Intermittent hypoxia in obstructive sleep apnoea mediates insulin resistance through adipose tissue inflammation

[摘要] 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.

[学科分类] 呼吸医学