Abstract 15270: Does Diltiazem Therapy Have Beneficial Effects on Diabetic Cardiomyopathy?
Diabetes induces hyperglycemia due to decreased glucose uptake into insulin-sensitive tissues, leading to multi-organ dysfunction including heart diseases. Glucose transport occurs via a family of proteins called the glucose transporters (GLUTs). GLUT4, the major isoform, is regulated by insulin- and calcium-mediated pathways. Calcium channel blockers (CCBs) are widely prescribed for cardiovascular diseases, including in diabetic patients. While we previously demonstrated that CCBs altered calcium-dependent signaling pathways in the diabetic myocardium, their effects on glucose transport in the heart are unknown. Our hypothesis was that long term treatment with diltiazem (DILT), a widely prescribed CCB, would impair glucose transporters in cardiac and skeletal muscle of diabetic subjects. Rats with streptozotocin-induced diabetes were randomized to treatment with DILT or placebo for 8 weeks, and compared to treated and untreated controls (n = 4-11 / group). Echocardiographic examinations were performed at baseline and at 8 weeks. Protein expression of GLUT4 and GLUT12 (one of the most recently discovered isoforms) was measured in crude membrane extract by Western Blot. Total and phosphorylated AS160 were measured by Western blot. DILT treatment worsened the hyperglycemia observed in diabetic subjects (P=0.009). Diabetic rats displayed systolic dysfunction, characteristic of diabetic cardiomyopathy, without any significant improvement after DILT treatment. GLUT4 protein content was significantly decreased in striated muscle of (treated and untreated) diabetic groups vs. controls, with a more pronounced reduction in the skeletal tissue of the treated diabetic group (by 83%, P<0.05). There was no difference in cardiac and skeletal GLUT12 protein content in all groups. Decreased AS160 activation in (treated and untreated) diabetic groups correlated with the decrease in cardiac GLUT4 content suggesting a key role for AS160 in regulating GLUT4 trafficking in the heart. Our data suggested that DILT treatment does not improve cardiac contractility, and in fact decreases GLUT4 mediated-glucose transport, by reducing calcium influx through inhibition of the L-type calcium channels; and thus may be contraindicated in diabetic patients.
- © 2013 by American Heart Association, Inc.