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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 [3H]-2-DG uptake in rat myocardium.Kinetics of [3H]-2-DG clearance from plasma after a single bolus injection for Vehicle (, n = 8), GLP-1 (300 pmol/kg/min) (∆, n = 8), or insulin (3 U/kg) (▼, N = 5) (A). Myocardial glucose uptake measured at the end of study; i.e. 30 min following tracer administration (B). Data are presented as mean±SEM. *p<0.05, ***p<0.001 vs Vehicle.
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pone.0130894.g003: In vivo [3H]-2-DG uptake in rat myocardium.Kinetics of [3H]-2-DG clearance from plasma after a single bolus injection for Vehicle (, n = 8), GLP-1 (300 pmol/kg/min) (∆, n = 8), or insulin (3 U/kg) (▼, N = 5) (A). Myocardial glucose uptake measured at the end of study; i.e. 30 min following tracer administration (B). Data are presented as mean±SEM. *p<0.05, ***p<0.001 vs Vehicle.

Mentions: Glucose disposal in the uninjured heart was assessed in vivo by monitoring 2DG clearance from blood and measuring uptake into cardiac tissue in rats receiving a continuous infusion of vehicle, GLP-1 or insulin (3 U/kg) comparator. A slightly accelerated rate of 2DG (i.e. glucose) clearance from blood with GLP-1 treatment versus vehicle (Fig 3A) translated to a significant increase in myocardial glucose uptake rate (from 10.5±1.7 to 18.0±2.1 μmol/100 g/min; (p<0.05) (Fig 3B). Insulin elicited an even higher rate of both plasma clearance and tissue uptake of 2DG (80.3±9.4 μmol/100 g/min; p<0.001).


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 [3H]-2-DG uptake in rat myocardium.Kinetics of [3H]-2-DG clearance from plasma after a single bolus injection for Vehicle (, n = 8), GLP-1 (300 pmol/kg/min) (∆, n = 8), or insulin (3 U/kg) (▼, N = 5) (A). Myocardial glucose uptake measured at the end of study; i.e. 30 min following tracer administration (B). Data are presented as mean±SEM. *p<0.05, ***p<0.001 vs Vehicle.
© Copyright Policy
Related In: Results  -  Collection

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

pone.0130894.g003: In vivo [3H]-2-DG uptake in rat myocardium.Kinetics of [3H]-2-DG clearance from plasma after a single bolus injection for Vehicle (, n = 8), GLP-1 (300 pmol/kg/min) (∆, n = 8), or insulin (3 U/kg) (▼, N = 5) (A). Myocardial glucose uptake measured at the end of study; i.e. 30 min following tracer administration (B). Data are presented as mean±SEM. *p<0.05, ***p<0.001 vs Vehicle.
Mentions: Glucose disposal in the uninjured heart was assessed in vivo by monitoring 2DG clearance from blood and measuring uptake into cardiac tissue in rats receiving a continuous infusion of vehicle, GLP-1 or insulin (3 U/kg) comparator. A slightly accelerated rate of 2DG (i.e. glucose) clearance from blood with GLP-1 treatment versus vehicle (Fig 3A) translated to a significant increase in myocardial glucose uptake rate (from 10.5±1.7 to 18.0±2.1 μmol/100 g/min; (p<0.05) (Fig 3B). Insulin elicited an even higher rate of both plasma clearance and tissue uptake of 2DG (80.3±9.4 μmol/100 g/min; p<0.001).

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