Abstract 16839: GLUT-12: A Novel Insulin-Sensitive Glucose Transporter in the Heart?

Abstract

The heart is one of the main organs to utilize glucose. Glucose uptake from the bloodstream, the rate-limiting step in whole body glucose utilization, is regulated by a family of membrane proteins called glucose transporters (GLUTs). Although GLUT4 is the predominant isoform in insulin-sensitive tissues, there is recent evidence that GLUT12 could be a novel second insulin-sensitive GLUT in skeletal muscle. However, its role in the heart is not known, as well as the regulation of insulin-stimulated myocardial GLUT12 trafficking to the cell surface. Finally, despite intensive research, the pathogenic cause of altered glucose transport observed during diabetes remains elusive, and the role of GLUT12 has never been investigated in the diabetic myocardium. Thus, we hypothesized that, as for GLUT4, insulin will regulate GLUT12 translocation to the myocardial cell surface, which will be impaired during diabetes. To test our hypothesis, mice were made diabetic (insulin deficient) by streptozotocin injection and compared to their respective healthy littermates (n=9-12/group). Active cell surface GLUT (4 & 12) content was quantified by a biotinylated photolabeled assay in the intact perfused myocardium (with or without insulin stimulation). To our knowledge, we are the first to apply this technique to GLUT12. Total GLUT (4 & 12) protein expression and Akt substrate of 160 kDa (AS160, the most distal signaling protein implicated in GLUT trafficking) were measured by Western blot. Insulin stimulation significantly increased translocation of GLUT-4, but not -12, in the heart of healthy mice. Active cell surface GLUT12 was significantly increased in the diabetic myocardium, potentially as a compensatory mechanism for the observed downregulation of active GLUT4. Total cardiac GLUT4 content, but not GLUT12, was decreased during diabetes. Changes in GLUT trafficking were not associated with alterations in total or phosphorylated AS160, suggesting that AS160 is not a major pathogenic factor in the heart during insulin-dependent diabetes. Overall our data suggest that, in contrast to GLUT4, the insulin-signaling pathway does not mediate myocardial translocation of GLUT12. Thus, in the heart, GLUT12 may function as a basal GLUT located primarily at the cell surface.