Effect of Acute Exercise on AMPK Signaling in Skeletal Muscle of Subjects With Type 2 Diabetes

Effect of Acute Exercise on AMPK Signaling in Skeletal Muscle of Subjects With Type 2 Diabetes A Time-Course and Dose-Response Study Apiradee Sriwijitkamol 1 2 , Dawn K. Coletta 1 , Estela Wajcberg 1 2 , Gabriela B. Balbontin 2 , Sara M. Reyna 1 2 , John Barrientes 2 , Phyllis A. Eagan 2 , Christopher P. Jenkinson 1 , Eugenio Cersosimo 1 2 , Ralph A. DeFronzo 1 2 , Kei Sakamoto 3 and Nicolas Musi 1 2 1 Diabetes Division, University of Texas Health Science Center at San Antonio, San Antonio, Texas 2 Texas Diabetes Institute, San Antonio, Texas 3 MRC Protein Phosphorylation Unit, School of Life Sciences, University of Dundee, Dundee, U.K Address correspondence and reprint requests to Nicolas Musi, MD, Texas Diabetes Institute, 701 S. Zarzamora, MS 10-5, San Antonio, TX 78207. E-mail: nicolas.musi{at}uhs-sa.com Abstract Activation of AMP-activated protein kinase (AMPK) by exercise induces several cellular processes in muscle. Exercise activation of AMPK is unaffected in lean (BMI ∼25 kg/m 2 ) subjects with type 2 diabetes. However, most type 2 diabetic subjects are obese (BMI >30 kg/m 2 ), and exercise stimulation of AMPK is blunted in obese rodents. We examined whether obese type 2 diabetic subjects have impaired exercise stimulation of AMPK, at different signaling levels, spanning from the upstream kinase, LKB1, to the putative AMPK targets, AS160 and peroxisome proliferator–activated receptor coactivator (PGC)-1α, involved in glucose transport regulation and mitochondrial biogenesis, respectively. Twelve type 2 diabetic, eight obese, and eight lean subjects exercised on a cycle ergometer for 40 min. Muscle biopsies were done before, during, and after exercise. Subjects underwent this protocol on two occasions, at low (50% V o 2max ) and moderate (70% V o 2max ) intensities, with a 4–6 week interval. Exercise had no effect on LKB1 activity. Exercise had a time- and intensity-dependent effect to increase AMPK activity and AS160 phosphorylation. Obese and type 2 diabetic subjects had attenuated exercise-stimulated AMPK activity and AS160 phosphorylation. Type 2 diabetic subjects had reduced basal PGC-1 gene expression but normal exercise-induced increases in PGC-1 expression. Our findings suggest that obese type 2 diabetic subjects may need to exercise at higher intensity to stimulate the AMPK-AS160 axis to the same level as lean subjects. ACC, acetyl CoA carboxylase AICAR, 5-aminoimidazole-4-carboxamide-1-β-d-ribofuranoside AMPK, AMP-activated protein kinase