title: Diabetes Alters the Expression and Translocation of the Insulin-Sensitive Glucose Transporters 4 and 8 in the Atria.
abstract: Although diabetes has been identified as a major risk factor for atrial fibrillation, little is known about glucose metabolism in the healthy and diabetic atria. Glucose transport into the cell, the rate-limiting step of glucose utilization, is regulated by the Glucose Transporters (GLUTs). Although GLUT4 is the major isoform in the heart, GLUT8 has recently emerged as a novel cardiac isoform. We hypothesized that GLUT-4 and -8 translocation to the atrial cell surface will be regulated by insulin and impaired during insulin-dependent diabetes. GLUT protein content was measured by Western blotting in healthy cardiac myocytes and type 1 (streptozotocin-induced, T1Dx) diabetic rodents. Active cell surface GLUT content was measured using a biotinylated photolabeled assay in the perfused heart. In the healthy atria, insulin stimulation increased both GLUT-4 and -8 translocation to the cell surface (by 100% and 240%, respectively, P<0.05). Upon insulin stimulation, we reported an increase in Akt (Th308 and s473 sites) and AS160 phosphorylation, which was positively (P<0.05) correlated with GLUT4 protein content in the healthy atria. During diabetes, active cell surface GLUT-4 and -8 content was downregulated in the atria (by 70% and 90%, respectively, P<0.05). Akt and AS160 phosphorylation was not impaired in the diabetic atria, suggesting the presence of an intact insulin signaling pathway. This was confirmed by the rescued translocation of GLUT-4 and -8 to the atrial cell surface upon insulin stimulation in the atria of type 1 diabetic subjects. In conclusion, our data suggest that: 1) both GLUT-4 and -8 are insulin-sensitive in the healthy atria through an Akt/AS160 dependent pathway; 2) GLUT-4 and -8 trafficking is impaired in the diabetic atria and rescued by insulin treatment. Alterations in atrial glucose transport may induce perturbations in energy production, which may provide a metabolic substrate for atrial fibrillation during diabetes.
authors.affiliation: Department of Physiological Sciences, Oklahoma State University, Stillwater, United States of America.|Department of Mechanical and Aerospace Engineering, Oklahoma State University, Stillwater, Oklahoma, United States of America.
authors.forename: Zahra
authors.initials: Z
authors.lastname: Maria
authors.affiliation: Department of Physiological Sciences, Oklahoma State University, Stillwater, United States of America.
authors.forename: Allison R
authors.initials: AR
authors.lastname: Campolo
authors.affiliation: Department of Physiological Sciences, Oklahoma State University, Stillwater, United States of America.|Harold Hamm Diabetes Center, University of Oklahoma Health Science Center, Oklahoma City, United States of America.
authors.forename: Veronique A
authors.initials: VA
authors.lastname: Lacombe
mesh_terms: D000818:Animals; D001692:Biological Transport / Q000502:physiology; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism; D003922:Diabetes Mellitus, Type 1 / Q000378:metabolism; D004195:Disease Models, Animal; D051246:Glucose Transport Proteins, Facilitative / Q000378:metabolism*; D051275:Glucose Transporter Type 4 / Q000378:metabolism*; D006325:Heart Atria / Q000378:metabolism*; D007328:Insulin / Q000378:metabolism*; D007333:Insulin Resistance / Q000502:physiology; D051379:Mice; D009206:Myocardium / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000378:metabolism; D021381:Protein Transport / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology
chemical_list: D051246:Glucose Transport Proteins, Facilitative; D051275:Glucose Transporter Type 4; D007328:Insulin; C495693:Slc2a4 protein, mouse; C498628:Slc2a8 protein, mouse