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Cardioprotection Resulting from Glucagon-Like Peptide-1 Administration Involves Shifting Metabolic Substrate Utilization to Increase Energy Efficiency in the Rat Heart.

Aravindhan K, Bao W, Harpel MR, Willette RN, Lepore JJ, Jucker BM - PLoS ONE (2015)

Bottom Line: Furthermore, in isolated CMs GLP-1 treatment increased glucose utilization (↑14%, p<0.05) and decreased fatty acid oxidation (↓15%, p<0.05) consistent with in vivo finding.Our results show that this benefit may derive from distinct and complementary roles of GLP-1 treatment on metabolism in myocardial sub-regions in response to this injury.In particular, a switch to anaerobic glycolysis in the ischemic area provides a compensatory substrate switch to overcome the energetic deficit in this region in the face of reduced tissue oxygenation, whereas a switch to more energetically favorable carbohydrate oxidation in more highly oxygenated remote regions supports maintaining cardiac contractility in a complementary manner.

View Article: PubMed Central - PubMed

Affiliation: Heart Failure Discovery Performance Unit, Metabolic Pathways and Cardiovascular Therapeutic Area, GlaxoSmithKline, King of Prussia, Pennsylvania, United States of America.

ABSTRACT
Previous studies have shown that glucagon-like peptide-1 (GLP-1) provides cardiovascular benefits independent of its role on peripheral glycemic control. However, the precise mechanism(s) by which GLP-1 treatment renders cardioprotection during myocardial ischemia remain unresolved. Here we examined the role for GLP-1 treatment on glucose and fatty acid metabolism in normal and ischemic rat hearts following a 30 min ischemia and 24 h reperfusion injury, and in isolated cardiomyocytes (CM). Relative carbohydrate and fat oxidation levels were measured in both normal and ischemic hearts using a 1-13C glucose clamp coupled with NMR-based isotopomer analysis, as well as in adult rat CMs by monitoring pH and O2 consumption in the presence of glucose or palmitate. In normal heart, GLP-1 increased glucose uptake (↑64%, p<0.05) without affecting glycogen levels. In ischemic hearts, GLP-1 induced metabolic substrate switching by increasing the ratio of carbohydrate versus fat oxidation (↑14%, p<0.01) in the LV area not at risk, without affecting cAMP levels. Interestingly, no substrate switching occurred in the LV area at risk, despite an increase in cAMP (↑106%, p<0.05) and lactate (↑121%, p<0.01) levels. Furthermore, in isolated CMs GLP-1 treatment increased glucose utilization (↑14%, p<0.05) and decreased fatty acid oxidation (↓15%, p<0.05) consistent with in vivo finding. Our results show that this benefit may derive from distinct and complementary roles of GLP-1 treatment on metabolism in myocardial sub-regions in response to this injury. In particular, a switch to anaerobic glycolysis in the ischemic area provides a compensatory substrate switch to overcome the energetic deficit in this region in the face of reduced tissue oxygenation, whereas a switch to more energetically favorable carbohydrate oxidation in more highly oxygenated remote regions supports maintaining cardiac contractility in a complementary manner.

No MeSH data available.


Related in: MedlinePlus

In vivo intermediary glucose metabolism in AAR and ANAR of rat left ventricle following a euinsulinemic-hyperglycemic clamp over 2 hr with 1-[13C] glucose infusion.Left ventricle intermediary metabolite 13C enrichments of alanine, lactate and glutamate are presented for AAR or ANAR myocardial tissue from Vehicle (n = 6) and GLP-1 (300 pmol/kg/min group, n = 6) treatment groups (A). Relative carbohydrate oxidation versus fat oxidation in Vehicle and GLP-1 treated AAR and ANAR myocardial tissue (B). The relative carbohydrate versus fat oxidation is calculated using isotopomer analysis of alanine and glutamate enrichments as described in the methods section. Data are presented as mean±SEM. *p<0.05 vs respective Vehicle.
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pone.0130894.g004: In vivo intermediary glucose metabolism in AAR and ANAR of rat left ventricle following a euinsulinemic-hyperglycemic clamp over 2 hr with 1-[13C] glucose infusion.Left ventricle intermediary metabolite 13C enrichments of alanine, lactate and glutamate are presented for AAR or ANAR myocardial tissue from Vehicle (n = 6) and GLP-1 (300 pmol/kg/min group, n = 6) treatment groups (A). Relative carbohydrate oxidation versus fat oxidation in Vehicle and GLP-1 treated AAR and ANAR myocardial tissue (B). The relative carbohydrate versus fat oxidation is calculated using isotopomer analysis of alanine and glutamate enrichments as described in the methods section. Data are presented as mean±SEM. *p<0.05 vs respective Vehicle.

Mentions: The effects of GLP-1 treatment on metabolic substrate oxidation within AAR and ANAR regions of the left ventricle following cardiac I/R injury were determined by [1-13C] glucose euinsulinemic-hyperglycemic clamp. A significant increase in [4-13C] glutamate enrichment (2.9 fold, p<0.05) was observed in the ANAR region, without changes in AAR, following GLP-1 treatment (Fig 4A). There were no differences in either [3-13C] lactate or [3-13C] alanine enrichment in the two regions following treatment with GLP-1. Isotopomer analysis of alanine, lactate and glutamate enrichments indicated that treatment with GLP-1 resulted in a significant increase in relative carbohydrate oxidation versus fat oxidation in the ANAR region (p<0.05, Fig 4B); carbohydrate oxidation (e.g. glucose, glycogen, and lactate oxidation) increased from 3.5% to 18.0% and fat oxidation decreased from 96.5% to 82.0%. However, GLP-1 treatment had no effect on altering the metabolic profile in the AAR region of the myocardium. It should be noted that the 13C enrichment (APE) of a metabolite pool (e.g. lactate, alanine, glutamate) simply reflects the amount of 13C label in that metabolite pool, but does not reflect actual metabolite concentration. In addition, metabolic flux as measured by Langendorff perfused heart or metabolite labeling experiments can be altered independently of metabolite concentration changes. Therefore, there can be an increase in glucose disposal and/or lactate production and release from the heart while steady state intracellular glucose or lactate concentrations may not increase or not increase substantially.


Cardioprotection Resulting from Glucagon-Like Peptide-1 Administration Involves Shifting Metabolic Substrate Utilization to Increase Energy Efficiency in the Rat Heart.

Aravindhan K, Bao W, Harpel MR, Willette RN, Lepore JJ, Jucker BM - PLoS ONE (2015)

In vivo intermediary glucose metabolism in AAR and ANAR of rat left ventricle following a euinsulinemic-hyperglycemic clamp over 2 hr with 1-[13C] glucose infusion.Left ventricle intermediary metabolite 13C enrichments of alanine, lactate and glutamate are presented for AAR or ANAR myocardial tissue from Vehicle (n = 6) and GLP-1 (300 pmol/kg/min group, n = 6) treatment groups (A). Relative carbohydrate oxidation versus fat oxidation in Vehicle and GLP-1 treated AAR and ANAR myocardial tissue (B). The relative carbohydrate versus fat oxidation is calculated using isotopomer analysis of alanine and glutamate enrichments as described in the methods section. Data are presented as mean±SEM. *p<0.05 vs respective Vehicle.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4476748&req=5

pone.0130894.g004: In vivo intermediary glucose metabolism in AAR and ANAR of rat left ventricle following a euinsulinemic-hyperglycemic clamp over 2 hr with 1-[13C] glucose infusion.Left ventricle intermediary metabolite 13C enrichments of alanine, lactate and glutamate are presented for AAR or ANAR myocardial tissue from Vehicle (n = 6) and GLP-1 (300 pmol/kg/min group, n = 6) treatment groups (A). Relative carbohydrate oxidation versus fat oxidation in Vehicle and GLP-1 treated AAR and ANAR myocardial tissue (B). The relative carbohydrate versus fat oxidation is calculated using isotopomer analysis of alanine and glutamate enrichments as described in the methods section. Data are presented as mean±SEM. *p<0.05 vs respective Vehicle.
Mentions: The effects of GLP-1 treatment on metabolic substrate oxidation within AAR and ANAR regions of the left ventricle following cardiac I/R injury were determined by [1-13C] glucose euinsulinemic-hyperglycemic clamp. A significant increase in [4-13C] glutamate enrichment (2.9 fold, p<0.05) was observed in the ANAR region, without changes in AAR, following GLP-1 treatment (Fig 4A). There were no differences in either [3-13C] lactate or [3-13C] alanine enrichment in the two regions following treatment with GLP-1. Isotopomer analysis of alanine, lactate and glutamate enrichments indicated that treatment with GLP-1 resulted in a significant increase in relative carbohydrate oxidation versus fat oxidation in the ANAR region (p<0.05, Fig 4B); carbohydrate oxidation (e.g. glucose, glycogen, and lactate oxidation) increased from 3.5% to 18.0% and fat oxidation decreased from 96.5% to 82.0%. However, GLP-1 treatment had no effect on altering the metabolic profile in the AAR region of the myocardium. It should be noted that the 13C enrichment (APE) of a metabolite pool (e.g. lactate, alanine, glutamate) simply reflects the amount of 13C label in that metabolite pool, but does not reflect actual metabolite concentration. In addition, metabolic flux as measured by Langendorff perfused heart or metabolite labeling experiments can be altered independently of metabolite concentration changes. Therefore, there can be an increase in glucose disposal and/or lactate production and release from the heart while steady state intracellular glucose or lactate concentrations may not increase or not increase substantially.

Bottom Line: Furthermore, in isolated CMs GLP-1 treatment increased glucose utilization (↑14%, p<0.05) and decreased fatty acid oxidation (↓15%, p<0.05) consistent with in vivo finding.Our results show that this benefit may derive from distinct and complementary roles of GLP-1 treatment on metabolism in myocardial sub-regions in response to this injury.In particular, a switch to anaerobic glycolysis in the ischemic area provides a compensatory substrate switch to overcome the energetic deficit in this region in the face of reduced tissue oxygenation, whereas a switch to more energetically favorable carbohydrate oxidation in more highly oxygenated remote regions supports maintaining cardiac contractility in a complementary manner.

View Article: PubMed Central - PubMed

Affiliation: Heart Failure Discovery Performance Unit, Metabolic Pathways and Cardiovascular Therapeutic Area, GlaxoSmithKline, King of Prussia, Pennsylvania, United States of America.

ABSTRACT
Previous studies have shown that glucagon-like peptide-1 (GLP-1) provides cardiovascular benefits independent of its role on peripheral glycemic control. However, the precise mechanism(s) by which GLP-1 treatment renders cardioprotection during myocardial ischemia remain unresolved. Here we examined the role for GLP-1 treatment on glucose and fatty acid metabolism in normal and ischemic rat hearts following a 30 min ischemia and 24 h reperfusion injury, and in isolated cardiomyocytes (CM). Relative carbohydrate and fat oxidation levels were measured in both normal and ischemic hearts using a 1-13C glucose clamp coupled with NMR-based isotopomer analysis, as well as in adult rat CMs by monitoring pH and O2 consumption in the presence of glucose or palmitate. In normal heart, GLP-1 increased glucose uptake (↑64%, p<0.05) without affecting glycogen levels. In ischemic hearts, GLP-1 induced metabolic substrate switching by increasing the ratio of carbohydrate versus fat oxidation (↑14%, p<0.01) in the LV area not at risk, without affecting cAMP levels. Interestingly, no substrate switching occurred in the LV area at risk, despite an increase in cAMP (↑106%, p<0.05) and lactate (↑121%, p<0.01) levels. Furthermore, in isolated CMs GLP-1 treatment increased glucose utilization (↑14%, p<0.05) and decreased fatty acid oxidation (↓15%, p<0.05) consistent with in vivo finding. Our results show that this benefit may derive from distinct and complementary roles of GLP-1 treatment on metabolism in myocardial sub-regions in response to this injury. In particular, a switch to anaerobic glycolysis in the ischemic area provides a compensatory substrate switch to overcome the energetic deficit in this region in the face of reduced tissue oxygenation, whereas a switch to more energetically favorable carbohydrate oxidation in more highly oxygenated remote regions supports maintaining cardiac contractility in a complementary manner.

No MeSH data available.


Related in: MedlinePlus