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Lipids and Ketones Dominate Metabolism at the Expense of Glucose Control in Pulmonary Arterial Hypertension: A Hyperglycemic Clamp and Metabolomics Study

Jacob T. Mey, Adithya Hari, Christopher L. Axelrod, Ciarán E. Fealy, Melissa L. Erickson, John P. Kirwan, Raed A. Dweik, Gustavo A. Heresi
European Respiratory Journal 2020; DOI: 10.1183/13993003.01700-2019
Jacob T. Mey
1Integrative Physiology and Molecular Medicine Laboratory, Pennington Biomedical Research Center, Baton Rouge, LA
2Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, OH
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  • ORCID record for Jacob T. Mey
Adithya Hari
2Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, OH
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Christopher L. Axelrod
1Integrative Physiology and Molecular Medicine Laboratory, Pennington Biomedical Research Center, Baton Rouge, LA
2Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, OH
3Department of Translational Services, Pennington Biomedical Research Center, Baton Rouge, LA
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Ciarán E. Fealy
2Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, OH
4Diabetes and Metabolism Research Group, Maastricht University, Maastricht, Netherlands
5Metabolic Translational Research Center, Endocrinology & Metabolism Institute, Cleveland Clinic, Cleveland, OH
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Melissa L. Erickson
1Integrative Physiology and Molecular Medicine Laboratory, Pennington Biomedical Research Center, Baton Rouge, LA
2Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, OH
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John P. Kirwan
1Integrative Physiology and Molecular Medicine Laboratory, Pennington Biomedical Research Center, Baton Rouge, LA
2Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, OH
5Metabolic Translational Research Center, Endocrinology & Metabolism Institute, Cleveland Clinic, Cleveland, OH
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Raed A. Dweik
2Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, OH
6Department of Pulmonary Care and Critical Medicine, Respiratory Institute, Cleveland Clinic, Cleveland, OH
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Gustavo A. Heresi
2Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, OH
6Department of Pulmonary Care and Critical Medicine, Respiratory Institute, Cleveland Clinic, Cleveland, OH
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  • For correspondence: heresig@ccf.org
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Abstract

Background Individuals with idiopathic pulmonary arterial hypertension (PAH) display reduced oral glucose tolerance. This may involve defects in pancreatic function or insulin sensitivity, but this hypothesis has not been tested; moreover, fasting nutrient metabolism remains poorly described in PAH. Thus, we aimed to characterise fasting nutrient metabolism and investigated the metabolic response to hyperglycemia in PAH.

Methods Twelve participants (6-PAH, 6-Controls) were administered a hyperglycemic clamp, while 52 (21-PAH, 31-Controls) underwent plasma metabolomic analysis. Glucose, insulin, C-peptide, free fatty acids and acylcarnitines were assessed from the clamp. Plasma metabolomics was conducted on fasting plasma samples.

Results The clamp verified a reduced insulin response to hyperglycemia in PAH (−53% versus Control), but with similar pancreatic insulin secretion. Skeletal muscle insulin sensitivity was unexpectedly greater in PAH. Hepatic insulin extraction was elevated in PAH (+11% versus Control). Plasma metabolomics identified 862 metabolites: 213 elevated, 145 reduced in PAH (p<0.05). In both clamp and metabolomic cohorts, lipid oxidation and ketones were elevated in PAH. Insulin sensitivity, fatty acids, acylcarnitines and ketones correlated with PAH severity, while hepatic extraction and fatty acid:ketone ratio correlated with longer 6-minute walk distance.

Conclusion Poor glucose control in PAH could not be explained by pancreatic ß-cell function or skeletal muscle insulin sensitivity. Instead, elevated hepatic insulin extraction emerged as an underlying factor. In agreement, nutrient metabolism in PAH favors lipid and ketone metabolism at the expense of glucose control. Future research should investigate the therapeutic potential of reinforcing lipid and ketone metabolism on clinical outcomes in PAH.

Footnotes

This manuscript has recently been accepted for publication in the European Respiratory Journal. It is published here in its accepted form prior to copyediting and typesetting by our production team. After these production processes are complete and the authors have approved the resulting proofs, the article will move to the latest issue of the ERJ online. Please open or download the PDF to view this article.

Conflict of interest: Dr. Mey reports grants from National Institutes of Health, during the conduct of the study.

Conflict of interest: Dr. Hari has nothing to disclose.

Conflict of interest: Dr. Axelrod has nothing to disclose.

Conflict of interest: Dr. Fealy has nothing to disclose.

Conflict of interest: Dr. Erickson has nothing to disclose.

Conflict of interest: Dr. Kirwan reports grants from National Institutes of Health, during the conduct of the study.

Conflict of interest: Dr. Dweik reports grants from National Institutes of Health, during the conduct of the study.

Conflict of interest: Dr. Heresi reports grants from National Institutes of Health, during the conduct of the study.

This is a PDF-only article. Please click on the PDF link above to read it.

  • Received August 27, 2019.
  • Accepted January 18, 2020.
  • Copyright ©ERS 2020
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Lipids and Ketones Dominate Metabolism at the Expense of Glucose Control in Pulmonary Arterial Hypertension: A Hyperglycemic Clamp and Metabolomics Study
Jacob T. Mey, Adithya Hari, Christopher L. Axelrod, Ciarán E. Fealy, Melissa L. Erickson, John P. Kirwan, Raed A. Dweik, Gustavo A. Heresi
European Respiratory Journal Jan 2020, 1901700; DOI: 10.1183/13993003.01700-2019

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Lipids and Ketones Dominate Metabolism at the Expense of Glucose Control in Pulmonary Arterial Hypertension: A Hyperglycemic Clamp and Metabolomics Study
Jacob T. Mey, Adithya Hari, Christopher L. Axelrod, Ciarán E. Fealy, Melissa L. Erickson, John P. Kirwan, Raed A. Dweik, Gustavo A. Heresi
European Respiratory Journal Jan 2020, 1901700; DOI: 10.1183/13993003.01700-2019
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