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
Commentaries

Central Regulation of Glucose Metabolism in Humans: Fact or Fiction?

  1. Sofiya Gancheva1,2 and
  2. Michael Roden1,2,3⇑
  1. 1Institute for Clinical Diabetology and Leibniz Center for Diabetes Research at Heinrich-Heine University Düsseldorf, German Diabetes Center, Düsseldorf, Germany
  2. 2German Center for Diabetes Research (DZD e.V.), München-Neuherberg, Germany
  3. 3Department of Endocrinology and Diabetology, Heinrich-Heine University Düsseldorf, Düsseldorf, Germany
  1. Corresponding author: Michael Roden, michael.roden{at}ddz.uni-duesseldorf.de.
Diabetes 2016 Sep; 65(9): 2467-2469. https://doi.org/10.2337/dbi16-0032
PreviousNext
  • Article
  • Figures & Tables
  • Info & Metrics
  • PDF
Loading

In the past few years, insulin action in the central nervous system (CNS) has attracted a growing interest to better understand the association between neurodegenerative diseases and insulin resistance (IR). Rodent studies have indicated that insulin signaling in the CNS is critical for the suppression of endogenous glucose production (EGP) in the liver (1) and for the regulation of adipose tissue lipolysis (2). These central insulin effects likely depend on PI3K-mediated regulation of several proteins and transcription factors, among which are FoxO1 (3) and AMPK (4), and on the activation of KATP channels (5) in the hypothalamus (Fig. 1). Recent findings show that subsequent activation of hepatic Kupffer cells and an increase in hepatic interleukin-6 induce signal transducer and activator of transcription 3 (STAT3) phosphorylation to inhibit gluconeogenic gene expression (6). Suppression of lipolysis in adipose tissue by brain insulin signaling reduces the availability of gluconeogenic substrates for the liver, which will further decrease EGP (2). In contrast, studies in dogs did not support the concept of a physiological relevance of CNS insulin action for controlling EGP (7).

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

Brain insulin regulation of hepatic glucose production and adipose tissue lipolysis. The insulin-signaling pathway in the arcuate hypothalamus involves the activation of PI3K and AKT and the subsequent inactivation of FoxO1. Also, the inhibition of AMPK and opening of KATP channels are linked to brain insulin’s peripheral metabolic effects. In addition to the reduction of lipolysis by modulation of sympathetic activity, brain insulin induces the suppression of hepatic glucose production, which is mediated by the vagus nerve–triggered hepatic interleukin (IL)-6 and STAT3 activation, leading to decreased hepatic gluconeogenic gene expression. Central insulin action also reduces liver fat content and increases hepatic energy status. This mechanism seems to be impaired in humans and rodents with type 2 diabetes. AKT, protein kinase B; FFA, free fatty acids; G6P, glucose 6-phosphate; HCL, liver fat content; Non-DM, nondiabetic; N. vagus, vagus nerve; T2D, type 2 diabetes.

In humans, intranasal insulin (IN) application has been established as one approach to noninvasively examine brain insulin action in vivo. The IN spray application transiently increases the insulin concentration in liquor (8), likely due to bulk flow within the perivascular space of cerebral blood vessels (9). Using this technique, evidence for the central insulin regulation of systemic lipolysis (10), modulation of liver fat content and hepatic energy metabolism (11), and improvement in whole-body insulin sensitivity (12) has been provided. Interestingly, effects of IN on EGP seem to depend on the experimental conditions with no changes in the fasting state (11) but with reduction during pancreatic clamps (13). Modulation of energy-demanding processes might contribute to the rise in hepatic energy status after IN application. Of note, central insulin regulation of peripheral insulin sensitivity and hepatic energy metabolism was blunted in obese humans and patients with type 2 diabetes (11,12), suggesting that the presence of a combined central and peripheral IR and a dysregulation of a brain-liver cross talk in type 2 diabetes. Nevertheless, IN may have some limitations resulting from variable cerebral insulin delivery and/or peripheral insulin spillover.

Another approach to mimic brain insulin action in humans is the administration of the KATP-channel opener and sulfonylurea drug diazoxide. Dr. Hawkins’ group showed that diazoxide treatment can suppress EGP in lean healthy humans, and complementary studies in rodents revealed increased hepatic STAT3 phosphorylation along with reduced hepatic gluconeogenic protein levels (14). The same group now presents a carefully planned and nicely performed follow-up study investigating the effects of diazoxide on EGP in patients with type 2 diabetes. Esterson et al. (15) combined diazoxide administration with euglycemic basal insulin and glucagon, growth hormone, and somatostatin clamps, allowing for the examination of glucose metabolism under carefully controlled conditions ruling out CNS effects on pancreatic insulin and glucagon secretion. By avoiding hepatic overinsulinization, this approach allows for the assessment of even minor changes in EGP over time. The possible limitation that the preceding overnight insulin infusion might suppress EGP and thereby attenuate the effect of diazoxide on EGP is discussed by the authors. Importantly, this study extends the group’s previous observations by clearly demonstrating that diazoxide has no effect on EGP in patients with moderately to poorly controlled type 2 diabetes. Even more, the study confirms the effect of diazoxide on EGP in healthy humans. It has to be stated that the experimental groups were small and the effects of longer-term treatment require further examination. Nevertheless, this study specifically benefits from the complementary studies in Zucker diabetic fatty rats, an established rodent model of type 2 diabetes, that support the findings in humans of a lack of effect of diazoxide on EGP and further probe the mechanism in greater detail by assessing molecular regulation of EGP.

In studies in humans with IR, IN or intravenous insulin application did not induce brain activity in the insulin-sensitive brain areas, i.e., the hippocampus, prefrontal cortex, fusiform gyrus, and hypothalamus, as measured by noninvasive brain imaging tools (16,17). Although such evidence for the activation of insulin-sensitive brain regions has not yet been demonstrated after diazoxide administration, the study by Esterson et al. (15) adds to the discussion on impaired central regulation of glucose and energy metabolism in type 2 diabetes (11). The question remains as to whether KATP channel activation and IN modulate peripheral insulin sensitivity by similar or different pathways. Specifically, it will be interesting to find out which and how brain-derived signals, induced either by IN or diazoxide, reach peripheral tissues to modulate glucose and energy metabolism. The autonomic nervous system is also a good candidate to mediate these effects in humans (5,12). Animal data revealed that CNS insulin-induced suppression of EGP depends on vagus nerve activation (6), whereas the sympathetic nervous system mediates for the reduction of adipose tissue lipolysis (2). However, it remains unclear how selective modulation of the autonomic nervous system tone could be used to improve glucose and lipid homeostasis. Finally, the observation that the sulfonylurea drug diazoxide fails to exert EGP-lowering effects in patients with diabetes contributes to a large body of evidence that does not raise the enthusiasm to use this drug class in type 2 diabetes.

Article Information

Funding. This work was supported by the Ministry of Innovation, Science and Research of the State of North Rhine-Westphalia and the German Federal Ministry of Health. This work was also supported in part by a grant from the Federal Ministry of Education and Research to the German Center for Diabetes Research and by a grant from the Helmholtz Alliance Imaging and Curing Environmental Metabolic Diseases.

The funding sources had no input in the preparation, review, or approval of the article.

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

Footnotes

  • See accompanying article, p. 2569.

  • © 2016 by the American Diabetes Association.

http://diabetesjournals.org/site/license

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. More information is available at http://diabetesjournals.org/site/license.

References

  1. ↵
    1. Obici S,
    2. Zhang BB,
    3. Karkanias G,
    4. Rossetti L
    . Hypothalamic insulin signaling is required for inhibition of glucose production. Nat Med 2002;8:1376–1382pmid:12426561
    OpenUrlCrossRefPubMedWeb of Science
  2. ↵
    1. Scherer T,
    2. O’Hare J,
    3. Diggs-Andrews K, et al
    . Brain insulin controls adipose tissue lipolysis and lipogenesis. Cell Metab 2011;13:183–194pmid:21284985
    OpenUrlCrossRefPubMedWeb of Science
  3. ↵
    1. Kim MS,
    2. Pak YK,
    3. Jang PG, et al
    . Role of hypothalamic Foxo1 in the regulation of food intake and energy homeostasis. Nat Neurosci 2006;9:901–906pmid:16783365
    OpenUrlCrossRefPubMedWeb of Science
  4. ↵
    1. Minokoshi Y,
    2. Alquier T,
    3. Furukawa N, et al
    . AMP-kinase regulates food intake by responding to hormonal and nutrient signals in the hypothalamus. Nature 2004;428:569–574pmid:15058305
    OpenUrlCrossRefPubMedWeb of Science
  5. ↵
    1. Pocai A,
    2. Lam TK,
    3. Gutierrez-Juarez R, et al
    . Hypothalamic K(ATP) channels control hepatic glucose production. Nature 2005;434:1026–1031pmid:15846348
    OpenUrlCrossRefPubMedWeb of Science
  6. ↵
    1. Kimura K,
    2. Tanida M,
    3. Nagata N, et al
    . Central insulin action activates Kupffer cells by suppressing hepatic vagal activation via the nicotinic alpha 7 acetylcholine receptor. Cell Reports 2016;14:2362–2374pmid:26947072
    OpenUrlCrossRefPubMed
  7. ↵
    1. Ramnanan CJ,
    2. Edgerton DS,
    3. Cherrington AD
    . Evidence against a physiologic role for acute changes in CNS insulin action in the rapid regulation of hepatic glucose production. Cell Metab 2012;15:656–664pmid:22560218
    OpenUrlCrossRefPubMedWeb of Science
  8. ↵
    1. Born J,
    2. Lange T,
    3. Kern W,
    4. McGregor GP,
    5. Bickel U,
    6. Fehm HL
    . Sniffing neuropeptides: a transnasal approach to the human brain. Nat Neurosci 2002;5:514–516pmid:11992114
    OpenUrlCrossRefPubMedWeb of Science
  9. ↵
    1. Lochhead JJ,
    2. Wolak DJ,
    3. Pizzo ME,
    4. Thorne RG
    . Rapid transport within cerebral perivascular spaces underlies widespread tracer distribution in the brain after intranasal administration. J Cereb Blood Flow Metab 2015;35:371–381pmid:25492117
    OpenUrlAbstract/FREE Full Text
  10. ↵
    1. Iwen KA,
    2. Scherer T,
    3. Heni M, et al
    . Intranasal insulin suppresses systemic but not subcutaneous lipolysis in healthy humans. J Clin Endocrinol Metab 2014;99:E246–E251pmid:24423295
    OpenUrlCrossRefPubMed
  11. ↵
    1. Gancheva S,
    2. Koliaki C,
    3. Bierwagen A, et al
    . Effects of intranasal insulin on hepatic fat accumulation and energy metabolism in humans. Diabetes 2015;64:1966–1975pmid:25576060
    OpenUrlAbstract/FREE Full Text
  12. ↵
    1. Heni M,
    2. Wagner R,
    3. Kullmann S, et al
    . Central insulin administration improves whole-body insulin sensitivity via hypothalamus and parasympathetic outputs in men. Diabetes 2014;63:4083–4088pmid:25028522
    OpenUrlAbstract/FREE Full Text
  13. ↵
    1. Dash S,
    2. Xiao C,
    3. Morgantini C,
    4. Koulajian K,
    5. Lewis GF
    . Intranasal insulin suppresses endogenous glucose production in humans compared with placebo in the presence of similar venous insulin concentrations. Diabetes 2015;64:766–774pmid:25288674
    OpenUrlAbstract/FREE Full Text
  14. ↵
    1. Kishore P,
    2. Boucai L,
    3. Zhang K, et al
    . Activation of K(ATP) channels suppresses glucose production in humans. J Clin Invest 2011;121:4916–4920pmid:22056385
    OpenUrlCrossRefPubMed
  15. ↵
    Esterson YB, Carey M, Boucai L, et al. Central regulation of glcose production may be impaired in type 2 diabetes. Diabetes 2016;65:2569–2579
  16. ↵
    1. Anthony K,
    2. Reed LJ,
    3. Dunn JT, et al
    . Attenuation of insulin-evoked responses in brain networks controlling appetite and reward in insulin resistance: the cerebral basis for impaired control of food intake in metabolic syndrome? Diabetes 2006;55:2986–2992pmid:17065334
    OpenUrlAbstract/FREE Full Text
  17. ↵
    1. Kullmann S,
    2. Heni M,
    3. Veit R, et al
    . Selective insulin resistance in homeostatic and cognitive control brain areas in overweight and obese adults. Diabetes Care 2015;38:1044–1050pmid:25795413
    OpenUrlAbstract/FREE Full Text
PreviousNext
Back to top
Diabetes: 65 (9)

In this Issue

September 2016, 65(9)
  • 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.
Central Regulation of Glucose Metabolism in Humans: Fact or Fiction?
(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
Central Regulation of Glucose Metabolism in Humans: Fact or Fiction?
Sofiya Gancheva, Michael Roden
Diabetes Sep 2016, 65 (9) 2467-2469; DOI: 10.2337/dbi16-0032

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

Central Regulation of Glucose Metabolism in Humans: Fact or Fiction?
Sofiya Gancheva, Michael Roden
Diabetes Sep 2016, 65 (9) 2467-2469; DOI: 10.2337/dbi16-0032
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

  • Adipose Tissue Malfunction Drives Metabolic Dysfunction in Alström Syndrome
  • Staying Connected: Transcriptomics in the Search for Novel Diabetic Kidney Disease Treatments
  • Going in Early: Hypoxia as a Target for Kidney Disease Prevention in Diabetes?
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
  • 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.