Metformin Inhibits Glutaminase Activity and Protects against Hepatic Encephalopathy
Metformin Inhibits Glutaminase Activity and Protects against Hepatic Encephalopathy
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DOI：
10.1371/journal.pone.0049279
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发表时间：
2012-11-15
期刊：
影响因子：
3.7
通讯作者：
Romero-Gomez, Manuel
中科院分区：
文献类型：
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作者：
Ampuero, Javier;Ranchal, Isidora;Romero-Gomez, Manuel
目的：通过对糖尿病肝硬变患者的回顾性队列研究，探讨二甲双胍对肝功能障碍和肝性脑病的影响。目的：分析二甲双胍对肝硬变合并2型糖尿病患者体内谷氨酰胺酶活力和氨产生的影响。41名患者被分为胰岛素增敏剂试验组(二甲双胍)和41名对照组(未接受二甲双胍治疗的肝硬变2型糖尿病患者)。基线分析包括：胰岛素、血糖、高血糖素、瘦素、脂联素、肿瘤坏死因子受体2、天冬氨酸氨基转移酶、丙氨酸氨基转移酶。计算HOMA-IR。根据轻度肝性脑病、口服谷氨酰胺激发和谷氨酰胺酶基因突变计算基线HE风险。我们在体外进行了一项实验研究，包括酶活性测定，根据不同浓度的二甲双胍测定谷氨酰胺酶抑制作用。结果：随访期间发现肝性脑病的发生率为23.2%(19/82)、4.9%(2/41)和41.5%(17/41)(P=0.002)。在多因素分析中，二甲双胍的使用[H.R.11.4(95%可信区间：1.2-108.8)；p=0.034]、确诊年龄[H.R.1.12(95%可信区间：1.04-1.2)；p=0.002]、女性[H.R.10.4(95%可信区间：1.5-71.6)；p=0.017]和HE风险[H.R.21.3(95%可信区间：2.8-163.4)；P=0.003]与肝性脑病独立相关。在酶促反应中，100 mM的二甲双胍对谷氨酰胺酶活力的抑制率达68%。在Caco 2细胞中，二甲双胍(20 MM)作用72小时后，谷氨酰胺酶活力下降达24%(p<；0.05)。结论：二甲双胍与2型糖尿病合并肝性脑病的高危患者的肝性脑病独立相关。二甲双胍在体外抑制谷氨酰胺酶活性。因此，二甲双胍的使用似乎对糖尿病肝硬变患者的肝性脑病具有保护作用。
Aim: To investigate the influence of metformin use on liver dysfunction and hepatic encephalopathy in a retrospective cohort of diabetic cirrhotic patients. To analyze the impact of metformin on glutaminase activity and ammonia production in vitro.Methods: Eighty-two cirrhotic patients with type 2 diabetes were included. Forty-one patients were classified as insulin sensitizers experienced (metformin) and 41 as controls (cirrhotic patients with type 2 diabetes mellitus without metformin treatment). Baseline analysis included: insulin, glucose, glucagon, leptin, adiponectin, TNFr2, AST, ALT. HOMA-IR was calculated. Baseline HE risk was calculated according to minimal hepatic encephalopathy, oral glutamine challenge and mutations in glutaminase gene. We performed an experimental study in vitro including an enzymatic activity assay where glutaminase inhibition was measured according to different metformin concentrations. In Caco2 cells, glutaminase activity inhibition was evaluated by ammonia production at 24, 48 and 72 hours after metformina treatment.Results: Hepatic encephalopathy was diagnosed during follow-up in 23.2% (19/82): 4.9% (2/41) in patients receiving metformin and 41.5% (17/41) in patients without metformin treatment (logRank 9.81; p = 0.002). In multivariate analysis, metformin use [H. R. 11.4 (95% CI: 1.2-108.8); p = 0.034], age at diagnosis [H. R. 1.12 (95% CI: 1.04-1.2); p = 0.002], female sex [H. R. 10.4 (95% CI: 1.5-71.6); p = 0.017] and HE risk [H. R. 21.3 (95% CI: 2.8-163.4); p = 0.003] were found independently associated with hepatic encephalopathy. In the enzymatic assay, glutaminase activity inhibition reached 68% with metformin 100 mM. In Caco2 cells, metformin (20 mM) decreased glutaminase activity up to 24% at 72 hours post-treatment (p < 0.05).Conclusions: Metformin was found independently related to overt hepatic encephalopathy in patients with type 2 diabetes mellitus and high risk of hepatic encephalopathy. Metformin inhibits glutaminase activity in vitro. Therefore, metformin use seems to be protective against hepatic encephalopathy in diabetic cirrhotic patients.