Research Article: Diabetes Alters the Expression and Translocation of the Insulin-Sensitive Glucose Transporters 4 and 8 in the Atria

Date Published: December 31, 2015

Publisher: Public Library of Science

Author(s): Zahra Maria, Allison R. Campolo, Veronique A. Lacombe, Makoto Kanzaki.


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.

Partial Text

Diabetes mellitus is a serious metabolic disorder affecting 387 million people worldwide [1; 2]. Diabetes has now reached epidemic levels and has been identified as the 7th leading cause of death in the USA [2; 3]. Hyperglycemia, the hallmark of diabetes, results from an impaired glucose uptake due to a lack of insulin production by pancreatic beta cell (type 1) or lack of insulin action (type 2). Diabetes results in multiple organ dysfunction including cardiomyopathy, coronary artery disease and atrial fibrillation [4–7].

Although the heart is one of the main organs to utilize glucose as a metabolic substrate, very little is known about atrial glucose metabolism in both healthy and diseased conditions. Our data demonstrates that 1) a regional heterogeneity exists between GLUT4 and 8 expression in atria vs. ventricle; 2) both GLUT-4 and -8 are insulin-sensitive in the healthy atria; 3) diabetes impaired GLUT-4 and -8 trafficking to the atrial cell surface; and 4) insulin stimulation rescued GLUT translocation to the atrial cell surface during type 1 diabetes.

Using a cell surface biotinylation assay, we demonstrated that the major GLUT isoform, GLUT4, and the novel GLUT8 isoform are both insulin-sensitive transporters. Our data further suggested that GLUT translocation to the cell surface is modulated by the downstream insulin signaling pathway via Akt and/or AS160 phosphorylation. We further demonstrated that diabetes impairs the trafficking of both GLUT-4 and -8, which was rescued by insulin stimulation in the diabetic atria. These alterations in atrial glucose transport may induce perturbations in energy production and could provide a metabolic substrate for atrial fibrillation. Therefore, better understanding of the regulation of glucose transport may lead to the discovery of novel therapeutic targets for the treatment of cardiovascular complications associated with diabetes, including atrial fibrillation.