Endocrine Abstracts

Background & Aims: Observational studies implicate glucocorticoid excess, principally due to altered steroid metabolism in target tissues, in both the insulin resistance and liver fat accumulation that accompanies type 2 diabetes. To test the contribution of glucocorticoid signalling to metabolic dysfunction we blocked cortisol secretion (with metyrapone) and action (with the GR antagonist mifepristone) simultaneously in men with type 2 diabetes ± fatty liver.

Methods: 14 men with type 2 diabetes, aged 58 ± 2 y with BMI 32 ± 2 kg/m², received metyrapone+mifepristone or placebo in a double-blind crossover study, administered 8 h + 0.5 h before infusions of 2H2-glucose, 2H5-glycerol and 13C1-palmitate ± a low dose (10 mU/m²/min) hyperinsulinaemic clamp. Using MR spectroscopy, subjects were stratified as low (4 ± 1%, n=7) or high (23 ± 4%, n=7) liver fat. Results are mean±SEM, compared by general linear model with repeated measures analysis.

Results: Glucocorticoid blockade increased ACTH, reduced cortisol levels, and lowered fasting glucose and insulin levels. However, it had no effect on glucose disposal, endogenous glucose production or fatty acid turnover during low dose hyperinsulinaemia. Men with fatty liver were more centrally obese and insulin resistant, with increased fasting plasma glucose and insulin levels, and impaired suppression of endogenous glucose production (37.8 ± 6.8 vs 61.4 ± 10.2% suppression, P<0.05) and fatty acid turnover (rate of appearance of palmitate 3.4 ± 0.8 vs 2.3 ± 0.2, P<0.05, at baseline and 2.1 ± 0.3 vs 1.3 ± 0.2 µmol/kg fat free mass/min, P<0.05) during hyperinsulinaemia. In the fatty liver group, the reduction in fasting insulin levels with glucocorticoid blockade was greater, but there were no other additional effects of glucocorticoid blockade.

Conclusions: Reducing glucocorticoid action, an approach being exemplified with 11β-HSD1 inhibitors, improves hyperinsulinaemia in patients with type 2 diabetes, but has no significant effects on glucose or fatty acid turnover during low dose hyperinsulinaemia and does not reverse the metabolic abnormalities accompanying liver fat accumulation.

Declaration of interest: There is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.

Funding: No specific grant from any funding agency in the public, commercial or not-for-profit sector.