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

Advanced Search

Main menu

  • Home
  • Current
    • Current Issue
    • Online Ahead of Print
    • ADA Scientific Sessions Abstracts
  • Browse
    • By Topic
    • Issue Archive
    • Saved Searches
    • ADA Scientific Sessions Abstracts
    • Diabetes COVID-19 Article Collection
    • Diabetes Symposium 2020
  • 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
  • Podcasts
    • Diabetes Core Update
    • Special Podcast Series: Therapeutic Inertia
    • Special Podcast Series: Influenza Podcasts
    • Special Podcast Series: SGLT2 Inhibitors
    • Special Podcast Series: COVID-19
  • Submit
    • Submit a Manuscript
    • Submit Cover Art
    • ADA Journal Policies
    • Instructions for Authors
    • ADA Peer Review
  • More from ADA
    • Diabetes Care
    • Clinical Diabetes
    • Diabetes Spectrum
    • ADA Standards of Medical Care in Diabetes
    • ADA Scientific Sessions Abstracts
    • BMJ Open Diabetes Research & Care

User menu

  • Subscribe
  • Log in
  • My Cart

Search

  • Advanced search
Diabetes
  • Home
  • Current
    • Current Issue
    • Online Ahead of Print
    • ADA Scientific Sessions Abstracts
  • Browse
    • By Topic
    • Issue Archive
    • Saved Searches
    • ADA Scientific Sessions Abstracts
    • Diabetes COVID-19 Article Collection
    • Diabetes Symposium 2020
  • 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
  • Podcasts
    • Diabetes Core Update
    • Special Podcast Series: Therapeutic Inertia
    • Special Podcast Series: Influenza Podcasts
    • Special Podcast Series: SGLT2 Inhibitors
    • Special Podcast Series: COVID-19
  • Submit
    • Submit a Manuscript
    • Submit Cover Art
    • ADA Journal Policies
    • Instructions for Authors
    • ADA Peer Review
Commentary

Unraveling the Mechanisms Underlying Olanzapine-Induced Insulin Resistance

  1. Nigel Irwin1 and
  2. Victor Alan Gault2⇑
  1. 1School of Pharmacy and Pharmaceutical Sciences, The SAAD Centre for Pharmacy and Diabetes, University of Ulster, Coleraine, Northern Ireland, U.K.
  2. 2School of Biomedical Sciences, The SAAD Centre for Pharmacy and Diabetes, University of Ulster, Coleraine, Northern Ireland, U.K.
  1. Corresponding author: Victor Alan Gault, va.gault{at}ulster.ac.uk.
Diabetes 2013 Sep; 62(9): 3022-3023. https://doi.org/10.2337/db13-0804
PreviousNext
  • Article
  • Figures & Tables
  • Info & Metrics
  • PDF
Loading

Atypical antipsychotics (AAPs) are widely prescribed agents for treatment of schizophrenia and other related psychiatric disorders. Although AAPs were a major development in psychopharmacology, so-called second-generation agents such as olanzapine have exhibited unexpected and unfavorable metabolic side effects. These side effects include weight gain, glucose intolerance, and insulin resistance, all of which increase the likelihood of developing diabetes and cardiovascular disease (1). Nonetheless, how these adverse metabolic effects arise following AAP treatment remains unclear. A key question is whether AAP-associated metabolic impairments are because of the psychiatric illness itself or if they are merely secondary to weight gain.

In this issue, Teff et al. (2) examine the direct effects of second-generation AAPs on insulin resistance and postprandial gut hormone profiles following a mixed meal. The antipsychotic drugs used in these experiments—olanzapine and aripiprazole—were administered to healthy volunteers for 9 consecutive days to exclude potential confounding issues associated with psychiatric disease or potential weight gain. In the clinic, olanzapine therapy tends to result in weight gain and metabolic dysregulation (3), whereas aripiprazole is considered metabolically neutral (4). Thus, Teff et al. logically hypothesized that detrimental effects on meal-related metabolism would be limited to olanzapine. Consistent with this hypothesis, the authors showed that aripiprazole had no effect on body weight, blood pressure, and circulating levels of key blood parameters over the 9-day treatment period. Aripiprazole also did not result in significant changes in postprandial metabolism following a mixed meal. In contrast, olanzapine increased fasting plasma insulin by day 9. This corresponded with postprandial hyperinsulinemia, suggesting that olanzapine had detrimental effects on insulin sensitivity. Indeed, hyperinsulinemic-euglycemic clamps supported this theory. However, aripiprazole also induced insulin resistance despite it generally being considered lacking in metabolic effects.

A unique aspect to the study by Teff et al. (2) was participant ingestion of a mixed meal that elicited both incretin responses (5) and neurally mediated insulin release (6), both of which could be critical for the metabolic effects of centrally acting drugs. Surprisingly, olanzapine administration increased postprandial glucagon-like peptide-1 (GLP-1) secretion and circulating glucagon levels. These responses were unexpected for two reasons. First, GLP-1 is believed to improve insulin sensitivity and reduce weight gain. Second, it directly inhibits glucagon release (7). The authors speculate that other unknown factors, such as glucose-dependent insulinotropic polypeptide (GIP) secretion or cholinergic vagally mediated actions, may mediate the altered postprandial metabolic profile following olanzapine administration. In this regard, it has recently been shown that biologic action of GIP can be potentiated by xenin-25, a peptide cosecreted with GIP from intestinal K cells, which is thought to indirectly activate muscarinic receptors (8). Olanzapine is a well-characterized muscarinic receptor antagonist (9). Thus, interactions between GIP and other vagal inputs could be of importance for the postprandial metabolic effects of AAPs (Fig. 1).

FIG. 1.
  • Download figure
  • Open in new tab
  • Download powerpoint
FIG. 1.

Direct effects of AAPs on insulin resistance independent of weight gain. Teff et al. (2) report that olanzapine induces insulin resistance concomitant with postprandial hormonal dysregulation in healthy humans.

The new data are interesting but need to be corroborated in studies with larger sample sizes to increase power and also to be verified in psychiatric patients. A previous study has shown no effect of olanzapine on gut hormone secretion (10). The direct effect of AAPs on GIP secretion and action certainly needs to be considered. Although weight gain did not affect data interpretation, Teff et al. (2) clearly acknowledge that adiposity could be a confounding factor. In addition, the nutrient composition of the mixed meal could have important implications on GIP and GLP-1 secretion. Both incretin hormones are strongly released in response to carbohydrates, but GIP is released much more powerfully than GLP-1 in response to fat (11).

Taken together, the data illustrate that olanzapine can induce insulin resistance and postprandial hormonal dysregulation independently of weight gain. Although the regulatory mechanisms involved remain to be fully elucidated, the well-characterized weight gain following prolonged olanzapine administration would likely exacerbate these effects. Thus, interventions to inhibit weight gain in patients receiving AAP therapy may only be partially effective in preventing metabolic disease. The report by Teff et al. (2) should stimulate continued efforts aimed at resolving the direct detrimental metabolic effects of AAPs that may ultimately lead to improved treatment options for these patients.

ACKNOWLEDGMENTS

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

Footnotes

  • See accompanying original article, p. 3232.

  • © 2013 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. Meyer JM
    . A retrospective comparison of weight, lipid, and glucose changes between risperidone- and olanzapine-treated inpatients: metabolic outcomes after 1 year. J Clin Psychiatry 2002;63:425–433pmid:12019668
    OpenUrlPubMedWeb of Science
  2. ↵
    1. Teff KL,
    2. Rickels MR,
    3. Grudziak J,
    4. et al
    . Antipsychotic-induced insulin resistance and postprandial hormonal dysregulation independent of weight gain or psychiatric disease. Diabetes 2013;62:3232–3240
  3. ↵
    1. Haupt DW,
    2. Fahnestock PA,
    3. Flavin KA,
    4. et al
    . Adiposity and insulin sensitivity derived from intravenous glucose tolerance tests in antipsychotic-treated patients. Neuropsychopharmacology 2007;32:2561–2569pmid:17375138
    OpenUrlCrossRefPubMedWeb of Science
  4. ↵
    1. Nielsen J,
    2. Skadhede S,
    3. Correll CU
    . Antipsychotics associated with the development of type 2 diabetes in antipsychotic-naïve schizophrenia patients. Neuropsychopharmacology 2010;35:1997–2004pmid:20520598
    OpenUrlCrossRefPubMedWeb of Science
  5. ↵
    1. Green BD,
    2. Flatt PR
    . Incretin hormone mimetics and analogues in diabetes therapeutics. Best Pract Res Clin Endocrinol Metab 2007;21:497–516pmid:18054732
    OpenUrlCrossRefPubMed
  6. ↵
    1. Teff KL,
    2. Engelman K
    . Oral sensory stimulation improves glucose tolerance in humans: effects on insulin, C-peptide, and glucagon. Am J Physiol 1996;270:R1371–R1379pmid:8764306
    OpenUrlPubMedWeb of Science
  7. ↵
    1. Lovshin JA,
    2. Drucker DJ
    . Incretin-based therapies for type 2 diabetes mellitus. Nat Rev Endocrinol 2009;5:262–269pmid:19444259
    OpenUrlCrossRefPubMedWeb of Science
  8. ↵
    1. Wice BM,
    2. Wang S,
    3. Crimmins DL,
    4. et al
    . Xenin-25 potentiates glucose-dependent insulinotropic polypeptide action via a novel cholinergic relay mechanism. J Biol Chem 2010;285:19842–19853pmid:20421298
    OpenUrlAbstract/FREE Full Text
  9. ↵
    1. Nasrallah HA
    . Atypical antipsychotic-induced metabolic side effects: insights from receptor-binding profiles. Mol Psychiatry 2008;13:27–35pmid:17848919
    OpenUrlCrossRefPubMedWeb of Science
  10. ↵
    1. Vidarsdottir S,
    2. Roelfsema F,
    3. Streefland T,
    4. Holst JJ,
    5. Rehfeld JF,
    6. Pijl H
    . Short-term treatment with olanzapine does not modulate gut hormone secretion: olanzapine disintegrating versus standard tablets. Eur J Endocrinol 2010;162:75–83pmid:19779025
    OpenUrlCrossRefPubMed
  11. ↵
    1. Irwin N,
    2. Flatt PR
    . Evidence for beneficial effects of compromised gastric inhibitory polypeptide action in obesity-related diabetes and possible therapeutic implications. Diabetologia 2009;52:1724–1731pmid:19533083
    OpenUrlCrossRefPubMedWeb of Science
View Abstract
PreviousNext
Back to top
Diabetes: 62 (9)

In this Issue

September 2013, 62(9)
  • Table of Contents
  • About the Cover
  • Index by Author
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.
Unraveling the Mechanisms Underlying Olanzapine-Induced Insulin Resistance
(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.
CAPTCHA
This question is for testing whether or not you are a human visitor and to prevent automated spam submissions.
Citation Tools
Unraveling the Mechanisms Underlying Olanzapine-Induced Insulin Resistance
Nigel Irwin, Victor Alan Gault
Diabetes Sep 2013, 62 (9) 3022-3023; DOI: 10.2337/db13-0804

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

Unraveling the Mechanisms Underlying Olanzapine-Induced Insulin Resistance
Nigel Irwin, Victor Alan Gault
Diabetes Sep 2013, 62 (9) 3022-3023; DOI: 10.2337/db13-0804
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
    • ACKNOWLEDGMENTS
    • Footnotes
    • REFERENCES
  • Figures & Tables
  • Info & Metrics
  • PDF

Related Articles

Cited By...

More in this TOC Section

  • Lifting the Veil on the “Phosphate Flush,” a Cryptic Phenomenon of Experimental Pancreatic Islet Physiology
  • Window of Opportunity: Targeting ANGPTL4 Improves Triglyceride Levels in Maternal Obesity During Pregnancy
  • New Antidiabetes Agent Targeting Both Mitochondrial Uncoupling and Pyruvate Catabolism: Two Birds With One Stone
Show more Commentary

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
  • Advertising
  • Privacy Policy: ADA Journals
  • Copyright Notice/Public Access Policy
  • Contact Us

Other ADA Resources

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

 

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

© 2021 by the American Diabetes Association. Diabetes Print ISSN: 0012-1797, Online ISSN: 1939-327X.