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

Hypoglycemic Detection at the Portal Vein

Absent in Humans or Yet to Be Elucidated?

  1. Casey M. Donovan and
  2. MaryAnn Bohland
  1. From the Department of Integrative & Evolutionary Biology, University of Southern California, Los Angeles, California
  1. Corresponding author: Casey Donovan, donovan{at}usc.edu
Diabetes 2009 Jan; 58(1): 21-23. https://doi.org/10.2337/db08-1437
PreviousNext
  • Article
  • Figures & Tables
  • Info & Metrics
  • PDF
Loading

With the advent of more intensive glucose management, hypoglycemia has emerged as a primary limitation in the treatment of insulin-dependent diabetes. It is now recognized that the increased incidence of hypoglycemia derives not only from imperfect insulin replacement but also from impaired counterregulation and hypoglycemic unawareness (1). The latter two observations have led to a renewed interest in the mechanisms underlying hypoglycemic detection. As a result of intensive research over the past decade, the traditional hypothalamocentric model of glucose sensing has been replaced with one emphasizing a widespread neural network involving numerous aspects of the central nervous system, as well as peripheral sensory input. Thus, in addition to the ventromedial hypothalamus, the paraventricular hypothalamus, arcuate nucleus, area postrema, nucleus of the solitary tract, and dorsal motor nucleus all appear to play important roles (2,3). In the periphery, important glucose sensors have been identified in the carotid bodies (4), gastrointestinal tract (5), and portal-mesenteric vein (6). For hypoglycemic detection, the glucose sensors of the portal-mesenteric vein have garnered the most attention. Animal studies have repeatedly demonstrated that blocking portal glucose sensing via portal glucose infusion (7) or denervating the portal vein (8) substantially suppresses the sympathoadrenal response to hypoglycemia. More recently, it was shown that portal-mesenteric vein glucose sensing is particularly important when hypoglycemia develops slowly and, under these conditions, modulates over 90% of the sympathoadrenal response to hypoglycemia (9).

While portal vein glucose sensing appears to be conserved across several species (7,9,10), demonstration of consistent findings in humans has proven elusive. An obvious limitation for human studies is the lack of direct access to the portal vein, which severely constrains experimental interventions. To circumvent this problem, Rossetti et al. (11) employed an oral glucose load to elevate portal glucose concentration during a hyperinsulinemic-hypoglycemic clamp. Oral glucose was administered before the clamp to establish a portal-arterial gradient before the onset of hypoglycemia. Hypoglycemia was then allowed to develop slowly—an important aspect of this study considering the previously mentioned animal experiments and the clinical relevance. Despite these efforts, they observed no effect of the oral glucose load on counterregulatory or symptomatic responses to hypoglycemia. The authors conclude that the portal glucose sensor plays no significant role in hypoglycemic detection for humans. This is not the first time such an approach has been employed in an attempt to elucidate the potential role of portal glucose sensing in humans (12–14). While all previous reports demonstrated a significant impact of an oral glucose load on the hormonal responses to hypoglycemia, results have been anything but consistent.

In addition to the negative findings for Rossetti et al., oral glucose during a hyperinsulinimic-hypoglycemic clamp has been shown to suppress (14), augment (13), and initially suppress and then augment (12) the sympathoadrenal response to hypoglycemia in humans. As noted by Rossetti et al. (11), subtle differences in the respective protocols (e.g., rate of fall in glycemia, the timing and/or mass of the oral glucose load) may explain some of the observed differences. However, critical to the interpretation of these findings is the assumption that the oral glucose load actually elevates the portal vein glucose concentration above the glycemic threshold for the duration of the experiment. Because portal glucose concentration cannot be measured directly in humans, it must be based on estimated rates of glucose appearance and portal blood flow. A number of sophisticated modeling approaches employing multiple tracers have been developed for estimating the appearance of an oral glucose load (15,16) but, to date, have not been used in studies of portal glucose sensing in humans. Further confounding estimates of portal glucose concentration is the wide range of values reported for human portal blood flow, (10–18 ml · kg−1 · min−1 [17]), which may increase substantially in response to oral glucose ingestion.

Alternatively, the disparate findings for these human studies may result from the complexity of introducing an oral glucose load, as opposed to simply infusing glucose in the portal vein (Fig. 1). As noted in one recent review (3), glucose sensing of an oral glucose load begins in the oral cavity and continues in the gut, the portal-mesenteric vein, and, finally, the systemic circulation. In particular, the gastrointestinal tract is now recognized as an important locus for glucose detection. The ability to sense glucose in the luminal contents of the gut not only allows for intrinsic control but also provides important sensory feedback to the central nervous system via extrinsic afferent nerves and blood-borne peptides (5). Many of the peptides secreted by the enteroendocrine cells of the gut (e.g., glucagon-like peptide 1 [GLP-1], glucose-dependent insulinotropic peptide, and peptide YY) are now well recognized for their impact on glucose and energy homeostasis. While considerable insight has been gained regarding their role in hyperglycemic and euglycemic states, their impact under hypoglycemic conditions is poorly understood and not always obvious. For example, the ability of GLP-1 to suppress glucagon secretion is apparently lost under hypoglycemic conditions (18). Also, the vagal glucose-sensitive afferents of the portal vein, which are inhibited by glucose, are activated by GLP-1 (19), a peptide released in response to oral glucose (5). While vagal afferents are apparently not involved in hypoglycemic detection at the portal vein (20), if the spinal glucose-sensitive afferents (8) demonstrate similar reciprocal responses to glucose and GLP-1, this might explain some of the observed disparity in these human studies. It is also important to recognize that all peripheral glucose sensory input, i.e., gut, portal-mesenteric, and gustatory, converges on the nucleus of the solitary tract, where local glycemic conditions are likely to impact on the eventual efferent response (3).

Given the marked disparity in findings for humans, it is perhaps premature to conclude that hypoglycemic detection at the portal vein is not important for humans as proposed by Rossetti et al. (11). Beyond the substantial technical obstacles faced by such studies, there is the fundamental question of whether glucose introduced to the portal circulation via the gut is equivalent to a direct glucose infusion. As our understanding of the neural network underlying glucose sensing improves, it is likely that at least some of the apparent differences in human and animal hypoglycemic detection will be resolved.

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

Glucose sensory input: For an oral glucose load, afferent inputs include the oral cavity, gastrointestinal tract, and portal-superior mesenteric veins (vagal and spinal), all of which converge on the nucleus of the solitary tract (NTS). In addition, gut peptides released by an oral glucose load can activate sensory neurons in the gastrointestinal tract and portal vein, as well as activate the central nervous system directly. For portal vein glucose infusion during a hyperinsulinimic-hypoglycemic clamp, input is restricted to glucose sensing afferents in the portal-mesenteric vein.

Acknowledgments

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

Footnotes

  • 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.

    See accompanying original article, p. 194.

  • DIABETES

REFERENCES

  1. ↵
    Cryer PE: Mechanisms of hypoglycemia-associated autonomic failure and its component syndromes in diabetes. Diabetes54 :3592 –3601,2005
    OpenUrlAbstract/FREE Full Text
  2. ↵
    Levin BE, Routh VH, Kang L, Sanders NM, Dunn Meynell AA: Neuronal glucosensing: what do we know after 50 years? Diabetes53 :2521 –2528,2004
    OpenUrlAbstract/FREE Full Text
  3. ↵
    Marty N, Dallaporta M, Thorens B: Brain glucose sensing, counterregulation, and energy homeostasis. Physiology22 :241 –251,2007
    OpenUrlAbstract/FREE Full Text
  4. ↵
    Koyama Y, Coker RH, Stone EE, Lacy B, Jabbour K, Williams PE, Wasserman DH: Evidence that carotid bodies play an important role in glucoregulation in vivo. Diabetes49 :1434 –1442,2000
    OpenUrlAbstract
  5. ↵
    Berthoud H-R: Vagal and hormonal gut-brain communication: from satiation to satisfaction. Neurogastroenterol Motil20 :64 –72,2008
    OpenUrlCrossRefPubMed
  6. ↵
    Donovan CM: Portal vein glucose sensing. Diabetes Nutr Metab15 :308 –312,2002
    OpenUrlPubMedWeb of Science
  7. ↵
    Donovan C, Hamilton-Wessler M, Halter J, Bergman R: Primacy of liver glucosensors in the sympathetic response to progressive hypoglycemia. Proc Natl Acad Sci91 :2863 –2867,1994
    OpenUrlAbstract/FREE Full Text
  8. ↵
    Fujita S, Bohland MA, Sanchez-Watts G, Watts AG, Donovan CM: Hypoglycemic detection at the portal vein is mediated by capsaicin-sensitive primary sensory neurons. Am J Physiol293 :E96 –E101,2007
    OpenUrl
  9. ↵
    Saberi M, Bohland MA, Donovan CM: The locus for hypoglycemic detection shifts with the rate of fall in glycemia: the role of the portal-superior mesenteric vein in glucose sensing. Diabetes57 :1380 –1386,2008
    OpenUrlAbstract/FREE Full Text
  10. ↵
    Burcelin R, Dolci W, Thorens B: Glucose sensing by the hepatoportal sensor is GLUT2-dependent. Diabetes49 :1643 –1648,2000
    OpenUrlAbstract
  11. ↵
    Rossetti P, Porcellati F, Lucidi P, Busciantella Ricci N, Candeloro P, Cioli P, Santeusanio F, Bolli GB, Fannelli CG: Portal vein glucose sensors do not play a major role in modulating physiological responses to insulin-induced hypoglycemia in humans. Diabetes58 :194 –202,2009
    OpenUrlAbstract/FREE Full Text
  12. ↵
    Ertl AC, Mann S, Richardson A, Briscoe VJ, Tate HB, Davis SN: Effects of oral carbohydrate on autonomic nervous system counterregulatory responses during hyperinsulinemic hypoglycemica and euglycemia. Am J Physiol295 :E618 –E625,2008
    OpenUrl
  13. ↵
    Heptulla RA, Tamborlane WV, Ma TY-Z, Rife F, Sherwin RS: Oral glucose augments the counterregulatory hormone response during insulin-induced hypoglycemia in humans. J Clin Endocrinol Metabol86 :645 –648,2001
    OpenUrlCrossRefPubMedWeb of Science
  14. ↵
    Smith D, Pernet A, Reid H, Bingham E, Rosenthal J, Macdonald I, Umpleby A, Amiel SA: The role of hepatic portal glucose sensing in modulating responses to hypoglycemia in man. Diabetologia45 :1416 –1424,2002
    OpenUrlCrossRefPubMedWeb of Science
  15. ↵
    Basu R, Di Camillo B, Toffolo G, Basu A, Shah P, Vella A, Rizza R, Cobelli C: Use of a novel triple-tracer approach to assess postprandial glucose metabolism. Am J Physiol284 :E55 –E69,2003
    OpenUrl
  16. ↵
    Livesey G, Wilson PDG, Dainty JR, Brown JC, Faulks RM, Roe MA, Newman TA, Eagles J, Mellon FA, Greenwood RH: Simultaneous time-varying systemic appearance of oral and hepatic glucose in adults monitored with stable isotopes. Am J Physiol275 :E717 –E728,1998
    OpenUrlPubMedWeb of Science
  17. ↵
    Tamada T, Moriyasu F, Ono S, Shimizu K, Kajimura K, Soh Y, Kawasaki T, Kimura T, Yamashita Y, Someda H: Portal blood flow: measurement with MR imaging. Radiology173 :639 –644,1989
    OpenUrlPubMed
  18. ↵
    Nauck MA, Heimesaat MM, Behle K, Holst JJ, Nauck MS, Ritzel R, Hufner M, Schmiegel WH: Effects of glucagon-like peptide 1 on counterregulatory hormone responses, cognitive functions, and insulin secretion during hyperinsulinemic, stepped hypoglycemic clamp experiments in healthy volunteers. J Clin Endocrinol Metab87 :1239 –1246,2002
    OpenUrlCrossRefPubMedWeb of Science
  19. ↵
    Nakabayashi H, Nishizawa M, Nakagawa A, Takeda R, Niijima A: Vagal hepatopancreatic reflex effect evoked by intraportal appearance of tGLP-1. Am J Physiol271 :E803 –E813,1996
    OpenUrl
  20. ↵
    Jackson P, Pagliassotti M, Shiota M, Neal D, Cardin S, Cherrington A: Effects of vagal blockade on the counterregulatory response to insulin-induced hypoglycemia in the dog. Am J Physiol273 :E1178 –E1188,1997
    OpenUrlPubMed
PreviousNext
Back to top

In this Issue

January 2009, 58(1)
  • Table of Contents
  • 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.
Hypoglycemic Detection at the Portal Vein
(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
Hypoglycemic Detection at the Portal Vein
Casey M. Donovan, MaryAnn Bohland
Diabetes Jan 2009, 58 (1) 21-23; DOI: 10.2337/db08-1437

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

Hypoglycemic Detection at the Portal Vein
Casey M. Donovan, MaryAnn Bohland
Diabetes Jan 2009, 58 (1) 21-23; DOI: 10.2337/db08-1437
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

  • Staying Connected: Transcriptomics in the Search for Novel Diabetic Kidney Disease Treatments
  • Adipose Tissue Malfunction Drives Metabolic Dysfunction in Alström Syndrome
  • 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.