Nutrigenomics Research Group, School of Public Health, Physiotherapy and Sports Science, Conway Institute, University College Dublin, Dublin, Ireland.
Université Grenoble Alpes, HP2, Inserm, U1042, CHU de Grenoble, Laboratoire EFCR, Pôle Thorax et Vaisseaux Grenoble, Grenoble, France.
Eur Respir J. 2017 Apr 19;49(4). doi: 10.1183/13993003.01731-2016. Print 2017 Apr.
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 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.
阻塞性睡眠呼吸暂停（OSA）与胰岛素抵抗的关系日益密切。其潜在的病理生理学机制尚不清楚，但间歇性低氧（IH）介导的炎症以及随后脂肪组织的功能障碍被认为发挥了关键作用。我们采用了一种综合的转化方法来验证这一假设，该方法使用了瘦鼠和饮食诱导肥胖鼠的 IH 模型、一种用于细胞培养的创新 IH 系统以及一个严格控制的患者队列。IH 导致了肥胖程度校正后的小鼠胰岛素抵抗的发展，并降低了 3T3-L1 脂肪细胞中胰岛素介导的葡萄糖摄取，这与胰岛素信号通路的抑制和胰岛素受体底物-1 mRNA 的下调有关。提供机制见解，IH 在肥胖的小鼠中诱导了内脏脂肪组织的促炎表型，与胰岛素抵抗的严重程度相关的 M1 巨噬细胞极化。补充分析表明，IH 导致了 THP1 衍生的巨噬细胞的 M1 极化。在没有合并症的受试者中（n=186），OSA 与胰岛素抵抗独立相关。此外，我们发现 OSA 严重程度与 M1 巨噬细胞炎症标志物 sCD163 独立相关。这项研究提供了证据表明，IH 诱导了脂肪组织的促炎表型，这可能是 OSA 与胰岛素抵抗发展之间的关键联系。
