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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

Western blot analysis and protein quantification of left ventricular myocardium harvested from 70-day-old TG9 mice.A. GLUT4 B. GLUT1 C. pan-AKT and phospho-AKT. D. AMPKα and phospho-AMPK. For each protein, the top panel represents expression as determined using antibody recognizing the protein of interest. Bottom panel: Data is represented as the mean protein intensity normalized to GAPDH from 4–6 independent mice. Each western blot was performed in triplicate. Values are expressed as the mean ± SEM; * indicates p<0.03, student's t-test.
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pone-0017178-g003: Western blot analysis and protein quantification of left ventricular myocardium harvested from 70-day-old TG9 mice.A. GLUT4 B. GLUT1 C. pan-AKT and phospho-AKT. D. AMPKα and phospho-AMPK. For each protein, the top panel represents expression as determined using antibody recognizing the protein of interest. Bottom panel: Data is represented as the mean protein intensity normalized to GAPDH from 4–6 independent mice. Each western blot was performed in triplicate. Values are expressed as the mean ± SEM; * indicates p<0.03, student's t-test.

Mentions: While the diabetic heart is known to use fatty acids almost exclusively as a fuel [14], [15], glucose utilization is increased in hypertrophic cardiomyopathy despite the development of insulin resistance [16]. This is accompanied by increased expression of the constitutively active glucose transporter GLUT1 [17]. In TG9 mice GLUT1 levels are similarly increased whereas the expression of GLUT4, the predominant glucose transporter in the adult heart, is unchanged [10]. We therefore examined whether GLUT expression was altered by exenatide in TG9 mice. At 75 days of age, total myocardial GLUT4 protein levels were increased by 40% in exenatide-treated versus non-treated TG9 mice whereas GLUT1 protein levels were unchanged (Figure 3A, B). Although previous studies have shown that exenatide can increase the expression of GLUT1, which is constitutively present on plasma membranes of multiple tissues including the heart and skeletal muscle [18], we did not detect any differences in total GLUT1 levels possibly because heart failure alone induces maximal up-regulation of this transporter [10].


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)

Western blot analysis and protein quantification of left ventricular myocardium harvested from 70-day-old TG9 mice.A. GLUT4 B. GLUT1 C. pan-AKT and phospho-AKT. D. AMPKα and phospho-AMPK. For each protein, the top panel represents expression as determined using antibody recognizing the protein of interest. Bottom panel: Data is represented as the mean protein intensity normalized to GAPDH from 4–6 independent mice. Each western blot was performed in triplicate. Values are expressed as the mean ± SEM; * indicates p<0.03, student's t-test.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0017178-g003: Western blot analysis and protein quantification of left ventricular myocardium harvested from 70-day-old TG9 mice.A. GLUT4 B. GLUT1 C. pan-AKT and phospho-AKT. D. AMPKα and phospho-AMPK. For each protein, the top panel represents expression as determined using antibody recognizing the protein of interest. Bottom panel: Data is represented as the mean protein intensity normalized to GAPDH from 4–6 independent mice. Each western blot was performed in triplicate. Values are expressed as the mean ± SEM; * indicates p<0.03, student's t-test.
Mentions: While the diabetic heart is known to use fatty acids almost exclusively as a fuel [14], [15], glucose utilization is increased in hypertrophic cardiomyopathy despite the development of insulin resistance [16]. This is accompanied by increased expression of the constitutively active glucose transporter GLUT1 [17]. In TG9 mice GLUT1 levels are similarly increased whereas the expression of GLUT4, the predominant glucose transporter in the adult heart, is unchanged [10]. We therefore examined whether GLUT expression was altered by exenatide in TG9 mice. At 75 days of age, total myocardial GLUT4 protein levels were increased by 40% in exenatide-treated versus non-treated TG9 mice whereas GLUT1 protein levels were unchanged (Figure 3A, B). Although previous studies have shown that exenatide can increase the expression of GLUT1, which is constitutively present on plasma membranes of multiple tissues including the heart and skeletal muscle [18], we did not detect any differences in total GLUT1 levels possibly because heart failure alone induces maximal up-regulation of this transporter [10].

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