authors.initials: GB
authors.lastname: Cutler
authors.forename: Stephen D
authors.initials: SD
authors.lastname: Wiss
mesh_terms: D000328:Adult; D015415:Biomarkers / Q000097:blood; D001786:Blood Glucose / Q000378:metabolism; D006801:Humans; D006854:Hydrocortisone / Q000097:blood / Q000378:metabolism*; D007003:Hypoglycemia / Q000139:chemically induced / Q000378:metabolism; D007004:Hypoglycemic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D007030:Hypothalamo-Hypophyseal System / Q000187:drug effects* / Q000378:metabolism; D007328:Insulin / Q000008:administration & dosage / Q000494:pharmacology*; D008297:Male; D008875:Middle Aged; D010865:Pilot Projects; D010913:Pituitary-Adrenal System / Q000187:drug effects* / Q000378:metabolism; D013312:Stress, Physiological / Q000502:physiology; D055815:Young Adult
chemical_list: D015415:Biomarkers; D001786:Blood Glucose; D007004:Hypoglycemic Agents; D007328:Insulin; D006854:Hydrocortisone