Journal Article

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

Sarah Lee, Felix N. Lee, Young I. Kim, Woo S. Choi, Jang H. Youn

2006

Overview

Insulin Regulation of Skeletal Muscle PDK4 mRNA Expression Is Impaired in Acute Insulin-Resistant States Young I. Kim , Felix N. Lee , Woo S. Choi , Sarah Lee and Jang H. Youn 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 Abstract 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. 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 Footnotes Y.I.K. and F.N.L. contributed equally to this work. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement‘ in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Accepted May 22, 2006. Received December 12, 2005. DIABETES

• Publisher: American Diabetes Association
• Subject: Animals / Biological and medical sciences / Blood Glucose - analysis / Blotting, Northern / Catheters / Dehydrogenases / Diabetes / Diabetes mellitus / Diabetes. Impaired glucose tolerance / Endocrine pancreas. Apud cells (diseases) / Endocrinopathies / Etiopathogenesis. Screening. Investigations. Target tissue resistance / Experiments / Fat Emulsions, Intravenous - administration & dosage / Fatty Acids, Nonesterified - blood / Forkhead Transcription Factors - metabolism / Fundamental and applied biological sciences. Psychology / Gastrointestinal surgery / Gene expression / Gene Expression Regulation, Enzymologic - drug effects / Glucose / Growth factors / Health aspects / Insulin - blood / Insulin - pharmacology / Insulin resistance / Insulin Resistance - physiology / Kinases / Kinetics / Lactic Acid - administration & dosage / Lactic Acid - blood / Male / Medical sciences / Messenger RNA / Muscle, Skeletal - enzymology / Musculoskeletal system / Nerve Tissue Proteins - metabolism / Oxidation / Phosphorylation / Plasma / Protein Kinases - genetics / Proto-Oncogene Proteins c-akt - metabolism / Rats / Rats, Wistar / RNA, Messenger - analysis / Striated muscle. Tendons / Transcription factors / Vertebrates: osteoarticular system, musculoskeletal system