Acute Consequences Of Food-induced Glucocorticoid Secretion In Healthy Individuals
Condition: Glucocorticoid Effect
Study type: Interventional
Phase: Early Phase 1

Summary: 
      In a randomized, cross-over study, 20 healthy volunteers will receive a block and replace
      therapy that mimics physiological GC rhythm (metyrapone plus hydrocortisone) or placebo.
      Participants will undergo two identical overfeeding periods with each treatment. With the
      block and replace therapy, food-induced GC peak will be suppressed. Metabolic and autonomic
      parameters will be compared to reveal, whether GCs mediate the physiological adaptions to
      excessive food intake.

      Understanding acute effects of GCs upon food intake is critical, since repetitive disruptions
      of GC secretion may become harmful in chronic conditions.
    

Detailed description: 
      Obesity is one of the most serious health problems of the 21st century. To understand how we
      regulate our body weight is crucial for developing new treatment targets. Even though body
      mass index of populations is increasing, the body weight of adults is usually kept stable
      over time. Indeed, acute excessive food intake triggers a set of adaptions in order to
      prevent weight gain. The signal that triggers these beneficial adaptions is still unknown.
      Glucocorticoid (GC) secretion increases with acute food intake and many physiological
      adaptions to overfeeding coincide with classical glucocorticoid actions. The investigators
      therefore hypothesize that GCs are the signal that prevents weight gain during acute
      overfeeding.

      The objective of this project is to test whether food-induced GCs represent the physiological
      signal that defends against weight gain.

      The primary objective is to investigate whether reduction in insulin sensitivity is abolished
      with the block and replace therapy.

      Secondary objectives are to investigate whether suppression of GC secretion during excessive
      food intake impairs the activation of sympathetic nervous system, satiety, satiation, energy
      expenditure, substrate utilization, blood pressure, secretion of neuroendocrine hormones,
      lipids and immune cells.

      This is a double-blind, randomized, placebo-controlled cross-over study. After screening,
      subjects will be randomized to two crossover 8-day study periods with a washout period of 28
      days:

      A) Participants will receive hydrocortisone 19.9 mg/d subcutaneously via a pump in a pulsed
      fashion (eight times/day) and metyrapone per os (starting with a dose of 500 mg/d on day 1 to
      2500mg/d on day 4, and then will be kept constant until day 8)

      B) Participants will receive placebo (0,9% NaCl solution) 19.9 mg/d subcutaneously via a pump
      in a pulsed fashion and placebo pills per os (starting with a dose of 500 mg/d on day 1 to
      2500mg/d on day 4, and then will be kept constant until day 8)
    

Intervention name(s): Metyrapone 250 mg Oral Tablets; Placebo 250 mg Tablets; Hydrocortisone 19,9mg s.c., pulsatile with a flow rate of 10μl/s; Placebo (0,9% NaCl solution)
Intervention type(s): Drug; Drug; Drug; Drug
Intervention description(s): During one phase of the study: Metyrapone (pills of 250mg) on full stomach: Day 1 0-1-1, day 2 1-2-2, day 3 2-2-3 day 4 3-3-4 day 5 3-3-4 day 6 3-3-4 day 7 3-3-4 day 8 3-0-0; During another phase of the study: identical looking placebo pills starting Day 1 0-1-1, day 2 1-2-2, day 3 2-2-3 day 4 3-3-4 day 5 3-3-4 day 6 3-3-4 day 7 3-3-4 day 8 3-0-0; Hydrocortisone will be delivered subcutaneously via a pump in a pulsed fashion with a flow rate of 10μl/s from day 1 to day 8 in a total daily dose of 19.9mg; Placebo (0,9% NaCl solution) 19.9 mg/d subcutaneously via a pump in a pulsed fashion with a flow rate of 10μl/s from day 1 to day 8
Intervention MeSH terms: Hydrocortisone; Metyrapone
Allocation: Randomized
Intervention model: Crossover Assignment
Intervention model description: Double-blind, randomized, placebo-controlled cross-over study
Masking: Double (Participant, Investigator)
Primary purpose: Prevention
Keywords: cortisol; overfeeding; glucocorticoids; insulin sensitivity