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Insulin Regulation of Skeletal Muscle PDK4 mRNA Expression Is Impaired in Acute Insulin-Resistant States

From the Department of Physiology and Biophysics, University of Southern California Keck School of Medicine, Los Angeles, California

Address correspondence and reprint requests to Jang H. Youn, Department of Physiology and Biophysics, University of Southern California Keck School of Medicine, 1333 San Pablo St., MMR 626, Los Angeles, CA 90089-9142. E-mail: youn{at}usc.edu

Abbreviations: FFA, free fatty acid; FOXO, forkhead box class O; GIR, glucose infusion rate; PDK, pyruvate dehydrogenase kinase; PI3K, phosphatidylinositol 3-kinase; PPAR, peroxisome proliferator–activated receptor

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.

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