title: Exenatide improves glucose homeostasis and prolongs survival in a murine model of dilated cardiomyopathy.
abstract: BACKGROUND
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  In heart failure secondary insulin resistance is maladaptive and myocardial glucose uptake is suboptimal. An incretin-based therapy, which addresses these changes, appears beneficial.
authors.affiliation: Department of Pediatrics, Washington University School of Medicine, St. Louis, Missouri, United States of America.
authors.forename: Arpita Kalla
authors.initials: AK
authors.lastname: Vyas
authors.forename: Kai-Chien
authors.initials: KC
authors.lastname: Yang
authors.forename: Dennis
authors.initials: D
authors.lastname: Woo
authors.forename: Anatoly
authors.initials: A
authors.lastname: Tzekov
authors.forename: Attila
authors.initials: A
authors.lastname: Kovacs
authors.forename: Patrick Y
authors.initials: PY
authors.lastname: Jay
authors.forename: Paul W
authors.initials: PW
authors.lastname: Hruz
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000187:drug effects / Q000378:metabolism*; D002311:Cardiomyopathy, Dilated / Q000188:drug therapy* / Q000378:metabolism / Q000401:mortality* / Q000503:physiopathology; D004195:Disease Models, Animal; D004334:Drug Administration Schedule; D004353:Drug Evaluation, Preclinical; D000077270:Exenatide; D005260:Female; D006706:Homeostasis / Q000187:drug effects / Q000502:physiology; D007004:Hypoglycemic Agents / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D051379:Mice; D008822:Mice, Transgenic; D010455:Peptides / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D016019:Survival Analysis; D013997:Time Factors; D014688:Venoms / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: D001786:Blood Glucose; D007004:Hypoglycemic Agents; D010455:Peptides; D014688:Venoms; D000077270:Exenatide