Pioglitazone ameliorates insulin resistance and diabetes by both adiponectin-dependent and -independent pathways
Pioglitazone ameliorates insulin resistance and diabetes by both adiponectin-dependent and -independent pathways
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DOI：
10.1074/jbc.m505649200
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发表时间：
2006-03-31
影响因子：
4.8
通讯作者：
Kadowaki, T
中科院分区：
文献类型：
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作者：
Kubota, N;Terauchi, Y;Kadowaki, T
噻唑烷二酮已显示上调白色脂肪组织中的脂联素表达和血浆脂联素水平，并且这些上调已被认为是噻唑烷二酮诱导改善与肥胖相关的胰岛素抵抗的主要机制。为了验证这一假设，我们产生了具有C57 B/6背景的脂联素敲除（adipo（-/-））ob/ob小鼠。10 mg/kg吡格列酮给药14 d后，肥胖基因突变小鼠的胰岛素抵抗和糖尿病明显改善，血清脂联素水平显著上调。ob/ob小鼠胰岛素抵抗的改善归因于肝脏中葡萄糖产生的减少和AMP活化蛋白激酶的增加，而不是骨骼肌中葡萄糖摄取的增加。与此相反，在adipo（-/-）ob/ob小鼠中，胰岛素抵抗和糖尿病没有改善。30 mg/kg吡格列酮给药14天后，ob/ob小鼠的胰岛素抵抗和糖尿病再次显著改善，这不仅归因于肝脏葡萄糖生成减少，还归因于骨骼肌葡萄糖摄取增加。有趣的是，adipo（-/-）ob/ob小鼠也显示出胰岛素抵抗和糖尿病的显著改善，这归因于骨骼肌中葡萄糖摄取的增加，但不是肝脏中葡萄糖产生的减少。10 mg/kg吡格列酮给药后，ob/ob和adipo（-/-）ob/ob小鼠的血清游离脂肪酸和甘油三酯水平以及脂肪细胞大小无变化，但30 mg/kg吡格列酮给药后显著降低至相似程度。此外，10 mg/kg吡格列酮给药后ob/ob和adipo（-/-）ob/ob小鼠脂肪组织中TNF α和cDNAn的表达无变化，但30 mg/kg吡格列酮给药后降低。因此，吡格列酮诱导的胰岛素抵抗和糖尿病的改善可能在肝脏中依赖于脂联素，而在骨骼肌中独立于脂联素。
Thiazolidinediones have been shown to up-regulate adiponectin expression in white adipose tissue and plasma adiponectin levels, and these up-regulations have been proposed to be a major mechanism of the thiazolidinedione-induced amelioration of insulin resistance linked to obesity. To test this hypothesis, we generated adiponectin knock-out (adipo(-/-)) ob/ob mice with a C57B/6 background. After 14 days of 10 mg/kg pioglitazone, the insulin resistance and diabetes of ob/ob mice were significantly improved in association with significant up-regulation of serum adiponectin levels. Amelioration of insulin resistance in ob/ob mice was attributed to decreased glucose production and increased AMP-activated protein kinase in the liver but not to increased glucose uptake in skeletal muscle. In contrast, insulin resistance and diabetes were not improved in adipo(-/-) ob/ob mice. After 14 days of 30 mg/kg pioglitazone, insulin resistance and diabetes of ob/ob mice were again significantly ameliorated, which was attributed not only to decreased glucose production in the liver but also to increased glucose uptake in skeletal muscle. Interestingly, adipo(-/-) ob/ob mice also displayed significant amelioration of insulin resistance and diabetes, which was attributed to increased glucose uptake in skeletal muscle but not to decreased glucose production in the liver. The serum-free fatty acid and triglyceride levels as well as adipocyte sizes in ob/ob and adipo(-/-) ob/ob mice were unchanged after 10 mg/kg pioglitazone but were significantly reduced to a similar degree after 30 mg/kg pioglitazone. Moreover, the expressions of TNF alpha and resistin in adipose tissues of ob/ob and adipo(-/-) ob/ob mice were unchanged after 10 mg/kg pioglitazone but were decreased after 30 mg/kg pioglitazone. Thus, pioglitazone-induced amelioration of insulin resistance and diabetes may occur adiponectin dependently in the liver and adiponectin independently in skeletal muscle.