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Exenatide improves glucose homeostasis and prolongs survival in a murine model of dilated cardiomyopathy.

Vyas AK, Yang KC, Woo D, Tzekov A, Kovacs A, Jay PY, Hruz PW - PLoS ONE (2011)

Bottom Line: Whether therapies that directly target these changes would be beneficial is unclear.In heart failure secondary insulin resistance is maladaptive and myocardial glucose uptake is suboptimal.An incretin-based therapy, which addresses these changes, appears beneficial.

View Article: PubMed Central - PubMed

Affiliation: Department of Pediatrics, Washington University School of Medicine, St. Louis, Missouri, United States of America.

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.

Methodology/principal findings: 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.

Conclusion/significance: In heart failure secondary insulin resistance is maladaptive and myocardial glucose uptake is suboptimal. An incretin-based therapy, which addresses these changes, appears beneficial.

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Related in: MedlinePlus

RT- PCR for brain naturetic peptide measurement in the TG9 left ventricular tissue harvested at 70 days of life.Mice were treated with exenatide or vehicle (40 µg/kg/day divided b.i.d.) starting at 56 days. n = 4 per group, p-value  = 0.02.
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pone-0017178-g005: RT- PCR for brain naturetic peptide measurement in the TG9 left ventricular tissue harvested at 70 days of life.Mice were treated with exenatide or vehicle (40 µg/kg/day divided b.i.d.) starting at 56 days. n = 4 per group, p-value  = 0.02.

Mentions: For an independent marker of the severity of heart failure, we measured mRNA expression of brain natriuretic peptide (BNP) in the left ventricle of exenatide-treated mice and the control counterparts. As shown in Figure 5, BNP levels were significantly lower in the exenatide-treated animals compared to littermate vehicle-treated control TG9 mice (0.28±0.07 versus 1.0±0.26 arbitrary units, respectively, p = 0.02).


Exenatide improves glucose homeostasis and prolongs survival in a murine model of dilated cardiomyopathy.

Vyas AK, Yang KC, Woo D, Tzekov A, Kovacs A, Jay PY, Hruz PW - PLoS ONE (2011)

RT- PCR for brain naturetic peptide measurement in the TG9 left ventricular tissue harvested at 70 days of life.Mice were treated with exenatide or vehicle (40 µg/kg/day divided b.i.d.) starting at 56 days. n = 4 per group, p-value  = 0.02.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3040766&req=5

pone-0017178-g005: RT- PCR for brain naturetic peptide measurement in the TG9 left ventricular tissue harvested at 70 days of life.Mice were treated with exenatide or vehicle (40 µg/kg/day divided b.i.d.) starting at 56 days. n = 4 per group, p-value  = 0.02.
Mentions: For an independent marker of the severity of heart failure, we measured mRNA expression of brain natriuretic peptide (BNP) in the left ventricle of exenatide-treated mice and the control counterparts. As shown in Figure 5, BNP levels were significantly lower in the exenatide-treated animals compared to littermate vehicle-treated control TG9 mice (0.28±0.07 versus 1.0±0.26 arbitrary units, respectively, p = 0.02).

Bottom Line: Whether therapies that directly target these changes would be beneficial is unclear.In heart failure secondary insulin resistance is maladaptive and myocardial glucose uptake is suboptimal.An incretin-based therapy, which addresses these changes, appears beneficial.

View Article: PubMed Central - PubMed

Affiliation: Department of Pediatrics, Washington University School of Medicine, St. Louis, Missouri, United States of America.

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.

Methodology/principal findings: 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.

Conclusion/significance: In heart failure secondary insulin resistance is maladaptive and myocardial glucose uptake is suboptimal. An incretin-based therapy, which addresses these changes, appears beneficial.

Show MeSH
Related in: MedlinePlus