Abstract 16373: Sarcoplasmic Reticulum Calcium ATPase Pump is a Major Regulator of Myocardial Glucose Transport and Whole Body Glucose Homeostasis in Healthy and Diabetic State
Diabetes is characterized by sustained hyperglycemia resulting from decreased glucose uptake into insulin-sensitive tissues. Glucose uptake is tightly regulated by a family of glucose transporter proteins (GLUT). Despite intensive research, the pathways that mediate calcium-stimulated glucose transport in the heart remain elusive during healthy and diabetic state. The sarcoplasmic reticulum calcium ATPase (SERCA) pump tightly regulates cytosolic [Ca], and its dysfunction contributes to diabetic cardiomyopathy. Thus, we hypothesized that SERCA pump is a major regulator of glucose transport in the heart and that SERCA overexpression will rescue cardiac glucose transport and thus reduce complications associated with diabetes. Four groups of mice were used (n=18/group): healthy transgenic (TG) mice overexpressing SERCA1a in the heart and their healthy wildtype (WT) littermates, and insulin-deficient diabetic TG mice (streptozotocin-induced) and their diabetic WT littermates. Active cell surface GLUT4 was quantified by a biotinylated photolabeled assay in intact perfused myocardium. Total GLUT4 protein expression was measured by Western blot. Akt substrate of 160kDa (AS160), the most distal signaling protein implicated in insulin- and calcium-mediated GLUT4 trafficking, was measured by Western blot. SERCA overexpression significantly increased active cell-surface and total GLUT4 content in the heart of healthy TG compared to WT mice, as well as improved myocardial glucose uptake (measured by micropositron emission tomography) and whole-body glucose tolerance. Diabetes reduced total and active cell surface (basal and insulin-stimulated) GLUT4 content in the heart of WT mice, all of which were preserved in TG diabetic mice. Decreased basal AS160 paralleled the increase in cell surface GLUT4 in the heart of TG mice, suggesting a key role for AS160 in regulating GLUT4 trafficking. Increased SERCA activity significantly increased myocardial glucose uptake and reduced the hyperglycemia in diabetic TG mice. These data suggested that SR calcium handling, through SERCA pump, is a major regulator of cardiac glucose transport by an AS160 mechanism. Insights gained from this study could provide novel therapeutic targets for diabetic patients.
- © 2011 by American Heart Association, Inc.