ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Endocrine Abstracts (2017) 49 EP728 | DOI: 10.1530/endoabs.49.EP728

Hepatic and adipose tissue insulin resistance as a consequence of intermittent hypoxia are exacerbated by glucocorticoid receptor antagonism in man

Jonathan Hazlehurst, Catriona Charlton, Diana Mantripp, Leanne Hodson & Jeremy Tomlinson

Oxford Centre for Diabetes, Endocrinology & Metabolism and NIHR Biomedical Research Centre, University of Oxford, Oxford, UK.

Introduction: Obstructive sleep apnea (OSA) affects up to 20% of a Western population and is associated with non-alcoholic fatty liver disease and type 2 diabetes (T2D). OSA is characterized by intermittent episodes of hypoxia (IH) that occur during sleep. It is not yet known if IH is directly linked to insulin resistance within key metabolic target tissues (adipose; liver and skeletal muscle) and what the potential underlying mechanism may be. It has been suggested that individuals with OSA have high circulating glucocorticoid levels which may be linked to the development of IR and T2D.

Methods: 17 healthy male volunteers were recruited and underwent detailed metabolic phenotyping in a fasted state including a hyperinsulinaemic-euglycaemic clamp, incorporating the use of stable isotopes of glucose and palmitate to measure fatty acid partitioning. Initial assessments were made in normoxic conditions; volunteers were then randomised either to no treatment (n=9) or treatment with the glucocorticoid antagonist Mifepristone (600 mg once a day) (n=8). After 1 week of treatment, assessments were repeated under conditions of IH (12 desaturations/h to arterial saturations of 85-91%).

Results: Global insulin sensitivity as measured by M/I values was unchanged by IH or by IH+Mifepristone (control: 8.65±4.1; IH: 9.13±5.4; control (pre_drug): 8.9±3.7; Mifeprisone+IH: 10.13±3.3). However, IH impaired the ability of insulin to suppress TAG, an effect that was worsened by Mifepristone ((insulin mediated suppression of TAG: control: −449±124; IH: −218±131 (P=0.0034); control (pre_drug): −339±201; Mifeprisone+IH: −76±128; (P=0.008). In addition, adipose tissue IR, as measured by a reduction in the ability of insulin to suppress circulating NEFA, was worsened by Mifepristone under conditions of IH (insulin mediated change in plasma NEFA control: −501±164; IH: −411±187 (P=ns); control (pre_drug): −549±130; Mifeprisone+IH: −367±109; (P=0.03)).

Conclusion: Acute IH causes insulin resistance in liver and adipose tissue. These effects are worsened rather than improved by antagonism of the glucocorticoid receptor, highlighting the importance of understanding tissue specific glucocorticoid actions and suggesting activation of the HPA axis is not the link between OSA and metabolic risk

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