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Abstract：
BACKGROUND: Virtually the entire spectrum of liver disease is observed in association with type 2 diabetes mellitus (T2DM); indeed, T2DM is now the most common cause of liver disease in the U.S. We conducted a pilot study to investigate the relevance of increased microbial translocation and systemic inflammation in the development of liver injury in patients with T2DM.
METHODS: Patients with T2DM (n = 17) and non-diabetic controls (NDC; n = 11) aged 25-80 yrs. participated in this study. Serum levels of endotoxin, calprotectin, soluble CD14 and CD163, and several inflammatory cytokines were measured. In addition to standard liver injury markers, ALT and AST, novel serum markers of liver injury, keratin 18 (K-18) M30 (apoptosis-associated caspase-cleaved keratin 18), and M65 (soluble keratin 18) were evaluated. Statistical analyses were performed using the Mann-Whitney test to assess differences between study groups. Pearson\'s correlation analysis was performed to determine the strength of association between two variables using GraphPad Prism 9.5.0 software.
RESULTS: Patients with T2DM had significantly higher levels of sCD14 in comparison to NDC, suggesting an increase in gut permeability, microbial translocation, and monocyte/macrophage activation. Importantly, relevant to the ensuing inflammatory responses, the increase in sCD14 in patients with T2DM was accompanied by a significant increase in sCD163, a marker of hepatic Kupffer cell activation and inflammation. Further, a positive correlation was observed between sCD163 and endotoxin and sCD14 in T2DM patients but not in NDC. In association with these changes, keratin 18 (K-18)-based serum markers (M65 and M30) that reflect hepatocyte death were significantly higher in the T2DM group indicating ongoing liver injury. Notably, both M65 and M30 levels correlated with sCD14 and sCD163, suggesting that immune cell activation and hepatic inflammation may be linked to the development of liver injury in T2DM.
CONCLUSIONS: These findings suggest that the pathogenic changes in the gut-liver axis, marked by increased microbial translocation, may be a major component in the etiology of hepatocyte inflammation and injury in patients with T2DM. However, larger longitudinal studies, including histological evidence, are needed to confirm these observations.
METHODS: Patients with T2DM (n = 17) and non-diabetic controls (NDC; n = 11) aged 25-80 yrs. participated in this study. Serum levels of endotoxin, calprotectin, soluble CD14 and CD163, and several inflammatory cytokines were measured. In addition to standard liver injury markers, ALT and AST, novel serum markers of liver injury, keratin 18 (K-18) M30 (apoptosis-associated caspase-cleaved keratin 18), and M65 (soluble keratin 18) were evaluated. Statistical analyses were performed using the Mann-Whitney test to assess differences between study groups. Pearson\'s correlation analysis was performed to determine the strength of association between two variables using GraphPad Prism 9.5.0 software.
RESULTS: Patients with T2DM had significantly higher levels of sCD14 in comparison to NDC, suggesting an increase in gut permeability, microbial translocation, and monocyte/macrophage activation. Importantly, relevant to the ensuing inflammatory responses, the increase in sCD14 in patients with T2DM was accompanied by a significant increase in sCD163, a marker of hepatic Kupffer cell activation and inflammation. Further, a positive correlation was observed between sCD163 and endotoxin and sCD14 in T2DM patients but not in NDC. In association with these changes, keratin 18 (K-18)-based serum markers (M65 and M30) that reflect hepatocyte death were significantly higher in the T2DM group indicating ongoing liver injury. Notably, both M65 and M30 levels correlated with sCD14 and sCD163, suggesting that immune cell activation and hepatic inflammation may be linked to the development of liver injury in T2DM.
CONCLUSIONS: These findings suggest that the pathogenic changes in the gut-liver axis, marked by increased microbial translocation, may be a major component in the etiology of hepatocyte inflammation and injury in patients with T2DM. However, larger longitudinal studies, including histological evidence, are needed to confirm these observations.
摘要：
背景：实际上，观察到整个肝病谱与2型糖尿病（T2DM）有关；T2DM现在是美国肝病的最常见原因我们进行了一项初步研究，以探讨微生物易位增加和全身性炎症在T2DM患者肝损伤发展中的相关性。
方法：T2DM患者（n=17）和非糖尿病对照组（NDC；n=11），年龄25-80岁。参与了这项研究。血清内毒素水平，钙卫蛋白,测量可溶性CD14和CD163以及几种炎性细胞因子。除了标准的肝损伤标志物，ALT和AST,肝损伤的新型血清标志物，角蛋白18（K-18）M30（凋亡相关的半胱天冬酶裂解的角蛋白18），对M65(可溶性角蛋白18)进行评价。使用Mann-Whitney检验进行统计分析以评估研究组之间的差异。使用GraphPadPrism9.5.0软件进行Pearson相关性分析以确定两个变量之间的关联强度。
结果：T2DM患者的sCD14水平明显高于NDC，表明肠道通透性增加，微生物易位,和单核细胞/巨噬细胞活化。重要的是,与随后的炎症反应有关，T2DM患者中sCD14的升高伴随着sCD163的显著升高,sCD163是肝Kupffer细胞活化和炎症的标志.Further,在T2DM患者中观察到sCD163与内毒素和sCD14之间呈正相关,但在NDC中没有。伴随着这些变化，反映肝细胞死亡的基于角蛋白18(K-18)的血清标志物(M65和M30)在T2DM组中显著升高,提示持续的肝损伤.值得注意的是,M65和M30水平均与sCD14和sCD163相关,提示免疫细胞活化和肝脏炎症可能与T2DM肝损伤的发生有关.
结论：这些发现表明，肠-肝轴的致病性变化，以增加的微生物易位为标志，可能是T2DM患者肝细胞炎症和损伤病因的主要组成部分。然而,更大的纵向研究，包括组织学证据,需要确认这些观察结果。
方法：T2DM患者（n=17）和非糖尿病对照组（NDC；n=11），年龄25-80岁。参与了这项研究。血清内毒素水平，钙卫蛋白,测量可溶性CD14和CD163以及几种炎性细胞因子。除了标准的肝损伤标志物，ALT和AST,肝损伤的新型血清标志物，角蛋白18（K-18）M30（凋亡相关的半胱天冬酶裂解的角蛋白18），对M65(可溶性角蛋白18)进行评价。使用Mann-Whitney检验进行统计分析以评估研究组之间的差异。使用GraphPadPrism9.5.0软件进行Pearson相关性分析以确定两个变量之间的关联强度。
结果：T2DM患者的sCD14水平明显高于NDC，表明肠道通透性增加，微生物易位,和单核细胞/巨噬细胞活化。重要的是,与随后的炎症反应有关，T2DM患者中sCD14的升高伴随着sCD163的显著升高,sCD163是肝Kupffer细胞活化和炎症的标志.Further,在T2DM患者中观察到sCD163与内毒素和sCD14之间呈正相关,但在NDC中没有。伴随着这些变化，反映肝细胞死亡的基于角蛋白18(K-18)的血清标志物(M65和M30)在T2DM组中显著升高,提示持续的肝损伤.值得注意的是,M65和M30水平均与sCD14和sCD163相关,提示免疫细胞活化和肝脏炎症可能与T2DM肝损伤的发生有关.
结论：这些发现表明，肠-肝轴的致病性变化，以增加的微生物易位为标志，可能是T2DM患者肝细胞炎症和损伤病因的主要组成部分。然而,更大的纵向研究，包括组织学证据,需要确认这些观察结果。
