Skip to main content
  • More from ADA
    • Diabetes Care
    • Clinical Diabetes
    • Diabetes Spectrum
    • Standards of Medical Care
    • Scientific Sessions Abstracts
    • BMJ Open Diabetes Research & Care
  • Subscribe
  • Log in
  • Follow ada on Twitter
  • RSS
  • Visit ada on Facebook
Diabetes

Advanced Search

Main menu

  • Home
  • Current
    • Current Issue
    • Online Ahead of Print
  • Browse
    • By Topic
    • Issue Archive
    • Scientific Sessions Abstracts
  • Info
    • About the Journal
    • Meet the Editors
    • Reprints & Permissions
    • Journal Policies
    • For Authors
    • For Reviewers
    • For Advertisers
  • Subscriptions
    • Manage Online Access
    • Individual Subscriptions
    • Institutional Subscriptions
    • Purchase Single Issues
  • Alerts
    • E­mail Alerts
    • RSS Feeds
  • Podcasts
    • Diabetes Core Update
    • Diabetes Discovery
  • Submit
    • Submit a Manuscript
    • Submit Cover Art
    • Journal Policies
    • Instructions for Authors
    • Peer Review
  • More from ADA
    • Diabetes Care
    • Clinical Diabetes
    • Diabetes Spectrum
    • Standards of Medical Care
    • Scientific Sessions Abstracts
    • BMJ Open Diabetes Research & Care

User menu

  • Subscribe
  • Log in

Search

  • Advanced search
Diabetes
  • Home
  • Current
    • Current Issue
    • Online Ahead of Print
  • Browse
    • By Topic
    • Issue Archive
    • Scientific Sessions Abstracts
  • Info
    • About the Journal
    • Meet the Editors
    • Reprints & Permissions
    • Journal Policies
    • For Authors
    • For Reviewers
    • For Advertisers
  • Subscriptions
    • Manage Online Access
    • Individual Subscriptions
    • Institutional Subscriptions
    • Purchase Single Issues
  • Alerts
    • E­mail Alerts
    • RSS Feeds
  • Podcasts
    • Diabetes Core Update
    • Diabetes Discovery
  • Submit
    • Submit a Manuscript
    • Submit Cover Art
    • Journal Policies
    • Instructions for Authors
    • Peer Review
Commentaries

Endoplasmic Reticulum: An Interface Between the Immune System and Metabolism

  1. Emil R. Unanue1 and
  2. Fumihiko Urano1,2⇑
  1. 1Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO
  2. 2Department of Medicine, Division of Endocrinology, Metabolism, and Lipid Research, Washington University School of Medicine, St. Louis, MO
  1. Corresponding author: Fumihiko Urano, urano{at}dom.wustl.edu.
Diabetes 2014 Jan; 63(1): 48-49. https://doi.org/10.2337/db13-1478
PreviousNext
  • Article
  • Figures & Tables
  • Info & Metrics
  • PDF
Loading

Endoplasmic reticulum (ER) is a busy cell organelle that participates in many important cellular tasks. It has been established that ER is involved in protein and lipid biosynthesis, calcium regulation, redox regulation, cell signaling, and cell death. Given the many vital and complex functions of ER, there is little wonder that its failure can trigger a range of diseases. Recent genetic and clinical evidence indicates that inherited or acquired dysregulation of ER homeostasis can give rise to genetic diseases, including Wolfram syndrome (which is characterized by juvenile-onset diabetes and neurodegeneration) and a number of common metabolic diseases including diabetes and atherosclerosis. Accelerating interest in the role of ER in metabolic disease has been fueled by recent reports showing pathways that link ER to inflammation. The role of ER as an interface between the immune system and metabolism is an emerging concept (Fig. 1). However, currently there is no treatment targeting ER for combating immunometabolic diseases. To fulfill this unmet medical need, we need to identify pathways and molecules that link the immune system to metabolism at ER.

Figure 1
  • Download figure
  • Open in new tab
  • Download powerpoint
Figure 1

ER is an interface between the immune system and metabolism. ER is an intersection between inflammation and metabolism and an attractive target for immunometabolic diseases, including type 1 and type 2 diabetes, atherosclerosis, and Wolfram syndrome.

ER dysfunction has been a suspect as a major pathogenic component of human chronic diseases, such as diabetes, atherosclerosis, and Wolfram syndrome (1–10). However, the precise role of ER in the etiology of these diseases is not clear. It has been recognized that inflammation plays a central role in chronic metabolic diseases, raising the possibility that ER is at the intersection of inflammation and metabolism (7,11–14). Over the past several years, this concept has been supported by genetic, experimental, and clinical evidence (10,15). One of the unmet scientific needs in this emerging field is to identify the pathways linking ER to production of inflammatory cytokines. Two molecular pathways linking ER to production of interleukin (IL)-1β, a major player in inflammation, have been recently identified. These are activating transcription factor (ATF) 5 and miR-17 (16,17). Both molecules are regulated by key regulators of the ER stress response, Perk and Ire1α.

In this issue, Iwasaki et al. (18) describe the molecular pathway linking ER to IL-6 production. Using DNA microarray and network analyses of macrophages, they show compelling evidence that ATF4, which is involved in the ER stress response, plays an essential role in IL-6 expression induced by various metabolic stresses, including ER stress. Furthermore, they reveal that the ATF4 pathway has a synergistic effect on the Toll-like receptor-4 signaling pathway, enhancing IL-6 expression. IL-6 has been shown to play crucial roles in insulin resistance and type 2 diabetes (19), raising the possibility that ATF4 signaling is a novel target for the treatment of metabolic diseases. The new findings from Iwasaki et al. (18) also suggest that ER-stressed macrophages may trigger autoimmune diseases through IL-6 production.

Compelling evidence indicates that ER is at the intersection of inflammation and metabolism and is therefore an attractive target for immunometabolic diseases. For example, recent evidence strongly suggests that ER dysfunction in antigen-presenting macrophages and β-cells triggers autoimmunity during the onset and progression of type 1 diabetes (20,21). Despite the underlying importance of ER dysfunction in these diseases, no current therapies target ER. The unmet scientific and medical need in the field of ER immunometabolism is to target the common molecular processes that are altered in ER diseases as a novel therapeutic discovery strategy. The strategy of performing clinical studies using drugs previously known to target ER, such as glucagon-like peptide 1 agonists and vitamin D, on patients with immunometabolic diseases should be explored (22,23).

Article Information

Funding. F.U. is supported by grants from the National Institutes of Health (DK-067493, DK-020579, and UL1 TR000448), JDRF (47-2012-760, 17-2013-512), American Diabetes Association (1-12-CT-61), the Ellie White Foundation for Rare Genetic Disorders, and the Jack and J.T. Snow Scientific Research Foundation.

Duality of Interest. No potential conflicts of interest relevant to this article were reported.

Footnotes

  • See accompanying original article, p. 152.

  • © 2014 by the American Diabetes Association.

Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.org/licenses/by-nc-nd/3.0/ for details.

References

  1. ↵
    1. Walter P,
    2. Ron D
    . The unfolded protein response: from stress pathway to homeostatic regulation. Science 2011;334:1081–1086pmid:22116877
    OpenUrlAbstract/FREE Full Text
    1. Scheuner D,
    2. Kaufman RJ
    . The unfolded protein response: a pathway that links insulin demand with beta-cell failure and diabetes. Endocr Rev 2008;29:317–333pmid:18436705
    OpenUrlCrossRefPubMedWeb of Science
    1. Oslowski CM,
    2. Urano F
    . The binary switch that controls the life and death decisions of ER stressed β cells. Curr Opin Cell Biol 2011;23:207–215pmid:21168319
    OpenUrlCrossRefPubMed
    1. Fonseca SG,
    2. Fukuma M,
    3. Lipson KL,
    4. et al
    . WFS1 is a novel component of the unfolded protein response and maintains homeostasis of the endoplasmic reticulum in pancreatic beta-cells. J Biol Chem 2005;280:39609–39615pmid:16195229
    OpenUrlAbstract/FREE Full Text
    1. Fonseca SG,
    2. Ishigaki S,
    3. Oslowski CM,
    4. et al
    . Wolfram syndrome 1 gene negatively regulates ER stress signaling in rodent and human cells. J Clin Invest 2010;120:744–755pmid:20160352
    OpenUrlCrossRefPubMedWeb of Science
    1. Hotamisligil GS
    . Endoplasmic reticulum stress and atherosclerosis. Nat Med 2010;16:396–399pmid:20376052
    OpenUrlCrossRefPubMed
  2. ↵
    1. Hotamisligil GS
    . Endoplasmic reticulum stress and the inflammatory basis of metabolic disease. Cell 2010;140:900–917pmid:20303879
    OpenUrlCrossRefPubMedWeb of Science
    1. Ozcan L,
    2. Tabas I
    . Role of endoplasmic reticulum stress in metabolic disease and other disorders. Annu Rev Med 2012;63:317–328pmid:22248326
    OpenUrlCrossRefPubMedWeb of Science
    1. Kaufman RJ
    . Beta-cell failure, stress, and type 2 diabetes. N Engl J Med 2011;365:1931–1933pmid:22087686
    OpenUrlCrossRefPubMed
  3. ↵
    1. Larsen CM,
    2. Faulenbach M,
    3. Vaag A,
    4. et al
    . Interleukin-1-receptor antagonist in type 2 diabetes mellitus. N Engl J Med 2007;356:1517–1526pmid:17429083
    OpenUrlCrossRefPubMedWeb of Science
  4. ↵
    1. Dinarello CA,
    2. Donath MY,
    3. Mandrup-Poulsen T
    . Role of IL-1beta in type 2 diabetes. Curr Opin Endocrinol Diabetes Obes 2010;17:314–321pmid:20588114
    OpenUrlPubMedWeb of Science
    1. Donath MY,
    2. Shoelson SE
    . Type 2 diabetes as an inflammatory disease. Nat Rev Immunol 2011;11:98–107pmid:21233852
    OpenUrlCrossRefPubMedWeb of Science
    1. Donath MY,
    2. Mandrup-Poulsen T
    . The use of interleukin-1-receptor antagonists in the treatment of diabetes mellitus. Nat Clin Pract Endocrinol Metab 2008;4:240–241pmid:18317479
    OpenUrlCrossRefPubMedWeb of Science
  5. ↵
    1. Eizirik DL,
    2. Cardozo AK,
    3. Cnop M
    . The role for endoplasmic reticulum stress in diabetes mellitus. Endocr Rev 2008;29:42–61pmid:18048764
    OpenUrlCrossRefPubMedWeb of Science
  6. ↵
    1. Ozcan U,
    2. Cao Q,
    3. Yilmaz E,
    4. et al
    . Endoplasmic reticulum stress links obesity, insulin action, and type 2 diabetes. Science 2004;306:457–461pmid:15486293
    OpenUrlAbstract/FREE Full Text
  7. ↵
    1. Oslowski CM,
    2. Hara T,
    3. O’Sullivan-Murphy B,
    4. et al
    . Thioredoxin-interacting protein mediates ER stress-induced β cell death through initiation of the inflammasome. Cell Metab 2012;16:265–273pmid:22883234
    OpenUrlCrossRefPubMedWeb of Science
  8. ↵
    1. Lerner AG,
    2. Upton JP,
    3. Praveen PV,
    4. et al
    . IRE1α induces thioredoxin-interacting protein to activate the NLRP3 inflammasome and promote programmed cell death under irremediable ER stress. Cell Metab 2012;16:250–264pmid:22883233
    OpenUrlCrossRefPubMedWeb of Science
  9. ↵
    1. Iwasaki Y,
    2. Suganami T,
    3. Hachiya R,
    4. et al
    . Activating transcription factor 4 links metabolic stress to interleukin-6 expression in macrophages. Diabetes 2014;63:152–161
    OpenUrlAbstract/FREE Full Text
  10. ↵
    1. Kristiansen OP,
    2. Mandrup-Poulsen T
    . Interleukin-6 and diabetes: the good, the bad, or the indifferent? Diabetes 2005;54(Suppl. 2):S114–S124pmid:16306329
    OpenUrlAbstract/FREE Full Text
  11. ↵
    1. Tersey SA,
    2. Nishiki Y,
    3. Templin AT,
    4. et al
    . Islet β-cell endoplasmic reticulum stress precedes the onset of type 1 diabetes in the nonobese diabetic mouse model. Diabetes 2012;61:818–827pmid:22442300
    OpenUrlAbstract/FREE Full Text
  12. ↵
    1. Hasnain SZ,
    2. Lourie R,
    3. Das I,
    4. Chen AC,
    5. McGuckin MA
    . The interplay between endoplasmic reticulum stress and inflammation. Immunol Cell Biol 2012;90:260–270pmid:22249202
    OpenUrlCrossRefPubMed
  13. ↵
    1. Yusta B,
    2. Baggio LL,
    3. Estall JL,
    4. et al
    . GLP-1 receptor activation improves beta cell function and survival following induction of endoplasmic reticulum stress. Cell Metab 2006;4:391–406pmid:17084712
    OpenUrlCrossRefPubMedWeb of Science
  14. ↵
    1. Riek AE,
    2. Oh J,
    3. Bernal-Mizrachi C
    . 1,25(OH)2 vitamin D suppresses macrophage migration and reverses atherogenic cholesterol metabolism in type 2 diabetic patients. J Steroid Biochem Mol Biol 2013;136:309–312pmid:23333932
    OpenUrlCrossRefPubMed
View Abstract
PreviousNext
Back to top
Diabetes: 63 (1)

In this Issue

January 2014, 63(1)
  • Table of Contents
  • Table of Contents (PDF)
  • About the Cover
  • Index by Author
  • Masthead (PDF)
Sign up to receive current issue alerts
View Selected Citations (0)
Print
Download PDF
Article Alerts
Sign In to Email Alerts with your Email Address
Email Article

Thank you for your interest in spreading the word about Diabetes.

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.
Endoplasmic Reticulum: An Interface Between the Immune System and Metabolism
(Your Name) has forwarded a page to you from Diabetes
(Your Name) thought you would like to see this page from the Diabetes web site.
Citation Tools
Endoplasmic Reticulum: An Interface Between the Immune System and Metabolism
Emil R. Unanue, Fumihiko Urano
Diabetes Jan 2014, 63 (1) 48-49; DOI: 10.2337/db13-1478

Citation Manager Formats

  • BibTeX
  • Bookends
  • EasyBib
  • EndNote (tagged)
  • EndNote 8 (xml)
  • Medlars
  • Mendeley
  • Papers
  • RefWorks Tagged
  • Ref Manager
  • RIS
  • Zotero
Add to Selected Citations
Share

Endoplasmic Reticulum: An Interface Between the Immune System and Metabolism
Emil R. Unanue, Fumihiko Urano
Diabetes Jan 2014, 63 (1) 48-49; DOI: 10.2337/db13-1478
del.icio.us logo Digg logo Reddit logo Twitter logo CiteULike logo Facebook logo Google logo Mendeley logo
  • Tweet Widget
  • Facebook Like
  • Google Plus One

Jump to section

  • Article
    • Article Information
    • Footnotes
    • References
  • Figures & Tables
  • Info & Metrics
  • PDF

Related Articles

Cited By...

More in this TOC Section

  • SRGAP2a: A New Player That Modulates Podocyte Cytoskeleton and Injury in Diabetes
  • Values and Limitations of Targeting lncRNAs in Diabetic Nephropathy
  • A Weighty Matter: Can PUFAs in Pregnancy Prevent Obesity?
Show more Commentaries

Similar Articles

Navigate

  • Current Issue
  • Online Ahead of Print
  • Scientific Sessions Abstracts
  • Collections
  • Archives
  • Submit
  • Subscribe
  • Email Alerts
  • RSS Feeds

More Information

  • About the Journal
  • Instructions for Authors
  • Journal Policies
  • Reprints and Permissions
  • For Advertisers
  • Privacy Policy: ADA Journals
  • Copyright Notice/Public Access Policy
  • Contact Us

Other ADA Resources

  • Diabetes Care
  • Clinical Diabetes
  • Diabetes Spectrum
  • Standards of Medical Care in Diabetes
  • BMJ Open - Diabetes Research & Care
  • Scientific Sessions Abstracts
  • Professional Books
  • Diabetes Forecast

 

  • DiabetesJournals.org
  • Diabetes Core Update
  • ADA's DiabetesPro
  • ADA Member Directory
  • Diabetes.org

© 2018 by the American Diabetes Association. Diabetes Print ISSN: 0012-1797, Online ISSN: 1939-327X.