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

Abstract

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• The insulin tolerance test (ITT) is commonly used to induce cortisol release in response to physiological stress. This methodology can be employed in studies evaluating the hypothalamic-pituitary-adrenocortical axis. WHAT THIS STUDY ADDS• An exploration of the threshold for cortisol release in response to blood glucose lowering, indicating that the induction of hypoglycaemia with significant symptoms is not required for a highly reproducible maximal cortisol response. AIMTo 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. METHODSCortisol 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). RESULTSHypoglycaemia 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 interand 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 . CONCLUSIONSGradual 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.

A Pilot Study to Examine the Correlation between Cognition and Blood Biomarkers in a Singapore Chinese Male Cohort with Type 2 Diabetes Mellitus

“…Blood samples were taken from all enrolled subjects in each of the 2 periods, approximately 1 week apart. The objective of this repeated measure design was to assess potential biological variation of the blood biomarkers over 2 periods [18] . This would help sample size assessments in future studies utilising these biomarkers.…”

“…Test-retest reliability estimates were calculated using intra-class correlation coefficients (ICC) [18] , corresponding to a mixed-effects model in SAS 9.2 with visit (1 or 2), diabetic status (diabetic or non-diabetic) and statin usage (yes or no) fitted as fixed effects and subject as a random effect The ICC theoretical range from 0 to 1 is calculated as follows; ICC = Between subject variance component/Total variance. An ICC≥0.70 is an acceptable level of test-retest reliability [27] .…”

Manipulating brain connectivity with δ9-tetrahydrocannabinol: A pharmacological resting state FMRI study

“…Prolactin levels (μg/l) were measured as a biomarker for dopaminergic activity (de Visser et al, 2001). Cortisol (μmol/ml), luteinizing hormone (LH, ng/ml) and follicle-stimulating hormone (FSH, U/l) were measured as exploratory biomarkers of hypothalamic-pituitary activity (Chen et al, 2010). Due to the diurnal rhythm of Visual representation of the chronological study day activities after each THC inhalation.…”

Editors' pick 2010

“…Some years ago we appealed for review papers about methods to study drug effects quantitatively. This appeal has not yet yielded a flood of papers but there has been a gratifying increase during 2010 [1,[3][4][5][6][7][8][9] and we hope that we will be able to refer to several more next year in our Editors' pick for 2011. While clinical pharmacologists have been closely involved for decades in the evaluation and monitoring of adverse drug reactions, a far more recent buzzword has been 'patient safety' .…”