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

Zahra Maria,Allison R Campolo,Veronique A Lacombe,Makoto Kanzaki

doi:10.1371/journal.pone.0146033

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.

Highlights

Diabetes mellitus is a serious metabolic disorder affecting 387 million people worldwide [1; 2]
Our results indicated an increase in total Glucose Transporters (GLUTs)-4 and -8 total protein content upon insulin stimulation (Fig 1C and 1D)
The response to insulin was greater in the atria compared to the ventricle, with an increase in GLUT8 trafficking by 240% vs. 40%, respectively (P

Summary

Introduction

Diabetes mellitus is a serious metabolic disorder affecting 387 million people worldwide [1; 2]. Cardiac glucose uptake and utilization is crucial for proper cardiac function This is germane to the fact that the atria, which is the pacemaker of the heart, significantly contributes to the overall cardiac function. The rate of glucose utilization in the heart is greater than in other tissue, little is known about glucose metabolism in the atria during both healthy and disease states [9]. Glucose transport into the cell is the rate limiting step of glucose utilization and is regulated by a family of membrane proteins known as Glucose Transporters (GLUTs) [10]. Whereas some other isoforms have been referred to as basal GLUTs located primarily at the cell surface (i.e., GLUT1, GLUT12), the translocation of the main GLUT protein, GLUT4, from an intracellular sequestration inactive site to the plasma membrane (active site) is largely regulated by insulindependent processes, other factors can alter myocardial glucose transport [16; 17]. Better understanding of the role and regulation of glucose transport in the healthy and diabetic atria will give novel insights in understanding the pathophysiology of diabetes and its associated cardiovascular complications

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