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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

Intraperitoneal glucose tolerance tests (1 g/kg) on age-matched female TG9 mice following a 5 hour fast.A. Baseline responses at 8 weeks of age. B. Following 2 weeks of treatment with either vehicle or exenatide (Age 10 weeks). Data is shown as the mean ± SEM (n = 4-6). *p<0.01, ANOVA.
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pone-0017178-g001: Intraperitoneal glucose tolerance tests (1 g/kg) on age-matched female TG9 mice following a 5 hour fast.A. Baseline responses at 8 weeks of age. B. Following 2 weeks of treatment with either vehicle or exenatide (Age 10 weeks). Data is shown as the mean ± SEM (n = 4-6). *p<0.01, ANOVA.

Mentions: To determine the effect of exenatide on glucose homeostasis, female TG9 mice fed a standard chow diet first underwent intraperitoneal glucose tolerance tests at 8 weeks of age. At this age, TG9 mice appear overtly normal and have normal fasting blood glucose levels but have echocardiographic evidence of mild dilated cardiomyopathy [10]. Glucose tolerance tests (GTT) were repeated after administering exenatide subcutaneously (40 µg/kg/day divided into two daily doses) or vehicle for 14 days. Baseline blood glucose levels and responses to GTT did not differ between the two treatment groups (Figure 1). At 10 weeks of age, TG9 mice receiving exenatide exhibited a response to glucose challenge that was similar to untreated non-transgenic littermates with fasting and peak blood glucose levels of 6.9±0.3 and 11.3±0.5 mmol/L, respectively. In contrast, vehicle-treated TG9 mice developed a significant worsening in both fasting blood glucose levels (12.2±1.7 mmol/L) and glucose tolerance (peak glucose 21.8±0.7 mmol/L). None of the mice experienced detectable hypoglycemia at any point during the study. As shown in Figure 2, there was no difference in fasting serum insulin levels in 10 week old exenatide-treated animals (0.26±0.08 ng/ml) compared to vehicle-treated littermate controls (0.27±0.04 ng/ml). There was also no difference in insulin levels 15 minutes (0.69±0.06 ng/ml exenatide vs 0.74±0.15 ng/ml vehicle) or 30 minutes (0.25±0.02 ng/ml exenatide vs 0.30±0.06 ng/ml vehicle) after a 1 g/kg intraperitoneal glucose load. Thus, exenatide appears to normalize the response to glucose challenge in treated TG9 animals by increasing insulin sensitivity rather than insulin secretion. Exenatide did not alter lipid profiles in TG9 mice (Table 1).


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)

Intraperitoneal glucose tolerance tests (1 g/kg) on age-matched female TG9 mice following a 5 hour fast.A. Baseline responses at 8 weeks of age. B. Following 2 weeks of treatment with either vehicle or exenatide (Age 10 weeks). Data is shown as the mean ± SEM (n = 4-6). *p<0.01, ANOVA.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3040766&req=5

pone-0017178-g001: Intraperitoneal glucose tolerance tests (1 g/kg) on age-matched female TG9 mice following a 5 hour fast.A. Baseline responses at 8 weeks of age. B. Following 2 weeks of treatment with either vehicle or exenatide (Age 10 weeks). Data is shown as the mean ± SEM (n = 4-6). *p<0.01, ANOVA.
Mentions: To determine the effect of exenatide on glucose homeostasis, female TG9 mice fed a standard chow diet first underwent intraperitoneal glucose tolerance tests at 8 weeks of age. At this age, TG9 mice appear overtly normal and have normal fasting blood glucose levels but have echocardiographic evidence of mild dilated cardiomyopathy [10]. Glucose tolerance tests (GTT) were repeated after administering exenatide subcutaneously (40 µg/kg/day divided into two daily doses) or vehicle for 14 days. Baseline blood glucose levels and responses to GTT did not differ between the two treatment groups (Figure 1). At 10 weeks of age, TG9 mice receiving exenatide exhibited a response to glucose challenge that was similar to untreated non-transgenic littermates with fasting and peak blood glucose levels of 6.9±0.3 and 11.3±0.5 mmol/L, respectively. In contrast, vehicle-treated TG9 mice developed a significant worsening in both fasting blood glucose levels (12.2±1.7 mmol/L) and glucose tolerance (peak glucose 21.8±0.7 mmol/L). None of the mice experienced detectable hypoglycemia at any point during the study. As shown in Figure 2, there was no difference in fasting serum insulin levels in 10 week old exenatide-treated animals (0.26±0.08 ng/ml) compared to vehicle-treated littermate controls (0.27±0.04 ng/ml). There was also no difference in insulin levels 15 minutes (0.69±0.06 ng/ml exenatide vs 0.74±0.15 ng/ml vehicle) or 30 minutes (0.25±0.02 ng/ml exenatide vs 0.30±0.06 ng/ml vehicle) after a 1 g/kg intraperitoneal glucose load. Thus, exenatide appears to normalize the response to glucose challenge in treated TG9 animals by increasing insulin sensitivity rather than insulin secretion. Exenatide did not alter lipid profiles in TG9 mice (Table 1).

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