Vanni Ester, Abate Maria Lorena, Gentilcore Elena, Hickman Ingrid, Gambino Roberto, Cassader Maurizio, Smedile Antonina, Ferrannini Ele, Rizzetto Mario, Marchesini Giulio, Gastaldelli Amalia, Bugianesi Elisabetta
Division of Gastro-Hepatology, San Giovanni Battista Hospital, University of Turin, Turin, Italy.
Hepatology. 2009 Sep;50(3):697-706. doi: 10.1002/hep.23031.
Chronic hepatitis C (CHC) has been associated with type 2 diabetes and insulin resistance, but the extent of impairment in insulin action, the target pathways involved, and the role of the virus per se have not been defined. In this study, we performed a euglycemic hyperinsulinemic clamp (1 mU x minute(-1) x kg(-1)) coupled with infusion of tracers ([6,6-(2)H(2)]glucose, [(2)H(5)]glycerol) and indirect calorimetry in 14 patients with biopsy-proven CHC, who were selected not to have any features of the metabolic syndrome, and in seven healthy controls. We also measured liver expression of inflammatory cytokines/mediators and tested their association with the metabolic parameters. Compared to controls, in patients with CHC: (1) total glucose disposal (TGD) during the clamp was 25% lower (P = 0.003) due to impaired glucose oxidation (P = 0.0002), (2) basal endogenous glucose production (EGP) was 20% higher (P = 0.011) and its suppression during the clamp was markedly reduced (P = 0.007), and (3) glycerol appearance was not different in the basal state or during the clamp, but lipid oxidation was less suppressed by insulin (P = 0.004). Lipid oxidation was higher in patients with CHC who had more steatosis and was directly related to EGP, TGD, and glucose oxidation. The decreased insulin-stimulated suppression of EGP was associated with increased hepatic suppressor of cytokine signaling 3 (SOCS3; P < 0.05) and interleukin-18 (P < 0.05) expression.
Hepatitis C infection per se is associated with peripheral and hepatic insulin resistance. Substrate competition by increased lipid oxidation and possibly enhanced hepatic expression of inflammatory cytokines/mediators could be involved in the defective glucose regulation.
慢性丙型肝炎（CHC）与2型糖尿病和胰岛素抵抗有关，但胰岛素作用受损的程度、涉及的靶途径以及病毒本身的作用尚未明确。在本研究中，我们对14例经活检证实为CHC且无代谢综合征任何特征的患者以及7例健康对照者进行了正常血糖高胰岛素钳夹试验（1 mU×分钟⁻¹×千克⁻¹），同时输注示踪剂（[6,6-(²)H₂]葡萄糖、[(²)H₅]甘油）并进行间接测热法。我们还测量了肝脏炎症细胞因子/介质的表达，并测试了它们与代谢参数的关联。与对照组相比，CHC患者：（1）钳夹期间的总葡萄糖处置（TGD）降低了25%（P = 0.003），原因是葡萄糖氧化受损（P = 0.0002）；（2）基础内源性葡萄糖生成（EGP）升高了20%（P = 0.011），且钳夹期间其抑制作用明显降低（P = 0.007）；（3）基础状态或钳夹期间甘油的出现无差异，但胰岛素对脂质氧化的抑制作用较小（P = 0.004）。在脂肪变性较多的CHC患者中脂质氧化较高，且与EGP、TGD和葡萄糖氧化直接相关。胰岛素刺激下EGP抑制作用的降低与肝脏细胞因子信号转导抑制因子3（SOCS3；P < 0.05）和白细胞介素-18（P < 0.05）表达增加有关。
丙型肝炎感染本身与外周和肝脏胰岛素抵抗有关。脂质氧化增加导致的底物竞争以及可能增强的肝脏炎症细胞因子/介质表达可能参与了葡萄糖调节缺陷。
