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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

Left ventricular myocardial glucose uptake in 75-day old female TG9 mice.A. TG9 mice treated with vehicle or exenatide starting at 56 days of age as determined by [3H]-2-deoxyglucose incorporation following a 5-h fast (n = 9 and 8 per group). B. TG9 mice treated with vehicle or exenatide as in panel A were treated with ritonavir (10 mg/kg) administered by i.p. injection 15 minutes prior to measurement of [3H]-2-deoxyglucose incorporation (n = 6 and 3 respectively per group). Tissue glucose metabolic index (Rg'); *p<0.05.
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pone-0017178-g004: Left ventricular myocardial glucose uptake in 75-day old female TG9 mice.A. TG9 mice treated with vehicle or exenatide starting at 56 days of age as determined by [3H]-2-deoxyglucose incorporation following a 5-h fast (n = 9 and 8 per group). B. TG9 mice treated with vehicle or exenatide as in panel A were treated with ritonavir (10 mg/kg) administered by i.p. injection 15 minutes prior to measurement of [3H]-2-deoxyglucose incorporation (n = 6 and 3 respectively per group). Tissue glucose metabolic index (Rg'); *p<0.05.

Mentions: We next determined whether exenatide affects relative cardiac glucose uptake in TG9 mice. We have previously demonstrated that in 75 day old TG9 mice 2-deoxyglucose (2-DG) uptake is reduced to approximately one third of that observed in non-transgenic littermate control animals, consistent with the development of insulin resistance in these animals [10]. Acute treatment of 56 day old TG-9 mice with exenatide did not alter basal 2-deoxyglucose uptake into left ventricular myocardium (10±3.8 µmol/100 g/min) compared to vehicle-treated animals (14.5±8.3 µmol/100 g/min). However, as shown in Figure 4A, after 3 weeks of exenatide treatment, 2-DG uptake was significantly increased (37.7±5.9 µmol/100 g/min) compared to vehicle treated animals (19.8±3.6 µmol/100 g/min, p<0.05). Under these fasting conditions, basal skeletal muscle 2-DG uptake was low and no significant change was detected (data not shown).


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)

Left ventricular myocardial glucose uptake in 75-day old female TG9 mice.A. TG9 mice treated with vehicle or exenatide starting at 56 days of age as determined by [3H]-2-deoxyglucose incorporation following a 5-h fast (n = 9 and 8 per group). B. TG9 mice treated with vehicle or exenatide as in panel A were treated with ritonavir (10 mg/kg) administered by i.p. injection 15 minutes prior to measurement of [3H]-2-deoxyglucose incorporation (n = 6 and 3 respectively per group). Tissue glucose metabolic index (Rg'); *p<0.05.
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3040766&req=5

pone-0017178-g004: Left ventricular myocardial glucose uptake in 75-day old female TG9 mice.A. TG9 mice treated with vehicle or exenatide starting at 56 days of age as determined by [3H]-2-deoxyglucose incorporation following a 5-h fast (n = 9 and 8 per group). B. TG9 mice treated with vehicle or exenatide as in panel A were treated with ritonavir (10 mg/kg) administered by i.p. injection 15 minutes prior to measurement of [3H]-2-deoxyglucose incorporation (n = 6 and 3 respectively per group). Tissue glucose metabolic index (Rg'); *p<0.05.
Mentions: We next determined whether exenatide affects relative cardiac glucose uptake in TG9 mice. We have previously demonstrated that in 75 day old TG9 mice 2-deoxyglucose (2-DG) uptake is reduced to approximately one third of that observed in non-transgenic littermate control animals, consistent with the development of insulin resistance in these animals [10]. Acute treatment of 56 day old TG-9 mice with exenatide did not alter basal 2-deoxyglucose uptake into left ventricular myocardium (10±3.8 µmol/100 g/min) compared to vehicle-treated animals (14.5±8.3 µmol/100 g/min). However, as shown in Figure 4A, after 3 weeks of exenatide treatment, 2-DG uptake was significantly increased (37.7±5.9 µmol/100 g/min) compared to vehicle treated animals (19.8±3.6 µmol/100 g/min, p<0.05). Under these fasting conditions, basal skeletal muscle 2-DG uptake was low and no significant change was detected (data not shown).

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