The Effect of Hyperglycaemia on In Vitro Cytokine Production and Macrophage Infection with Mycobacterium tuberculosis

Type 2 diabetes mellitus is an established risk factor for tuberculosis but the underlying mechanisms are largely unknown. We examined the effects of hyperglycaemia, a hallmark of diabetes, on the cytokine response to and macrophage infection with Mycobacterium tuberculosis. Increasing in vitro glucose concentrations from 5 to 25 mmol/L had marginal effects on cytokine production following stimulation of peripheral blood mononuclear cells (PBMCs) with M. tuberculosis lysate, LPS or Candida albicans, while 40 mmol/L glucose increased production of TNF-α, IL-1β, IL-6 and IL-10, but not of IFN-γ, IL-17A and IL-22. Macrophage differentiation under hyperglycaemic conditions of 25 mmol/L glucose was also associated with increased cytokine production upon stimulation with M. tuberculosis lysate and LPS but in infection experiments no differences in M. tuberculosis killing or outgrowth was observed. The phagocytic capacity of these hyperglycaemic macrophages also remained unaltered. The fact that only very high glucose concentrations were able to significantly influence cytokine production by macrophages suggests that hyperglycaemia alone cannot fully explain the increased susceptibility of diabetes mellitus patients to tuberculosis.2型糖尿病（Type 2 diabetes mellitus）是已被证实的结核病易感危险因素，但其潜在致病机制迄今尚未明确。本研究探讨了高血糖症（hyperglycaemia，糖尿病的标志性特征）对结核分枝杆菌（Mycobacterium tuberculosis）刺激下的细胞因子应答，以及巨噬细胞感染结核分枝杆菌过程的影响。体外实验中，将葡萄糖浓度从5 mmol/L提升至25 mmol/L时，外周血单个核细胞（peripheral blood mononuclear cells，PBMCs）经结核分枝杆菌裂解液、脂多糖（LPS）或白色念珠菌（Candida albicans）刺激后，其细胞因子生成仅出现轻微变化；而当葡萄糖浓度为40 mmol/L时，肿瘤坏死因子-α（TNF-α）、白细胞介素-1β（IL-1β）、白细胞介素-6（IL-6）及白细胞介素-10（IL-10）的生成量均显著升高，但干扰素-γ（IFN-γ）、白细胞介素-17A（IL-17A）及白细胞介素-22（IL-22）的生成量无明显改变。当巨噬细胞在25 mmol/L葡萄糖的高糖环境中分化成熟后，经结核分枝杆菌裂解液与脂多糖刺激时，其细胞因子生成量同样升高；但在感染实验中，并未观察到结核分枝杆菌的杀灭或增殖存在显著差异。此类高糖环境培养的巨噬细胞的吞噬能力也未发生明显改变。仅极高浓度葡萄糖才可显著影响巨噬细胞的细胞因子生成，这一结果提示，单纯的高血糖症无法完全解释糖尿病患者结核病易感性升高的现象。