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

Advanced Search

Main menu

  • Home
  • Current
    • Current Issue
    • Online Ahead of Print
    • Special Article Collections
    • ADA Standards of Medical Care
  • Browse
    • By Topic
    • Issue Archive
    • Saved Searches
    • Special Article Collections
    • ADA Standards of Medical Care
  • Info
    • About the Journal
    • About the Editors
    • ADA Journal Policies
    • Instructions for Authors
    • Guidance for Reviewers
  • Reprints/Reuse
  • Advertising
  • Subscriptions
    • Individual Subscriptions
    • Institutional Subscriptions and Site Licenses
    • Access Institutional Usage Reports
    • Purchase Single Issues
  • Alerts
    • E­mail Alerts
    • RSS Feeds
  • Podcast
  • Submit
    • Submit a Manuscript
    • Journal Policies
    • Instructions for Authors
    • ADA Peer Review
  • More from ADA
    • Diabetes
    • Clinical Diabetes
    • Diabetes Spectrum
    • ADA Standards of Medical Care
    • ADA Scientific Sessions Abstracts
    • BMJ Open Diabetes Research & Care

User menu

  • Subscribe
  • Log in
  • My Cart

Search

  • Advanced search
Diabetes Care
  • Home
  • Current
    • Current Issue
    • Online Ahead of Print
    • Special Article Collections
    • ADA Standards of Medical Care
  • Browse
    • By Topic
    • Issue Archive
    • Saved Searches
    • Special Article Collections
    • ADA Standards of Medical Care
  • Info
    • About the Journal
    • About the Editors
    • ADA Journal Policies
    • Instructions for Authors
    • Guidance for Reviewers
  • Reprints/Reuse
  • Advertising
  • Subscriptions
    • Individual Subscriptions
    • Institutional Subscriptions and Site Licenses
    • Access Institutional Usage Reports
    • Purchase Single Issues
  • Alerts
    • E­mail Alerts
    • RSS Feeds
  • Podcast
  • Submit
    • Submit a Manuscript
    • Journal Policies
    • Instructions for Authors
    • ADA Peer Review
e-Letters: Observations

Association Between Serum Total Bilirubin Levels and the Morphology of Corneal Nerve Fibers in Japanese Patients With Uncontrolled Type 2 Diabetes

  1. Fukashi Ishibashi,
  2. Asami Kawasaki,
  3. Rie Kojima,
  4. Miki Taniguchi,
  5. Aiko Kosaka and
  6. Harumi Uetake
  1. Ishibashi Clinic, Hatsukaichi, Hiroshima, Japan
  1. Corresponding author: Fukashi Ishibashi, ishiclic{at}urban.ne.jp.
Diabetes Care 2014 Jun; 37(6): e131-e132. https://doi.org/10.2337/dc14-0027
PreviousNext
  • Article
  • Figures & Tables
  • Info & Metrics
  • PDF
Loading

Oxidative stress (OS) plays a key role in the development of diabetes complications. Bilirubin is a potent antioxidant, and serum total bilirubin (TB) levels in the low-normal range are associated with diabetic retinopathy (1) and nephropathy (2) and are predictive of lower-limb amputation (3). However, the relationship between serum TB and diabetic neuropathy has not been reported. Due to constant exposure to OS (sunlight and ambient air) and poor antioxidant activity due to its avascularity, the cornea is vulnerable to OS (4). Diabetes increases the OS burden on the cornea. Corneal nerve fibers (CNFs) are composed of unmyelinated C-fibers, which are the first nerve fibers to undergo damage and subsequent repair. We examined the association between serum TB and CNF morphology in patients with uncontrolled type 2 diabetes (T2D).

Cross-sectional data were collected from 384 Japanese T2D patients with severe (HbA1c ≥8.5% [69.4 mmol/mol], n = 143), moderate (7.2% [55.2 mmol/mol] to <8.5% [69.4 mmol/mol], n = 104), or mild (6.5% [47.5 mmol/mol] to <7.2% [55.2 mmol/mol], n = 137) hyperglycemia and compared with age- and sex-matched controls (n = 57). CNF morphological parameters (CNF density [CNFD] and length [CNFL], CNF branch density [CNBD] and length [CNBL], tortuosity, and beading frequency) were examined by corneal confocal microscopy (5). HbA1c, serum TB, γ-glutamyl transpeptidase (GGT), high-sensitivity C-reactive protein (hsCRP), creatinine, and the urinary albumin-to-creatinine ratio (ACR) were determined. The independent associations of serum TB with CNF morphological parameters and clinical factors were assessed. Written informed consent was obtained from all subjects prior to participation. The ethics committee of Ishibashi Clinic approved the study protocol.

Serum TB (12.3 ± 0.45–14.3 ± 0.76 μmol/L) was similar among the four groups. GGT and hsCRP in T2D patients with severe hyperglycemia were higher than those in the other two groups (P < 0.0001), despite similar BMIs and alcohol consumption. All CNF parameters except CNBL in T2D patients differed from those of control subjects (P < 0.0001 to <0.001). In patients with severe hyperglycemia, serum TB was positively associated with CNFD, CNFL, CNBD, and CNBL, and was inversely associated with tortuosity. By contrast, log-hsCRP, GGT, triglycerides, log-ACR, and smoking habit were negative predictors of CNFD, and systolic blood pressure (SBP), GGT, triglycerides, log-ACR, and smoking habit were negative predictors of CNFL. SBP, GGT, log-ACR, and smoking habit were positive predictors of tortuosity (Table 1). In patients with moderate, but not mild, hyperglycemia, serum TB levels were associated only with CNFD (P = 0.039) and CNFL (P = 0.023). Serum TB levels were negatively correlated with hsCRP (P = 0.017–0.031), triglycerides (P = 0.005 to <0.0001), and smoking habit (P = 0.022 to <0.0001) in all diabetes subgroups.

View this table:
  • View inline
  • View popup
  • Download powerpoint
Table 1

Correlation between morphological parameters of CNFs visualized by corneal confocal microscopy and clinical factors in patients with T2D under severe hyperglycemia (HbA1c ≥8.5% [69.4 mmol/mol])

In uncontrolled T2D patients with severe hyperglycemia who were exposed to marked OS, normal serum TB was associated with CNF morphology. Triglycerides, hsCRP, and smoking might influence CNF pathology in part by lowering serum TB levels. The present cross-sectional study identified an association between the TB level and CNF changes. The prospective study clarifies a pivotal role of lower serum TB levels in CNF degeneration in uncontrolled T2D that is similar to its role in lower-limb amputation (3).

Article Information

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

Author Contributions. F.I. designed the study, analyzed data, and wrote the entire manuscript. A.K., R.K., and M.T. performed the corneal confocal microscopy examination and determined the morphological parameters of the CNFs. A.K. and H.U. gathered the clinical and laboratory data and statistically analyzed all data. F.I. is the guarantor of this work and, as such, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

  • © 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. Yasuda M,
    2. Kiyohara Y,
    3. Wang JJ,
    4. et al
    . High serum bilirubin levels and diabetic retinopathy: the Hisayama Study. Ophthalmology 2011;118:1423–1428
    OpenUrlPubMed
  2. ↵
    1. Fukui M,
    2. Tanaka M,
    3. Shiraishi E,
    4. et al
    . Relationship between serum bilirubin and albuminuria in patients with type 2 diabetes. Kidney Int 2008;74:1197–1201
    OpenUrlCrossRefPubMedWeb of Science
  3. ↵
    1. Chan KH,
    2. O’Connell RL,
    3. Sullivan DR,
    4. et al.,
    5. FIELD Study Investigators
    . Plasma total bilirubin levels predict amputation events in type 2 diabetes mellitus: the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study. Diabetologia 2013;56:724–736
    OpenUrlCrossRefPubMed
  4. ↵
    1. Abraham NG,
    2. Kappas A
    . Pharmacological and clinical aspects of heme oxygenase. Pharmacol Rev 2008;60:79–127
    OpenUrlAbstract/FREE Full Text
  5. ↵
    1. Ishibashi F,
    2. Okino M,
    3. Ishibashi M,
    4. et al
    . Corneal nerve fiber pathology in Japanese type 1 diabetic patients and its correlation with antecedent glycemic control and blood pressure. J Diabetes Invest 2012;3:191–198
    OpenUrlCrossRef
View Abstract
PreviousNext
Back to top
Diabetes Care: 37 (6)

In this Issue

June 2014, 37(6)
  • 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 Care.

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.
Association Between Serum Total Bilirubin Levels and the Morphology of Corneal Nerve Fibers in Japanese Patients With Uncontrolled Type 2 Diabetes
(Your Name) has forwarded a page to you from Diabetes Care
(Your Name) thought you would like to see this page from the Diabetes Care web site.
Citation Tools
Association Between Serum Total Bilirubin Levels and the Morphology of Corneal Nerve Fibers in Japanese Patients With Uncontrolled Type 2 Diabetes
Fukashi Ishibashi, Asami Kawasaki, Rie Kojima, Miki Taniguchi, Aiko Kosaka, Harumi Uetake
Diabetes Care Jun 2014, 37 (6) e131-e132; DOI: 10.2337/dc14-0027

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

Association Between Serum Total Bilirubin Levels and the Morphology of Corneal Nerve Fibers in Japanese Patients With Uncontrolled Type 2 Diabetes
Fukashi Ishibashi, Asami Kawasaki, Rie Kojima, Miki Taniguchi, Aiko Kosaka, Harumi Uetake
Diabetes Care Jun 2014, 37 (6) e131-e132; DOI: 10.2337/dc14-0027
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
    • References
  • Figures & Tables
  • Info & Metrics
  • PDF

Related Articles

Cited By...

More in this TOC Section

  • The Role of Lipoprotein (a) as a Marker of Residual Risk in Patients With Diabetes and Established Cardiovascular Disease on Optimal Medical Therapy: Post-Hoc Analysis of ACCELERATE
  • Plasma Apelin and Risk of Type 2 Diabetes in a Cohort From the Community
  • Trends in HbA1c and LDL Cholesterol in Patients With Type 2 Diabetes Receiving First-Time Treatment in Northern Denmark, 2000–2017: Population-Based Sequential Cross-Sectional Analysis
Show more e-Letters: Observations

Similar Articles

Navigate

  • Current Issue
  • Standards of Care Guidelines
  • Online Ahead of Print
  • Archives
  • Submit
  • Subscribe
  • Email Alerts
  • RSS Feeds

More Information

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

Other ADA Resources

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

 

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

© 2019 by the American Diabetes Association. Diabetes Care Print ISSN: 0149-5992, Online ISSN: 1935-5548.