Insulin regulation of skeletal muscle PDK4 mRNA expression is impaired in acute insulin-resistant states 10.107/db05-1606
Insulin regulation of skeletal muscle PDK4 mRNA expression is impaired in acute insulin-resistant states 10.107/db05-1606
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DOI：
10.2337/db05-1606
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发表时间：
2006-08-01
期刊：
影响因子：
7.7
通讯作者：
Youn, Jang H.
中科院分区：
文献类型：
--
作者：
Kim, Young I.;Lee, Felix N.;Youn, Jang H.
我们以前发现，胰岛素具有抑制大鼠骨骼肌中丙酮酸脱氢酶激酶（PDK）4表达的深远影响。在本研究中，我们研究了在急性胰岛素抵抗状态下胰岛素对PDK 4表达的影响是否受损，如果是这样，这种变化是否伴随着胰岛素刺激Akt和forkhead box class O（FOXO）1磷酸化的作用降低。为了诱导胰岛素抵抗，清醒的过夜禁食大鼠接受Intraperoid或乳酸盐的恒定输注5小时，而对照组接受生理盐水输注。初始输注后，每组接受盐水或胰岛素输注（每组n = 6或7），持续5 h，同时继续输注盐水、胰岛素或乳酸盐。在胰岛素输注期间，将血糖钳制在基础水平。与对照组相比，胰岛素和乳酸盐输注降低了钳夹血浆葡萄糖所需的葡萄糖输注速率约60%（P < 0.01），证实了胰岛素抵抗的诱导。胰岛素抑制骨骼肌中PDK 4 mRNA水平的能力在胰岛素和乳酸盐输注中受损，导致胰岛素的PDK 4 mRNA水平升高2 - 3倍（P < 0.05）。胰岛素刺激Akt和FOXO 1磷酸化也显著降低Intraperoid和乳酸输注。这些数据表明，胰岛素抑制骨骼肌中PDK 4基因表达的作用在胰岛素抵抗状态下受损，这可能是由于刺激Akt和FOXO 1磷酸化的胰岛素信号传导受损。胰岛素抑制PDK 4表达的作用受损可能解释了骨骼肌中PDK 4过表达与胰岛素抵抗之间的关联。
We previously showed that insulin has a profound effect to suppress pyruvate dehydrogenase kinase (PDK) 4 expression in rat skeletal muscle. In the present study, we examined whether insulin's effect on PDK4 expression is impaired in acute insulin-resistant states and, if so, whether this change is accompanied by decreased insulin's effects to stimulate Akt and forkhead box class O (FOXO) 1 phosphorylation. To induce insulin resistance, conscious overnight-fasted rats received a constant infusion of Intralipid or lactate for 5 h, while a control group received saline infusion. Following the initial infusions, each group received saline or insulin infusion (n = 6 or 7 each) for an additional 5 h, while saline, Intralipid, or lactate infusion was continued. Plasma glucose was clamped at basal levels during the insulin infusion. Compared with the control group, Intralipid and lactate infusions decreased glucose infusion rates required to clamp plasma glucose by -60% (P < 0.01), confirming the induction of insulin resistance. Insulin's ability to suppress PDK4 mRNA level was impaired in skeletal muscle with Intralipid and lactate infusions, resulting in two- to threefold higher PDK4 mRNA levels with insulin (P < 0.05). Insulin stimulation of Akt and FOXO1 phosphorylation was also significantly decreased with Intralipid and lactate infusions. These data suggest that insulin's effect to suppress PDK4 gene expression in skeletal muscle is impaired in insulin-resistant states, and this may be due to impaired insulin signaling for stimulation of Akt and FOXO1 phosphorylation. Impaired insulin's effect to suppress PDK4 expression may explain the association between PDK4 overexpression and insulin resistance in skeletal muscle.