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Altered myocardial substrate metabolism is associated with myocardial dysfunction in early diabetic cardiomyopathy in rats: studies using positron emission tomography.

van den Brom CE, Huisman MC, Vlasblom R, Boontje NM, Duijst S, Lubberink M, Molthoff CF, Lammertsma AA, van der Velden J, Boer C, Ouwens DM, Diamant M - Cardiovasc Diabetol (2009)

Bottom Line: Myocardial functional changes were significantly associated with whole-body insulin sensitivity and decreased myocardial glucose utilisation.ZL hearts a 2.4-fold reduced insulin-mediated phosphorylation of Akt was found (p < 0.05).Using PET and echocardiography, we found increases in myocardial FA oxidation with a concomitant decrease of insulin-mediated myocardial glucose utilisation in early DCM.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Endocrinology, Diabetes Centre, VU University Medical Centre, Amsterdam, The Netherlands. c.vandenbrom@vumc.nl

ABSTRACT

Background: In vitro data suggest that changes in myocardial substrate metabolism may contribute to impaired myocardial function in diabetic cardiomyopathy (DCM). The purpose of the present study was to study in a rat model of early DCM, in vivo changes in myocardial substrate metabolism and their association with myocardial function.

Methods: Zucker diabetic fatty (ZDF) and Zucker lean (ZL) rats underwent echocardiography followed by [11C]palmitate positron emission tomography (PET) under fasting, and [18F]-2-fluoro-2-deoxy-D-glucose PET under hyperinsulinaemic euglycaemic clamp conditions. Isolated cardiomyocytes were used to determine isometric force development.

Results: PET data showed a 66% decrease in insulin-mediated myocardial glucose utilisation and a 41% increase in fatty acid (FA) oxidation in ZDF vs. ZL rats (both p < 0.05). Echocardiography showed diastolic and systolic dysfunction in ZDF vs. ZL rats, which was paralleled by a significantly decreased maximal force (68%) and maximal rate of force redevelopment (69%) of single cardiomyocytes. Myocardial functional changes were significantly associated with whole-body insulin sensitivity and decreased myocardial glucose utilisation. ZDF hearts showed a 68% decrease in glucose transporter-4 mRNA expression (p < 0.05), a 22% decrease in glucose transporter-4 protein expression (p = 0.10), unchanged levels of pyruvate dehydrogenase kinase-4 protein expression, a 57% decreased phosphorylation of AMP activated protein kinase alpha1/2 (p < 0.05) and a 2.4-fold increased abundance of the FA transporter CD36 to the sarcolemma (p < 0.01) vs. ZL hearts, which are compatible with changes in substrate metabolism. In ZDF vs. ZL hearts a 2.4-fold reduced insulin-mediated phosphorylation of Akt was found (p < 0.05).

Conclusion: Using PET and echocardiography, we found increases in myocardial FA oxidation with a concomitant decrease of insulin-mediated myocardial glucose utilisation in early DCM. In addition, the latter was associated with impaired myocardial function. These in vivo data expand previous in vitro findings showing that early alterations in myocardial substrate metabolism contribute to myocardial dysfunction.

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Molecular alterations in myocardial insulin signaling. Quantification of immunoblots showing relative phosphorylation/total protein levels of Akt-Ser473/Akt2 after saline (-; open bars) or insulin (+; filled bars) injection. Data are expressed as mean ± SEM, n = 4–8, * p < 0.05 different from basal, # p < 0.05 different from ZL.
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Figure 4: Molecular alterations in myocardial insulin signaling. Quantification of immunoblots showing relative phosphorylation/total protein levels of Akt-Ser473/Akt2 after saline (-; open bars) or insulin (+; filled bars) injection. Data are expressed as mean ± SEM, n = 4–8, * p < 0.05 different from basal, # p < 0.05 different from ZL.

Mentions: ZDF versus ZL hearts showed a significant decrease in myocardial insulin-mediated Akt-Ser473 phosphorylation (Figure 4), whereas no differences were found in basal phosphorylation. Finally, intracellular signaling molecules related to myocardial calcium handling, like PLB and SERCA2a were studied. No difference was found in SERCA2a protein expression (see additional file 2A). Basal phosphorylation of PLB-ser16, however, was decreased in ZDF compared to ZL hearts, although it failed to reach significance (p = 0.08, see additional file 2B).


Altered myocardial substrate metabolism is associated with myocardial dysfunction in early diabetic cardiomyopathy in rats: studies using positron emission tomography.

van den Brom CE, Huisman MC, Vlasblom R, Boontje NM, Duijst S, Lubberink M, Molthoff CF, Lammertsma AA, van der Velden J, Boer C, Ouwens DM, Diamant M - Cardiovasc Diabetol (2009)

Molecular alterations in myocardial insulin signaling. Quantification of immunoblots showing relative phosphorylation/total protein levels of Akt-Ser473/Akt2 after saline (-; open bars) or insulin (+; filled bars) injection. Data are expressed as mean ± SEM, n = 4–8, * p < 0.05 different from basal, # p < 0.05 different from ZL.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2722582&req=5

Figure 4: Molecular alterations in myocardial insulin signaling. Quantification of immunoblots showing relative phosphorylation/total protein levels of Akt-Ser473/Akt2 after saline (-; open bars) or insulin (+; filled bars) injection. Data are expressed as mean ± SEM, n = 4–8, * p < 0.05 different from basal, # p < 0.05 different from ZL.
Mentions: ZDF versus ZL hearts showed a significant decrease in myocardial insulin-mediated Akt-Ser473 phosphorylation (Figure 4), whereas no differences were found in basal phosphorylation. Finally, intracellular signaling molecules related to myocardial calcium handling, like PLB and SERCA2a were studied. No difference was found in SERCA2a protein expression (see additional file 2A). Basal phosphorylation of PLB-ser16, however, was decreased in ZDF compared to ZL hearts, although it failed to reach significance (p = 0.08, see additional file 2B).

Bottom Line: Myocardial functional changes were significantly associated with whole-body insulin sensitivity and decreased myocardial glucose utilisation.ZL hearts a 2.4-fold reduced insulin-mediated phosphorylation of Akt was found (p < 0.05).Using PET and echocardiography, we found increases in myocardial FA oxidation with a concomitant decrease of insulin-mediated myocardial glucose utilisation in early DCM.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Endocrinology, Diabetes Centre, VU University Medical Centre, Amsterdam, The Netherlands. c.vandenbrom@vumc.nl

ABSTRACT

Background: In vitro data suggest that changes in myocardial substrate metabolism may contribute to impaired myocardial function in diabetic cardiomyopathy (DCM). The purpose of the present study was to study in a rat model of early DCM, in vivo changes in myocardial substrate metabolism and their association with myocardial function.

Methods: Zucker diabetic fatty (ZDF) and Zucker lean (ZL) rats underwent echocardiography followed by [11C]palmitate positron emission tomography (PET) under fasting, and [18F]-2-fluoro-2-deoxy-D-glucose PET under hyperinsulinaemic euglycaemic clamp conditions. Isolated cardiomyocytes were used to determine isometric force development.

Results: PET data showed a 66% decrease in insulin-mediated myocardial glucose utilisation and a 41% increase in fatty acid (FA) oxidation in ZDF vs. ZL rats (both p < 0.05). Echocardiography showed diastolic and systolic dysfunction in ZDF vs. ZL rats, which was paralleled by a significantly decreased maximal force (68%) and maximal rate of force redevelopment (69%) of single cardiomyocytes. Myocardial functional changes were significantly associated with whole-body insulin sensitivity and decreased myocardial glucose utilisation. ZDF hearts showed a 68% decrease in glucose transporter-4 mRNA expression (p < 0.05), a 22% decrease in glucose transporter-4 protein expression (p = 0.10), unchanged levels of pyruvate dehydrogenase kinase-4 protein expression, a 57% decreased phosphorylation of AMP activated protein kinase alpha1/2 (p < 0.05) and a 2.4-fold increased abundance of the FA transporter CD36 to the sarcolemma (p < 0.01) vs. ZL hearts, which are compatible with changes in substrate metabolism. In ZDF vs. ZL hearts a 2.4-fold reduced insulin-mediated phosphorylation of Akt was found (p < 0.05).

Conclusion: Using PET and echocardiography, we found increases in myocardial FA oxidation with a concomitant decrease of insulin-mediated myocardial glucose utilisation in early DCM. In addition, the latter was associated with impaired myocardial function. These in vivo data expand previous in vitro findings showing that early alterations in myocardial substrate metabolism contribute to myocardial dysfunction.

Show MeSH
Related in: MedlinePlus