Department of Physiology, University of Toronto, Medical Sciences Building, 1 King's College Circle, Toronto, Ontario, Canada.
J Endocrinol. 2013 Mar 15;217(1):31-43. doi: 10.1530/JOE-12-0214. Print 2013 Apr.
We have shown in rats that sodium salicylate (SS), which inhibits IkBa kinase B (IKKB), prevents hepatic and peripheral insulin resistance caused by short-term (7 h) i.v. administration of Intralipid and heparin (IH). We wished to further determine whether this beneficial effect of SS persisted after prolonged (48 h) IH infusion, which better mimics the chronic free fatty acid (FFA) elevation of obesity. Hence, we performed hyperinsulinemic euglycemic clamps with tritiated glucose methodology to determine hepatic and peripheral insulin sensitivity in rats infused with saline, IH, IH and SS, or SS alone. SS prevented peripheral insulin resistance (P<0.05) caused by prolonged plasma FFA elevation; however, it did not prevent hepatic insulin resistance. In skeletal muscle, protein levels of phospho-IkBa were augmented by prolonged IH administration and this was prevented by SS, suggesting that IH activates while SS prevents the activation of IKKB. Markers of IKKB activation, namely protein levels of phospho-IkBa and IkBa, indicated that IKKB is not activated in the liver after prolonged FFA elevation. Phosphorylation of serine 307 at insulin receptor substrate (IRS)-1, which is a marker of proximal insulin resistance, was not altered by IH administration in the liver, suggesting that this is not a site of hepatic insulin resistance in the prolonged lipid infusion model. Our results suggest that the role of IKKB in fat-induced insulin resistance is time and tissue dependent and that hepatic insulin resistance induced by prolonged lipid elevation is not due to an IRS-1 serine 307 kinase.
我们已经在大鼠中表明，水杨酸钠（SS）抑制 IkBa 激酶 B（IKKB），可预防短期（7 小时）静脉内给予脂肪乳剂和肝素（IH）引起的肝和外周胰岛素抵抗。我们希望进一步确定 SS 是否在延长（48 小时）IH 输注后仍具有这种有益作用，因为这种输注更能模拟肥胖症中慢性游离脂肪酸（FFA）升高。因此，我们使用氚标记葡萄糖方法进行高胰岛素正葡萄糖钳夹，以确定输注盐水、IH、IH 和 SS 或 SS 单独的大鼠的肝和外周胰岛素敏感性。SS 可预防延长的血浆 FFA 升高引起的外周胰岛素抵抗（P<0.05）；然而，它不能预防肝胰岛素抵抗。在骨骼肌中，延长 IH 给药会增加磷酸化 IkBa 的蛋白水平，而 SS 可防止这种增加，这表明 IH 激活而 SS 阻止 IKKB 的激活。IKKB 激活的标志物，即磷酸化 IkBa 和 IkBa 的蛋白水平，表明在延长的 FFA 升高后，肝脏中 IKKB 并未被激活。胰岛素受体底物（IRS）-1 丝氨酸 307 的磷酸化，这是近端胰岛素抵抗的标志物，在肝脏中给予 IH 后没有改变，这表明在延长的脂质输注模型中，这不是肝胰岛素抵抗的部位。我们的结果表明，IKKB 在脂肪诱导的胰岛素抵抗中的作用与时间和组织有关，并且延长的脂质升高引起的肝胰岛素抵抗不是由于 IRS-1 丝氨酸 307 激酶。
