Effects of antihyperlipidemic agents on hepatic insulin sensitivity in perfused Goto-Kakizaki rat liver
Effects of antihyperlipidemic agents on hepatic insulin sensitivity in perfused Goto-Kakizaki rat liver
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DOI：
10.1007/s00535-003-1300-y
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发表时间：
2004-04-01
影响因子：
6.3
通讯作者：
Onji, M
中科院分区：
文献类型：
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作者：
Matsuura, B;Kanno, S;Onji, M
背景。我们之前报道了Goto-Kakizaki （GK）大鼠，一种2型糖尿病的动物模型。用灌注大鼠肝脏模型研究肝脏胰岛素抵抗。吡格列酮，二十碳五烯酸（EPA）和非诺贝特是抗高脂血症药物和改善葡萄糖耐量。很少有研究表明这些药物能直接改善2型糖尿病患者的肝脏胰岛素敏感性。本研究的目的是利用灌注的GK大鼠肝脏模型，直接探讨这些药物对肝脏胰岛素敏感性的影响。方法。GK大鼠分别口服吡格列酮（6或10 mg/kg体重）、EPA（1或2 g/kg体重）或非诺贝特（30 mg/kg体重）治疗2周。原位灌注胰高血糖素或胰高血糖素与胰岛素。测量肝脏葡萄糖输出量。结果。吡格列酮处理的GK大鼠血糖水平明显降低。在吡格列酮和epa处理的GK大鼠中，胰岛素输注显著减弱胰高血糖素刺激的肝脏葡萄糖输出。非诺贝特处理的GK大鼠与未处理的GK大鼠相比，肝细胞脂肪沉积减少，胰高血糖素诱导的葡萄糖输出量明显减少。而胰岛素输注不影响胰高血糖素的葡萄糖输出。结论。这些发现提示吡格列酮和EPA可能通过直接增加肝脏胰岛素敏感性来改善葡萄糖耐量，而非诺贝特可能通过改善GK大鼠肝糖原代谢来改善葡萄糖耐量。
Background. We previously reported that the Goto-Kakizaki (GK) rat, an animal model of type 2 diabetes. has hepatic insulin resistance using a perfused rat liver model. Pioglitazone, eicosapentaenoic acid (EPA), and fenofibrate are antihyperlipidemic agents and improve glucose tolerance. There have been few studies showing that these agents directly improve hepatic insulin sensitivity in type 2 diabetes mellitus. The aim of this Study was to explore the effects of these agents oil hepatic insulin sensitivity directly using a perfused GK rat liver model. Methods. GK rats were treated with oral pioglitazone (6 or 10 mg/kg body weight), EPA (1 or 2 g/kg body weight), or fenofibrate (30 mg/kg body weight) for 2 weeks. Livers were perfused in situ with glucagon or with glucagon and insulin. and hepatic glucose outputs were measured. Results. In the pioglitazone-treated GK rats, blood glucose levels were significantly decreased. In the pioglitazone- and EPA-treated GK rats, insulin infusion significantly attenuated hepatic glucose output stimulated by glucagon. In the fenofibrate-treated GK rats, fat deposits in the hepatocytes were decreased, and glucose output elicited by glucagon was significantly decreased compared with that In the untreated GK rats. whereas insulin infusion did not affect glucose output by glucagon. Conclusions. These findings suggest that pioglitazone and EPA may improve glucose tolerance by directly increasing hepatic insulin sensitivity, while fenofibrate may improve glucose tolerance by improving hepatic glycogen metabolism in the GK rats.