Intermittent hypoxia in obstructive sleep apnoea mediates insulin resistance through adipose tissue inflammation
Aoife M Murphy, Amandine Thomas, Sophie J Crinion, Brian D Kent, Murtaza M Tambuwala, Aurelie Fabre, Jean-Louis Pepin, Helen M Roche, Claire Arnaud, Silke Ryan, Aoife M Murphy, Amandine Thomas, Sophie J Crinion, Brian D Kent, Murtaza M Tambuwala, Aurelie Fabre, Jean-Louis Pepin, Helen M Roche, Claire Arnaud, Silke Ryan
Abstract
Obstructive sleep apnoea (OSA) is increasingly associated with insulin resistance. The underlying pathophysiology remains unclear but intermittent hypoxia (IH)-mediated inflammation and subsequent dysfunction of the adipose tissue has been hypothesised to play a key role.We tested this hypothesis employing a comprehensive translational approach using a murine IH model of lean and diet-induced obese mice, an innovative IH system for cell cultures and a tightly controlled patient cohort.IH led to the development of insulin resistance in mice, corrected for the degree of obesity, and reduced insulin-mediated glucose uptake in 3T3-L1 adipocytes, associated with inhibition of the insulin-signalling pathway and downregulation of insulin-receptor substrate-1 mRNA. Providing mechanistic insight, IH induced a pro-inflammatory phenotype of visceral adipose tissue in mice with pro-inflammatory M1 macrophage polarisation correlating with the severity of insulin resistance. Complimentary in vitro analysis demonstrated that IH led to M1 polarisation of THP1-derived macrophages. In subjects without comorbidities (n=186), OSA was independently associated with insulin resistance. Furthermore, we found an independent correlation of OSA severity with the M1 macrophage inflammatory marker sCD163.This study provides evidence that IH induces a pro-inflammatory phenotype of the adipose tissue, which may be a crucial link between OSA and the development of insulin resistance.
Conflict of interest statement
Conflict of interest: None declared.
Copyright ©ERS 2017.
Source: PubMed