Thesis

Discovering the biological and clinical implications of modulating glucocorticoid action using metabolomic profiling of human plasma samples

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Awarding institution
  • University of Strathclyde
Date of award
  • 2016
Thesis identifier
  • T14469
Person Identifier (Local)
  • 201258532
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Department, School or Faculty
Abstract
  • Background: Glucocorticoid deficiency and excess are difficult to identify because ofthe non-specificity of their clinical and biochemical features which are also poorlycorrelated with levels of circulating steroids. The lack of reliable biomarkers forglucocorticoid action makes it challenging to determine precise therapeutic needsof patients with GC-deficient or excessive conditions such as congenital adrenalhyperplasia and Cushing’s syndrome, respectively.Aim: To identify the main biomarkers indicative of changes in cortisol action inhealthy individuals and those with different metabolic diseases.Study design and methodology: Plasma samples were collected from threeseparate studies. The first study was a randomised double-blind crossover designinvolving 8 men with type 2 diabetes given either placebo or metyrapone +mifepristone (‘glucocorticoid blockade’) for 12 hours. In the second study, 20healthy men were given metyrapone with either low or high doses of insulin, plussuch a dose of hydrocortisone as to achieve low, medium or high plasma cortisollevels. Finally, plasma samples were also obtained from 119 patients with CAHreceiving standard clinical care. Liquid chromatography-mass spectrometry wasthen employed for the metabolomic profiling of all the plasma samples, andMzMatch software was used to identify the metabolites present. Multivariate andunivariate analyses were employed to determine the most reliable metabolites asbiomarkers for glucocorticoid action.Results: Branched chain amino acids, bile acids and their conjugates, and free fattyacids were the main metabolite groups that were significantly altered by at leasttwo of the three interventions. Compared to placebo, bile acids and theirconjugates were significantly (p < 0.05) elevated following glucocorticoid blockade,but subsequent insulin administration significantly lowered their levels. On theother hand, high glucocorticoid dose significantly (p < 0.05) increased the levels ofchenodeoxyglycocholate in patients with conginetal adrenal hyperplasia, but noeffects on bile acids were observed in similarly treated healthy men. Branched chainamino acids were significantly lowered in healthy men following high insulin dose,but were significantly (p < 0.05) increased upon high hydrocortisone infusion. HighBCAs levels were associated with high body mass index , and high systolic anddiastolic blood pressure in pateints with conginetal adrenal hyperplasia. In contrast,L-valine, was significantly elevated following glucocorticoid blockade in patientswith type 2 diabetes. A number of saturated and unsaturated fatty acids weresignificantly (p < 0.05) elevated following hydrocortisone infusion in healthy men,but insulin reduced their levels significantly (p < 0.05). High glucocorticoid dose inpatients with conginetal adrenal hyperplasia significantly increased C15:0, C16:0and C20:0 while C16:1 reduced. In contrast, use of insulin following glucocorticoidblockade in patients with type 2 diabetes significantly (p < 0.05) reduced levels ofC12:0, C18:0 and C18:3. Conclusion: These hypothesis-free metabolomics screening studies have identifiedmetabolites in plasma which are differentially sensitive to glucocorticoid deficiencyor excess and may be useful in clinical assessment of glucocorticoid therapy.
Advisor / supervisor
  • Watson, David G., 1952-
Resource Type
Note
  • Previously held under moratorium from 22 December 2016 until 17 January 2022
DOI
Date Created
  • 2016
Former identifier
  • 9912538569102996

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