結核分枝桿菌(M. tuberculosis)感染目前仍是造成人類疾病和死亡的主要原因之一， 據估計，全世界有1/3的人口受到結核菌感染，然而，只有5-10%的人會發病，可見宿主的免疫力在結核菌的暴露後扮演了是否發展成結核病的決定性關鍵角色。 目前已知在某些續發性的免疫功能不足情況下，宿主和結核菌之間的平衡會被打破而造成結核病的發生。在許多已開發國家中，糖尿病(DM)是造成這些續發性免疫功能不足最嚴重的疾病。 在台灣，肺結核病患有14%-19%合併糖尿病。甚且， 糖尿病患罹患肺結核的機率是正常人的5-6倍。然而，糖尿病對於肺結核患者的臨床表現及治療結果的影響，至今尚未有完整的研究。 同時，糖尿病病患因免疫能力缺陷而易被感染的分子機轉，目前也仍不清楚。 之前的研究指出，當全血受到BCG分枝桿菌刺激時，在monocytes, DC, NK以及T細胞之間有一個IL-12/IFN-γaxis的反應。 在這個研究中，我們利用臨床表現, 皮膚結核菌素測驗(TST)以及Th1相關細胞激素的體外實驗來比較正常人, 肺結核病患及以肺結核合併糖尿病病患之間免疫能力的差異。
　　首先，我們根據病歷從衛生署胸腔病院(Chest Hospital)挑選自2004年10月至2005年2月所有痰結核菌培養陽性病患, 總共140位，並且分成合併糖尿病(DMTB)、未合併糖尿病(TB)兩組，然後，比較兩組的致病率以及產生MDR菌種的比例。 結果告訴我們，DMTB組不僅致病率高(30%)，同時也有較高的MDR菌種產生率（28.5% vs 14.2%）。進一步分析糖尿病對於肺結核的影響，我們挑選103位新近診斷肺結核的病患（75位TB，平均年齡：54.8+/- 20.8歲，男：女＝52：23； 28位DMTB，平均年齡：58.6+/- 13.4歲，男：女＝21：7，平均HbA1C：10.61%），並追蹤1年。 我們分析臨床表現，皮膚結核菌素測驗反應以及治療結果比較。 結果顯示， DMTB病患的肺部空洞性病灶較多，結核菌數量也較高，同時，痰陰轉速率較慢（平均4.2個月vs 1.9個月），而且皮膚結核菌素測驗反應有較弱的趨勢。追蹤1年後，DMTB病患的完治率較低（54.5% vs 87.7%），而且治療失敗率較高（27.2% vs 0%）。 這些資料顯示，在台灣，糖尿病對於結核病的防治有很大的影響。
　　接下來，我們使用BCG，BCG+IL-12，及BCG+IFN-γ，分別刺激全血中的白血球，以比較正常人，DMTB以及TB病患之間Th1相關細胞激素產生的能力。 同時，我們也嘗試利用TNF-α antagonist、insulin及GSK3抑制劑以揭開糖尿病這個代謝性疾病和分枝桿菌感染之間的機轉。 實驗數據顯示，當白血球在體外受到BCG刺激時，DMTB病患產生IL-12的能力有較弱的趨勢。 很有趣的，當加入TNF-α antagonist、insulin及GSK3抑制劑時，IFN-γ的產生出現被抑制的現象，而且這個現象在DMTB病患特別明顯。
　　總結上面的結果，本篇研究顯示肺結核病患合併糖尿病時，肺部空洞性病灶較及結核菌數量較多，但是痰陰轉速率較慢， 而且皮膚結核菌素測驗反應有較弱的趨勢。 同時，DMTB病患的完治率較低，治療失敗率較高。 DMTB病患的IL-12產生能力有較低的趨勢，而胰島素訊號傳遞途徑與IFN-γ的產生有相關。 這個結果顯示，胰島素的訊息傳遞機轉與發炎反應有關，而糖尿病病人在這個部份是有缺陷的。 這個缺陷可能是導致糖尿病病患免疫能力不足以及臨床表現和TB病患不一樣的原因。 因此，這個訊號傳遞途徑的功能缺陷在未來可能可以成為治療的標的。 本篇研究的結果對於結核病免疫致病機轉的了解以及對於未來結核病的防治提供了新的視野及某種程度的幫助。

　　Mycobacterium tuberculosis (M. tuberculosis) infection is a leading cause of morbidity and mortality in humans. It was estimated that while approximately 1/3 of the world population has been infected by tuberculosis (TB) bacilli, only 5-10% of the infected people develop the disease of TB. The immunity of the hosts thus may determine whether TB happens after exposure to M. tuberculosis. The balance of M. tuberculosis and host immunity is tipped by conditions leading to secondary immunodeficiency which contribute to the resurgence of TB. Among these disease, diabetes mellitus (DM) is the most serious underling disease in most developed countries. In Taiwan, 14%- 19% of pulmonary TB patients are complicated with DM. Moreover, the chance of TB in DM patients is 5 -6 times higher than healthy people. However, the influence of diabetes on clinical manifestations and treatment outcome of pulmonary TB patients are not fully investigated in Taiwan. Meanwhile, the molecular mechanism which underlies the immune defects of diabetic patients is not completely understood. Previous studies showed that there is an IL-12/ IFN-γaxis between monocytes, dendritic cells (DC), natural killer cells (NK), and T lymphocytes when whole blood is stimulated with live BCG bacilli. In this study, we investigated the different immune responses of healthy individuals and patients with pulmonary TB complicated with or without diabetes by analyzing clinical manifestations, skin tuberculin response and in vitro Th1 related cytokines production in these groups.
　　Firstly, sputum M. tuberculosis cultured-positive patients of Chest Hospital from October, 2004 to February, 2005 were investigated retrospectively by reviewing their medical records. There were 140 patients enrolled and classified as pulmonary tuberculosis complicated with diabetes (DMTB) or not (TB). We then compared the susceptibility and the incidence of multiple drug resistance (MDR) strains between these groups. The data showed that not only a higher susceptibility of TB (30%) but a higher incidence of MDR TB strains (28.5% vs 14.2%) were noted in DMTB group. To further analyzing the influence of diabetes, 103 (75TB, mean age: 54.8±20.8y/o, M:F=52:23; 28 DMTB, mean age: 58.6±13.4y/o, M:F=21:7, mean HbA1c: 10.61%) new patients were enrolled from these 140 patients and followed retrospectively for 1 year. The clinical manifestations, skin tuberculin response, and treatment outcome between TB and DMTB groups were analyzed. The data showed that the cavitary lesions of lungs, and bacterial load were higher in DMTB group. Meanwhile, the sputum conversion rate was slower (mean 4.2 months vs 1.9 months) and there was a trend of less responsive tuberculin skin test in DMTB patients. A lower completed treatment rate (54.5% vs 87.7%) within one year and a higher treatment failure rate (27.2% vs 0%) were noted in the DMTB group. These data indicated that diabetes has a great influence in TB control in Taiwan.
　　Secondly, we used BCG alone or BCG+IL-12, and BCG + IFN-γto stimulate whole blood leukocytes to investigate the difference of Th1 cytokines production between healthy volunteers, DMTB, and TB patients who were admitted to Chest Hospital. We also tried to unravel the mechanism underling the interaction between this metabolic disease and mycobacterial infection by using TNF-αantagonist, insulin and GSK3 inhibitors in the stimulation assays. The experimental data showed that when stimulated in vitro, the whole blood leukocytes of DMTB patients had a trend of lower ability to produce IL-12. Interestingly, inhibitory effects on IFN-γproduction by TNF-αantagonist, insulin, and GSK3 inhibitor were noted during in vitro stimulations and more obvious in DMTB patients.
　　In conclusion, this study showed that DMTB patients had higher cavitary lesions of lungs and bacterial load, but a slower sputum conversion rate and a trend of less responsive tuberculin skin test. Meanwhile, a poor treatment outcome and a higher treatment failure rate were noted in the DMTB group. DMTB patients had a trend of lower expression of IL-12 during in vitro BCG stimulation. The signaling pathway of insulin was involved in the production of IFN-γ. These results indicate that the signaling pathway of insulin was involved in inflammatory responses. The defect of insulin signaling transduction of diabetic patients probably underlies the molecular mechanism that leads to the clinical difference between DMTB and TB patients and may become a treatment target in the future. The results from these investigations are helpful for understanding the immunopathogenesis of TB and provide novel insights in controlling mycobacterial infection in the population.

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