Skip to main content

Main menu

  • Home
  • Current issue
  • ERJ Early View
  • Past issues
  • Authors/reviewers
    • Instructions for authors
    • Submit a manuscript
    • Open access
    • COVID-19 submission information
    • Peer reviewer login
  • Alerts
  • Podcasts
  • Subscriptions
  • ERS Publications
    • European Respiratory Journal
    • ERJ Open Research
    • European Respiratory Review
    • Breathe
    • ERS Books
    • ERS publications home

User menu

  • Log in
  • Subscribe
  • Contact Us
  • My Cart

Search

  • Advanced search
  • ERS Publications
    • European Respiratory Journal
    • ERJ Open Research
    • European Respiratory Review
    • Breathe
    • ERS Books
    • ERS publications home

Login

European Respiratory Society

Advanced Search

  • Home
  • Current issue
  • ERJ Early View
  • Past issues
  • Authors/reviewers
    • Instructions for authors
    • Submit a manuscript
    • Open access
    • COVID-19 submission information
    • Peer reviewer login
  • Alerts
  • Podcasts
  • Subscriptions

Altered metabolism in pulmonary hypertension: fuelling the fire or just smoke?

Daisy Duan, Chenjuan Gu, Jonathan C. Jun
European Respiratory Journal 2020 55: 2000447; DOI: 10.1183/13993003.00447-2020
Daisy Duan
1Division of Endocrinology, Diabetes and Metabolism, Dept of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Chenjuan Gu
2Division of Pulmonary and Critical Care Medicine, Dept of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Jonathan C. Jun
2Division of Pulmonary and Critical Care Medicine, Dept of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Jonathan C. Jun
  • For correspondence: jjun2@jhmi.edu
  • Article
  • Figures & Data
  • Info & Metrics
  • PDF
Loading

Abstract

Glucose and fat metabolism are altered in pulmonary arterial hypertension, but it is not yet clear if these changes are causes or effects of the disease http://bit.ly/3cWyf66

Pulmonary arterial hypertension (PAH) is characterised by progressive obliteration of the pulmonary vasculature, culminating in right-sided heart failure (HF). In recent years, studies have observed an association between systemic metabolic dysfunction, PAH and right ventricular failure [1]. Patients with PAH have an increased prevalence of obesity [2] and type 2 diabetes [3, 4]. Interestingly, abnormal glucose metabolism is evident even in non-diabetic individuals with PAH [5–7], and serves as an independent predictor of prognosis [8]. Right ventricular function is also associated with metabolic syndrome [9, 10], and myocardial tissue in mouse models of PAH exhibit defects in fatty acid oxidation associated with increased lipid deposition [11]. In addition, peroxisome proliferator-activated receptor-γ (PPARγ), a master regulator of adipogenesis and glucose homeostasis, has been implicated in the pathogenesis of vascular remodelling and subsequent development of PAH [12, 13]. PPARγ is also a downstream target of bone morphogenic protein receptor 2 (BMPR2) [14]. BMPR2 mutations are seen in up to 80% of hereditary PAH, and BMPR2 sporadic mutations occur in idiopathic PAH [15]. A rodent model of inducible BMPR2 overexpression develops insulin resistance preceding features of PAH [16]. Collectively, these observations suggest that impaired glucose metabolism may be a causative factor in PAH. However, most of the clinical data above is derived from cross-sectional studies with very limited metabolic outcomes.

In this issue of European Respiratory Journal, Mey et al. [17] utilised hyperglycaemic clamp methodology and plasma metabolomics to further characterise metabolism in patients with idiopathic PAH (n=6) compared to age-, sex- and BMI-matched controls (n=6). To perform the hyperglycaemic clamp, glucose was infused at a variable rate to maintain continuous hyperglycaemia (180 mg·dL−1). Levels of insulin and C-peptide were measured to quantify pancreatic β-cell function, while the rate of glucose infused was used as a surrogate for insulin sensitivity. During the clamp, the authors found that peripheral insulin concentrations were lower in subjects with PAH, which translated to a 92% increase in insulin sensitivity in the PAH group. Hepatic insulin extraction (calculated as insulin/C-peptide molar ratio) was greater in PAH than in controls. However, pancreatic β-cell insulin secretion, as assessed by C-peptide concentrations, was similar between the two groups. In addition, PAH was associated with increased fatty acid oxidation and ketogenesis, as evidenced by elevated acetylcarnitine and β-hydroxybutyrate (βOHB) levels. The authors confirmed this metabolic shift using plasma metabolomics in a larger cohort of PAH patients. Interestingly, hepatic insulin extraction had a positive correlation while free fatty acids (FFA):βOHB ratio had a negative correlation with greater 6-min walk distance. The investigators suggested that increased hepatic insulin extraction mediates reduced insulin response to hyperglycaemia and may contribute to impaired glucose tolerance in PAH. Also, they proposed that upregulated conversion of FFA to βOHB may be a beneficial metabolic adaptation in PAH.

There are several novel findings to this study, which is the first to apply hyperglycaemic clamp methodology to PAH. Given that PAH is associated with insulin resistance in other contexts [5–8], it is surprising that PAH patients exhibited increased insulin sensitivity and hepatic insulin extraction. Upon closer examination, however, other studies in PAH [7, 18] have also found decreased insulin concentrations during oral glucose tolerance testing which indirectly suggests greater insulin sensitivity (calculated by HOMA-IR). Hepatic insulin extraction is typically reduced in individuals with impaired glucose tolerance, diabetes [19], and obesity [20], and contributes to the hyperinsulinaemia associated with these pathological states. Thus, altered glucose metabolism in PAH may be distinct from the insulin resistance seen in obesity and early type 2 diabetes.

There are several potential explanations for the metabolic changes described in this article. Insulin concentrations are significantly influenced by first pass hepatic metabolism, in which approximately 50% of secreted insulin is extracted. Generally, excess carbohydrate/energy intake reduces hepatic insulin clearance while low carbohydrate/energy intake increases hepatic insulin clearance [21]. Increased hepatic insulin clearance has also been described in catabolic states such as exercise [22] and weight loss [23]. During exercise, low insulin is thought to be physiologically important to enhance lipolysis and fat utilisation in order to meet the energy demands of the exercising muscles. In this study and in previous work by the same investigators [7], basal metabolic rate was elevated in PAH, perhaps due to chronically increased cardiac workloads. Indeed, patients with reduced left ventricular ejection fraction manifest low insulin concentrations and increased hepatic insulin clearance [24]. Melenovsky et al. [24] speculate that low insulin and high glucagon levels facilitate myocardial utilisation of fatty acids and ketones. In support of this, both animal and human studies demonstrate that ketone bodies are utilised as an alternative fuel in HF [25, 26]. Hence, the low insulin, ketogenic state found in this PAH study bears a resemblance to other energetically costly states such as exercise and HF.

There are limitations to this study, some of which were acknowledged by the authors. The insulin/C-peptide ratio was used as an index of hepatic insulin extraction, but may over-simplify different distribution kinetics and half-lives of C-peptide and insulin [27]. Next, the hyperglycaemic clamp is the gold standard to assess pancreatic β-cell function, but is not optimal for measuring insulin sensitivity. The latter is estimated by the M/I ratio (quantity of glucose metabolised per unit of plasma insulin) and does not account for effects of hyperglycaemia itself on glucose uptake or inactive pro-insulin in the circulation [28]. Instead, the euglycaemic–hyperinsulinaemic clamp (infusing insulin while titrating glucose to normal levels) is the more reliable method to assess insulin resistance. Regardless of technique, these methods can only provide information about glucose homeostasis at the whole body level, and not in specific compartments, such as the right ventricle or pulmonary vasculature. Finally, the study has a small sample size with unclear generalisability to PAH or other forms of pulmonary hypertension.

We applaud the authors of this study for shedding new light on glucose and nutrient metabolism in PAH. However, the role of metabolism in PAH is still in its infancy. A paramount question remains whether these metabolic abnormalities are “the fire” (causes), “the smoke” (consequences), or mere spectators in the PAH narrative. We should seek improved understanding of these metabolic shifts before therapies targeting these pathways are investigated.

Shareable PDF

Supplementary Material

This one-page PDF can be shared freely online.

Shareable PDF ERJ-00447-2020.Shareable

Footnotes

  • Conflict of interest: D. Duan has nothing to disclose.

  • Conflict of interest: C. Gu has nothing to disclose.

  • Conflict of interest: J.C. Jun has nothing to disclose.

  • Support statement: This work was supported by the National Institutes of Health (T32DK062707 to D. Duan), American Heart Association (Postdoctoral Fellowship Award 20POST35210763 to C. Gu), National Institutes of Health (R01HL135483 to J.C. Jun). Funding information for this article has been deposited with the Crossref Funder Registry.

  • Received February 26, 2020.
  • Accepted February 29, 2020.
  • Copyright ©ERS 2020
https://www.ersjournals.com/user-licence

References

  1. ↵
    1. Assad TR,
    2. Hemnes AR
    . Metabolic dysfunction in pulmonary arterial hypertension. Curr Hypertens Rep 2015; 17: 20. doi:10.1007/s11906-014-0524-y
    OpenUrlCrossRefPubMed
  2. ↵
    1. Burger C,
    2. Foreman A,
    3. Miller D, et al.
    Comparison of body habitus in patients with pulmonary arterial hypertension enrolled in the registry to evaluate early and long-term PAH disease management with normative values from the National Health and Nutrition Examination Survey. Mayo Clin Proc 2011; 86: 105–112. doi:10.4065/mcp.2010.0394
    OpenUrlCrossRefPubMedWeb of Science
  3. ↵
    1. Badesch DB,
    2. Raskob GE,
    3. Elliott CG, et al.
    Pulmonary arterial hypertension: baseline characteristics from the REVEAL registry. Chest 2010; 137: 376–387. doi:10.1378/chest.09-1140
    OpenUrlCrossRefPubMedWeb of Science
  4. ↵
    1. Ling Y,
    2. Johnson MK,
    3. Kiely DG, et al.
    Changing demographics, epidemiology, and survival of incident pulmonary arterial hypertension: results from the pulmonary hypertension registry of the United Kingdom and Ireland. Am J Respir Crit Care Med 2012; 186: 790–796. doi:10.1164/rccm.201203-0383OC
    OpenUrlCrossRefPubMedWeb of Science
  5. ↵
    1. Zamanian RT,
    2. Hansmann G,
    3. Snook S, et al.
    Insulin resistance in pulmonary arterial hypertension. Eur Respir J 2009; 33: 318–324. doi:10.1183/09031936.00000508
    OpenUrlAbstract/FREE Full Text
    1. Pugh ME,
    2. Robbins IM,
    3. Rice TW, et al.
    Unrecognized glucose intolerance is common in pulmonary arterial hypertension. J Heart Lung Transplant 2011; 30: 904–911.
    OpenUrlPubMedWeb of Science
  6. ↵
    1. Heresi GA,
    2. Malin SK,
    3. Barnes JW, et al.
    Abnormal glucose metabolism and high-energy expenditure in idiopathic pulmonary arterial hypertension. Ann Am Thorac Soc 2017; 14: 190–199.
    OpenUrl
  7. ↵
    1. Belly MJ,
    2. Tiede H,
    3. Morty RE, et al.
    HbA1c in pulmonary arterial hypertension: a marker of prognostic relevance? J Heart Lung Transplant 2012; 31: 1109–1114. doi:10.1016/j.healun.2012.08.014
    OpenUrlPubMed
  8. ↵
    1. Talati M,
    2. Hemnes A
    . Fatty acid metabolism in pulmonary arterial hypertension: role in right ventricular dysfunction and hypertrophy. Pulm Circ 2015; 5: 269–278. doi:10.1086/681227
    OpenUrlCrossRefPubMed
  9. ↵
    1. Tadic M,
    2. Ivanovic B,
    3. Grozdic I
    . Metabolic syndrome impacts the right ventricle: true or false? Echocardiography 2011; 28: 530–538. doi:10.1111/j.1540-8175.2011.01390.x
    OpenUrlCrossRefPubMed
  10. ↵
    1. Hemnes AR,
    2. Brittain EL,
    3. Trammell AW, et al.
    Evidence for right ventricular lipotoxicity in heritable pulmonary arterial hypertension. Am J Respir Crit Care Med 2014; 189: 325–334. doi:10.1164/rccm.201306-1086OC
    OpenUrlCrossRefPubMed
  11. ↵
    1. Ameshima S,
    2. Golpon H,
    3. Cool CD, et al.
    Peroxisome proliferator-activated receptor gamma (PPARγ) expression is decreased in pulmonary hypertension and affects endothelial cell growth. Circ Res 2003; 92: 1162–1169. doi:10.1161/01.RES.0000073585.50092.14
    OpenUrlAbstract/FREE Full Text
  12. ↵
    1. Hansmann G,
    2. Wagner RA,
    3. Schellong S, et al.
    Pulmonary arterial hypertension is linked to insulin resistance and reversed by peroxisome proliferator-activated receptor-gamma activation. Circulation 2007; 115: 1275–1284. doi:10.1161/CIRCULATIONAHA.106.663120
    OpenUrlAbstract/FREE Full Text
  13. ↵
    1. Hansmann G,
    2. Zamanian RT
    . PPAR activation: a potential treatment for pulmonary hypertension. Sci Transl Med 2009; 1: 12ps14. doi:10.1126/scitranslmed.3000267
    OpenUrlFREE Full Text
  14. ↵
    1. Austin ED,
    2. Loyd JE
    . The genetics of pulmonary arterial hypertension. Circ Res 2014; 115: 189–202. doi:10.1161/CIRCRESAHA.115.303404
    OpenUrlAbstract/FREE Full Text
  15. ↵
    1. West J,
    2. Niswender KD,
    3. Johnson JA, et al.
    A potential role for insulin resistance in experimental pulmonary hypertension. Eur Respir J 2013; 41: 861–871. doi:10.1183/09031936.00030312
    OpenUrlAbstract/FREE Full Text
  16. ↵
    1. Mey JT,
    2. Hari A,
    3. Axelrod CL, et al.
    Lipids and ketones dominate metabolism at the expense of glucose control in pulmonary arterial hypertension: a hyperglycaemic clamp and metabolomics study. Eur Respir J 2020; 55: 1901700. doi:10.1183/09031936.00030312
    OpenUrlAbstract/FREE Full Text
  17. ↵
    1. Hemnes AR,
    2. Luther JM,
    3. Rhodes CJ, et al.
    Human PAH is characterized by a pattern of lipid-related insulin resistance. JCI Insight 2019; 4: e123611. doi:10.1172/jci.insight.123611
    OpenUrl
  18. ↵
    1. Bonora E,
    2. Zavaroni I,
    3. Coscelli C, et al.
    Decreased hepatic insulin extraction in subjects with mild glucose intolerance. Metab Clin Exp 1983; 32: 438–446. doi:10.1016/0026-0495(83)90004-5
    OpenUrl
  19. ↵
    1. Polonsky KS,
    2. Given BD,
    3. Hirsch L, et al.
    Quantitative study of insulin secretion and clearance in normal and obese subjects. J Clin Invest 1988; 81: 435–441. doi:10.1172/JCI113338
    OpenUrlCrossRefPubMedWeb of Science
  20. ↵
    1. Bojsen-Møller KN,
    2. Lundsgaard A-M,
    3. Madsbad S, et al.
    Hepatic insulin clearance in regulation of systemic insulin concentrations – role of carbohydrate and energy availability. Diabetes 2018; 67: 2129–2136. doi:10.2337/db18-0539
    OpenUrlCrossRef
  21. ↵
    1. Tuominen JA,
    2. Ebeling P,
    3. Koivisto VA
    . Exercise increases insulin clearance in healthy man and insulin-dependent diabetes mellitus patients. Clin Physiol 1997; 17: 19–30. doi:10.1046/j.1365-2281.1997.01717.x
    OpenUrlCrossRefPubMedWeb of Science
  22. ↵
    1. Escobar O,
    2. Mizuma H,
    3. Sothern MS, et al.
    Hepatic insulin clearance increases after weight loss in obese children and adolescents. Am J Med Sci 1999; 317: 282–286. doi:10.1016/S0002-9629(15)40529-4
    OpenUrlCrossRefPubMedWeb of Science
  23. ↵
    1. Melenovsky V,
    2. Benes J,
    3. Franekova J, et al.
    Glucose homeostasis, pancreatic endocrine function, and outcomes in advanced heart failure. J Am Hear Assoc 2017; 6: 1–11.
    OpenUrl
  24. ↵
    1. Aubert G,
    2. Martin OJ,
    3. Horton JL, et al.
    The failing heart relies on ketone bodies as a fuel. Circulation 2016; 133: 698–705. doi:10.1161/CIRCULATIONAHA.115.017355
    OpenUrlAbstract/FREE Full Text
  25. ↵
    1. Bedi Jr KC,
    2. Snyder NW,
    3. Brandimarto J, et al.
    Evidence for intramyocardial disruption of lipid metabolism and increased myocardial ketone utilization in advanced human heart failure. Circulation 2016; 133: 706–716. doi:10.1161/CIRCULATIONAHA.115.017545
    OpenUrlAbstract/FREE Full Text
  26. ↵
    1. Polonsky KS,
    2. Rubenstein AH
    . C-peptide as a measure of the secretion and hepatic extraction of insulin. Pitfalls and limitations. Diabetes 1984; 33: 486–494. doi:10.2337/diab.33.5.486
    OpenUrlFREE Full Text
  27. ↵
    1. DeFronzo RA,
    2. Tobin JD,
    3. Andres R
    . Glucose clamp technique: a method for quantifying insulin secretion and resistance. Am J Physiol 1979; 237: E214–E223.
    OpenUrlCrossRefPubMedWeb of Science
PreviousNext
Back to top
View this article with LENS
Vol 55 Issue 4 Table of Contents
European Respiratory Journal: 55 (4)
  • Table of Contents
  • Index by author
Email

Thank you for your interest in spreading the word on European Respiratory Society .

NOTE: We only request your email address so that the person you are recommending the page to knows that you wanted them to see it, and that it is not junk mail. We do not capture any email address.

Enter multiple addresses on separate lines or separate them with commas.
Altered metabolism in pulmonary hypertension: fuelling the fire or just smoke?
(Your Name) has sent you a message from European Respiratory Society
(Your Name) thought you would like to see the European Respiratory Society web site.
CAPTCHA
This question is for testing whether or not you are a human visitor and to prevent automated spam submissions.
Print
Citation Tools
Altered metabolism in pulmonary hypertension: fuelling the fire or just smoke?
Daisy Duan, Chenjuan Gu, Jonathan C. Jun
European Respiratory Journal Apr 2020, 55 (4) 2000447; DOI: 10.1183/13993003.00447-2020

Citation Manager Formats

  • BibTeX
  • Bookends
  • EasyBib
  • EndNote (tagged)
  • EndNote 8 (xml)
  • Medlars
  • Mendeley
  • Papers
  • RefWorks Tagged
  • Ref Manager
  • RIS
  • Zotero

Share
Altered metabolism in pulmonary hypertension: fuelling the fire or just smoke?
Daisy Duan, Chenjuan Gu, Jonathan C. Jun
European Respiratory Journal Apr 2020, 55 (4) 2000447; DOI: 10.1183/13993003.00447-2020
del.icio.us logo Digg logo Reddit logo Technorati logo Twitter logo CiteULike logo Connotea logo Facebook logo Google logo Mendeley logo
Full Text (PDF)

Jump To

  • Article
    • Abstract
    • Shareable PDF
    • Footnotes
    • References
  • Figures & Data
  • Info & Metrics
  • PDF
  • Tweet Widget
  • Facebook Like
  • Google Plus One

More in this TOC Section

  • Addressing the effect of ancestry on lung volume
  • Bronchodilators in bronchiectasis: there is light but it is still too dim
  • Consensus statement on quality standards for managing children with bronchiectasis
Show more Editorials

Related Articles

Navigate

  • Home
  • Current issue
  • Archive

About the ERJ

  • Journal information
  • Editorial board
  • Reviewers
  • Press
  • Permissions and reprints
  • Advertising

The European Respiratory Society

  • Society home
  • myERS
  • Privacy policy
  • Accessibility

ERS publications

  • European Respiratory Journal
  • ERJ Open Research
  • European Respiratory Review
  • Breathe
  • ERS books online
  • ERS Bookshop

Help

  • Feedback

For authors

  • Instructions for authors
  • Publication ethics and malpractice
  • Submit a manuscript

For readers

  • Alerts
  • Subjects
  • Podcasts
  • RSS

Subscriptions

  • Accessing the ERS publications

Contact us

European Respiratory Society
442 Glossop Road
Sheffield S10 2PX
United Kingdom
Tel: +44 114 2672860
Email: journals@ersnet.org

ISSN

Print ISSN:  0903-1936
Online ISSN: 1399-3003

Copyright © 2022 by the European Respiratory Society