Rapid Effects of Hydrocortisone on Glucose-induced Insulin Secretion in Healthy Humans
Condition: Healthy
Study type: Interventional
Phase: Phase 4

Summary: 
      The purpose of this study is to investigate the effect of hydrocortisone on glucose-induced
      insulin secretion and sensitivity, by means of an intravenous glucose tolerance test with
      frequent sampling (FSIGT) followed by minimal model analysis. In a randomized single-blind
      cross-over design, the subjects will receive either hydrocortisone or placebo 4 minutes
      before an intravenous glucose load.
    

Detailed description: 
      Glucocorticoids (mainly cortisol in men and corticosterone in rodents) are secreted in the
      adrenal cortex under the control of the hypothalamic-pituitary-adrenal (HPA) axis. They are
      known for and named after their combined actions on glucose metabolism: suppression of
      insulin secretion, inhibition of glucose uptake in peripheral tissues, and promotion of
      gluconeogenesis in the liver. As a result, glucose intolerance accompanies syndromes of
      cortisol excess, while recurrent hypoglycemia, especially in response to stress, is a typical
      feature of isolated familial glucocorticoid deficiency. Almost any acute severe challenge to
      homeostasis or stress will activate the hypothalamic-pituitary-adrenal (HPA) axis and cause a
      rise in plasma glucocorticoid levels, which is essential for survival. Thanks to their
      immunosuppressive and antiinflammatory actions, glucocorticoids are widely-used
      therapeuticals with important adverse effects.

      The need to optimize the benefit-risk ratio of glucocorticoid therapy has lead to a recent
      focus of research in the pathways mediating their effects. Glucocorticoids act rapidly and
      within minutes, exerting effects which contradict the classical genomic signalling pathway.
      Little is known on the clinical rapid effects of glucocorticoids on carbohydrate metabolism.
      Corticosterone acutely lowers insulin plasma concentrations and their response to
      hyperglycemia in rodents in vivo. Intraperitoneally administered hydrocortisone suppresses
      the insulin levels stimulated by intravenous glucose in mice. Although subject to numerous
      studies, the metabolic effects of glucocorticoids have been generally tested after giving
      dexamethasone for a few days.

      To our knowledge, there are no data on rapid effects of glucocorticoids on insulin secretion
      and sensitivity in humans. Despite the increased interest in rapid effects of steroids in the
      last decade, the immediate effects of glucocorticoids on carbohydrate metabolism have not yet
      been studied. This question is not easy to address in vivo because of the multiple (also
      compensatory) influences that can impact the endocrine pancreas. Therefore, we propose to use
      a rapid approach, studying the effect of a bolus of hydrocortisone on the response to an
      intravenous glucose tolerance test with frequent sampling (FSIGT).

      The FSIGT consists in giving intravenously a glucose bolus and taking frequently blood
      samples afterwards for determining glucose, insulin and C-peptide. The glucose and insulin
      data analysed with the minimal model technique allow the calculation of the acute insulin
      response, glucose effectiveness and the insulin sensitivity index. The data on C-peptide will
      be used to evaluate the beta cell function.

      The effects of Hydrocortisone on glucose-induced insulin secretion and sensitivity will be
      investigated by means of an FSIGT followed by minimal model analysis. The subjects will
      receive in a randomized single-blind cross-over design:

        1. 0.6 mg/kg body wt Hydrocortisone + 330 mg/kg body wt glucose

        2. Placebo + 330 mg/kg body wt glucose
    

Intervention name(s): Hydrocortisone; Glucose 33%
Intervention type(s): Drug; Drug
Intervention description(s): 0.6 mg/kg body weight, intravenous bolus given at time-point minus 4'; 1ml/kg body weight, intravenous bolus given at time-point 0'
Intervention MeSH terms: Hydrocortisone
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: Single (Participant)
Primary purpose: Basic Science
Keywords: glucocorticoid; hydrocortisone; carbohydrate metabolism; appetite-regulatory hormones