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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

Effect of fatty acid oxidation on GLP-1 induced oxygen consumption in cultured CMs.OCR changes following stimulation with 100 nM GLP-1 (maximal effective dose) or 70 nM insulin are presented following palmitate challenge. GLP-1 or insulin was injected at 21 min and Vehicle (bovine serum albumin) or Palmitate was injected at 52 min following initiation of data collection. The responses are presented as percentage changes in OCR before and after Vehicle or Palmitate injection (A). Quantitation of percentage changes before (left bars; first arrow in panel A) and after (right bars; second arrow in Panel A) Palmitate or Vehicle challenge (B). Data are presented as mean ±SEM of 3–4 replicates per treatment. *p<0.05, **p<0.01, ***p<0.001.
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pone.0130894.g006: Effect of fatty acid oxidation on GLP-1 induced oxygen consumption in cultured CMs.OCR changes following stimulation with 100 nM GLP-1 (maximal effective dose) or 70 nM insulin are presented following palmitate challenge. GLP-1 or insulin was injected at 21 min and Vehicle (bovine serum albumin) or Palmitate was injected at 52 min following initiation of data collection. The responses are presented as percentage changes in OCR before and after Vehicle or Palmitate injection (A). Quantitation of percentage changes before (left bars; first arrow in panel A) and after (right bars; second arrow in Panel A) Palmitate or Vehicle challenge (B). Data are presented as mean ±SEM of 3–4 replicates per treatment. *p<0.05, **p<0.01, ***p<0.001.

Mentions: The effects of GLP-1 treatment on fatty acid oxidation assay in CMs were observed as changes in OCR from baseline upon challenge with palmitate in the presence of low (2.5 mM) glucose. A small and transient decrease in OCR was observed upon addition of GLP-1 or insulin (by net 16% and 23% from control, respectively; Fig 6A and 6B); this transient response was lost within 10 min for GLP-1. Following challenge with palmitate, OCR decreased from 61.3±3.2% (vehicle) to 46.8±2.7% (p<0.05) and 32.3±5.6% in the presence of GLP-1 and insulin, respectively (Fig 6B), reflecting a decrease in fatty acid oxidation in each case.


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)

Effect of fatty acid oxidation on GLP-1 induced oxygen consumption in cultured CMs.OCR changes following stimulation with 100 nM GLP-1 (maximal effective dose) or 70 nM insulin are presented following palmitate challenge. GLP-1 or insulin was injected at 21 min and Vehicle (bovine serum albumin) or Palmitate was injected at 52 min following initiation of data collection. The responses are presented as percentage changes in OCR before and after Vehicle or Palmitate injection (A). Quantitation of percentage changes before (left bars; first arrow in panel A) and after (right bars; second arrow in Panel A) Palmitate or Vehicle challenge (B). Data are presented as mean ±SEM of 3–4 replicates per treatment. *p<0.05, **p<0.01, ***p<0.001.
© Copyright Policy
Related In: Results  -  Collection

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

pone.0130894.g006: Effect of fatty acid oxidation on GLP-1 induced oxygen consumption in cultured CMs.OCR changes following stimulation with 100 nM GLP-1 (maximal effective dose) or 70 nM insulin are presented following palmitate challenge. GLP-1 or insulin was injected at 21 min and Vehicle (bovine serum albumin) or Palmitate was injected at 52 min following initiation of data collection. The responses are presented as percentage changes in OCR before and after Vehicle or Palmitate injection (A). Quantitation of percentage changes before (left bars; first arrow in panel A) and after (right bars; second arrow in Panel A) Palmitate or Vehicle challenge (B). Data are presented as mean ±SEM of 3–4 replicates per treatment. *p<0.05, **p<0.01, ***p<0.001.
Mentions: The effects of GLP-1 treatment on fatty acid oxidation assay in CMs were observed as changes in OCR from baseline upon challenge with palmitate in the presence of low (2.5 mM) glucose. A small and transient decrease in OCR was observed upon addition of GLP-1 or insulin (by net 16% and 23% from control, respectively; Fig 6A and 6B); this transient response was lost within 10 min for GLP-1. Following challenge with palmitate, OCR decreased from 61.3±3.2% (vehicle) to 46.8±2.7% (p<0.05) and 32.3±5.6% in the presence of GLP-1 and insulin, respectively (Fig 6B), reflecting a decrease in fatty acid oxidation in each case.

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