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Endocrine Abstracts (2017) 50 P319 | DOI: 10.1530/endoabs.50.P319

SFEBES2017 Poster Presentations Obesity and Metabolism (31 abstracts)

The adverse metabolic phenotype associated with obstructive sleep apnoea is not driven by activation of the hypothalamo-pituitary-adrenal axis

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


NIHR Bioresource Centre, OCDEM, University of Oxford, Oxford, UK.

Glucocorticoid (GC) excess drives obesity, insulin resistance and type 2 diabetes. Obstructive sleep apnoea (OSA) is a prevalent condition associated with both activation of the hypothalamic-pituitary-adrenal (HPA) axis and an adverse metabolic phenotype. However, a causal link between these two features has not been established. We designed a novel human model of intermittent hypoxia (IH) aimed at replicating the systemic insulin resistance associated with OSA to determine whether limiting GC availability has a beneficial metabolic effect.

Healthy male participants (n=17, age: 25±6 yrs; BMI:24.1±1.7 kg/m2) underwent a hyperinsulinaemic-euglycaemic clamp incorporating stable isotopes with adipose tissue microdialysis and biopsy, under conditions of normoxia. Volunteers were then randomized to receive either the GC receptor antagonist, RU486 (600 mg od, 1 week) or no treatment. All investigations were then repeated under conditions of IH. IH was achieved by alternating the FiO2 of inspired gases between air (FiO2 21%) and a hypoxic gas mix (FiO2 5%; balance nitrogen) to achieve 12 desaturations/hr.

In the fasted-state under normoxia, RU486 improved adipose tissue insulin sensitivity (significant reductions circulating non-esterified fatty acids (NEFA), glycerol and Adipo-IR all P<0.05). Our model of IH successfully replicated features of OSA (11.4+/−0.8 desaturation/hr. 87+/−4 %O2 saturations). IH induced insulin resistance as measured by reduced insulin-mediated suppression of circulating triglyceride (TAG) and VLDL TAG (P<0.05). In the fed, hyperinsulinaemic-state, and under IH, RU486 worsened the adverse metabolic features (reduced insulin-mediated suppression of TAG; VLDL-TAG; βOH-Butyrate, all P<0.05). These data endorse our previous observations demonstrating that GCs enhance insulin action in vitro and in vivo in the fed-state.

In conclusion, we have demonstrated a differential effect of GC receptor antagonism in the fed and fasted-state. Limiting GC action under conditions of IH worsened insulin resistance suggesting that activation of the HPA axis in OSA does not drive the development of an adverse metabolic phenotype.

Volume 50

Society for Endocrinology BES 2017

Harrogate, UK
06 Nov 2017 - 08 Nov 2017

Society for Endocrinology 

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