exenatide and Cardiomyopathy--Dilated

Increasing experimental evidence points to direct effects of glucagon-like peptide-1 (GLP-1) and its analogs on the heart and circulatory system, in addition to the well-established, antidiabetic actions of these agents on glucose and on the energy metabolism. These effects are primarily vasodilation, diminished heart muscle loss after myocardial infarction and a contractility increase of a weak left ventricle. A few, small patient trials appear to support the latter effect. Experimental results suggest the myocardium-saving effect following coronary occlusion and reperfusion as particularly suitable for clinical testing.

Topics: Cardiomyopathy, Dilated; Cardiovascular System; Energy Metabolism; Exenatide; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Heart; Humans; Hypoglycemic Agents; Liraglutide; Myocardial Reperfusion Injury; Myocardium; Peptides; Receptors, Glucagon; Venoms

There is growing awareness of secondary insulin resistance and alterations in myocardial glucose utilization in congestive heart failure. Whether therapies that directly target these changes would be beneficial is unclear. We previously demonstrated that acute blockade of the insulin responsive facilitative glucose transporter GLUT4 precipitates acute decompensated heart failure in mice with advanced dilated cardiomyopathy. Our current objective was to determine whether pharmacologic enhancement of insulin sensitivity and myocardial glucose uptake preserves cardiac function and survival in the setting of primary heart failure.. The GLP-1 agonist exenatide was administered twice daily to a murine model of dilated cardiomyopathy (TG9) starting at 56 days of life. TG9 mice develop congestive heart failure and secondary insulin resistance in a highly predictable manner with death by 12 weeks of age. Glucose homeostasis was assessed by measuring glucose tolerance at 8 and 10 weeks and tissue 2-deoxyglucose uptake at 75 days. Exenatide treatment improved glucose tolerance, myocardial GLUT4 expression and 2-deoxyglucose uptake, cardiac contractility, and survival over control vehicle-treated TG9 mice. Phosphorylation of AMP kinase and AKT was also increased in exenatide-treated animals. Total myocardial GLUT1 levels were not different between groups. Exenatide also abrogated the detrimental effect of the GLUT4 antagonist ritonavir on survival in TG9 mice.. In heart failure secondary insulin resistance is maladaptive and myocardial glucose uptake is suboptimal. An incretin-based therapy, which addresses these changes, appears beneficial.

Topics: Animals; Blood Glucose; Cardiomyopathy, Dilated; Disease Models, Animal; Drug Administration Schedule; Drug Evaluation, Preclinical; Exenatide; Female; Homeostasis; Hypoglycemic Agents; Mice; Mice, Transgenic; Peptides; Survival Analysis; Time Factors; Venoms