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Effects of acute glucocorticoid blockade on metabolic dysfunction in patients with Type 2 diabetes with and without

D P Macfarlane1, P J Raubenheimer1, T Preston2

  • 1University/BHF Centre for Cardiovascular Science, Queen's Medical Research Institute, University of Edinburgh, Edinburgh, Scotland, United Kingdom;

American Journal of Physiology. Gastrointestinal and Liver Physiology
|August 9, 2014
PubMed

Insights

Reducing glucocorticoid action in type 2 diabetes patients improved glucose control and insulin sensitivity. Therapies targeting glucocorticoid action may benefit patients with or without fatty liver disease.

Area of Science:

  • Endocrinology
  • Metabolic Diseases
  • Pharmacology

Background:

  • Glucocorticoids significantly impact glucose and lipid metabolism.
  • Elevated glucocorticoid action is implicated in Type 2 diabetes pathogenesis.
  • Liver fat content influences metabolic dysfunction in Type 2 diabetes.

Purpose of the Study:

  • To assess the efficacy of acute glucocorticoid blockade in men with Type 2 diabetes.
  • To investigate the role of liver fat content in modulating the response to glucocorticoid blockade.
  • To evaluate the impact of glucocorticoid receptor antagonism and cortisol biosynthesis inhibition on glucose and lipid metabolism.

Main Methods:

  • Randomized, double-blinded, placebo-controlled crossover study design.
  • Utilized glucocorticoid receptor antagonist RU38486 (mifepristone) and cortisol biosynthesis inhibitor metyrapone.
  • Employed stable isotope dilution techniques and hyperinsulinemic-euglycemic clamp to measure substrate turnover (glucose, glycerol, FFAs).
  • Subgroup analysis based on liver fat content (measured by MRI).

Main Results:

  • Glucocorticoid blockade significantly reduced fasting glucose and insulin levels.
  • Improved insulin sensitivity in glycerol and free fatty acid (FFA) turnover and suppressed hepatic glucose production.
  • High liver fat was associated with insulin resistance, hyperinsulinemia, and impaired FFA metabolism.
  • Glucocorticoid blockade demonstrated comparable benefits in patients with and without high liver fat.

Conclusions:

  • Acute glucocorticoid blockade improves metabolic parameters in Type 2 diabetes.
  • Liver fat content did not alter the beneficial effects of glucocorticoid blockade.
  • Targeting glucocorticoid action represents a potential therapeutic strategy for Type 2 diabetes, irrespective of fatty liver status.
Keywords:
Type 2 diabetesfatty acid metabolismglucocorticoidsnonalcoholic fatty liver disease

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