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Cited by 8Liver physiology and pathologyDiabetes Treatment and ManagementPancreatic function and diabetes

Glucagon-like peptide-1 and glucagon-like peptide-2 regulation during human liver regeneration

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Ammann, Markus, Santol, Jonas, Pereyra, David, Kalchbrenner, Tamara, Wuerger, Tanja, Laengle, Johannes, Smoot, Rory L., Hulla, Wolfgang +2 more·2023·Scientific Reports
DOI 10.1038/s41598-023-43283-8PMC PMC10519971

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Abstract

Accumulating evidence suggests that metabolic demands of the regenerating liver are met via lipid metabolism and critical regulators of this process. As such, glucagon-like peptide-1 (GLP-1) and glucagon-like peptide-2 (GLP-2) critically affect hepatic regeneration in rodent models. The present study aimed to evaluate potential alterations and dynamics of circulating GLP-1 and GLP-2 in patients undergoing liver resections, focusing on post-hepatectomy liver failure (PHLF). GLP-1, GLP-2, Interleukin-6 (IL-6) and parameters of lipid metabolism were determined perioperatively in fasting plasma of 46 patients, who underwent liver resection. GLP-1 and GLP-2 demonstrated a rapid and consistently inverse time course during hepatic regeneration with a significant decrease of GLP-1 and increase of GLP-2 on POD1. Importantly, these postoperative dynamics were significantly more pronounced when PHLF occurred. Of note, the extent of resection or development of complications were not associated with these alterations. IL-6 mirrored the time course of GLP-2. Assessing the main degradation protein dipeptidyl peptidase 4 (DPP4) no significant association with either GLP-1 or -2 could be found. Additionally, in PHLF distinct postoperative declines in plasma lipid parameters were present and correlated with GLP-2 dynamics. Our data suggest dynamic inverse regulation of GLP-1 and GLP-2 during liver regeneration, rather caused by an increase in expression/release than by changes in degradation capacity and might be associated with inflammatory responses. Their close association with circulating markers of lipid metabolism and insufficient hepatic regeneration after liver surgery suggest a critical involvement during these processes in humans.

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Crossref · 10.1038/s41598-023-43283-8

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  • In Ammann et al. 2023, IL-6 levels rose early after both minor and major resections, but differences were driven by postoperative complications rather than resection extent.

    “Most recently, a 2023 prospective observational study by Ammann et al. (n = 46 minor and major liver resections) showed that IL-6 levels rose early after both minor and major resections, but differences were driven by postoperative complications rather than resection extent.”

    From The Role of Perioperative Interleukin-6 Serum Levels on Liver Dysfunction and Infectious Complications After Hepatectomy—A Systematic Review (2025) · cites this paper as [31]

    The Methods describe a prospective observational study of 46 patients undergoing minor or major liver resection. The Results report an early postoperative IL-6 increase and higher levels later in patients with post-hepatectomy liver failure (PHLF), with no disparity by resection extent after excluding PHLF and severe morbidity. The paper associates elevated IL-6 with impaired liver regeneration, but does not establish that postoperative complications generally drove the differences. (LLM, conf=0.84)

    Experimental — accuracy not yet measured

  • In Ammann et al., there was no difference in postoperative day 5 IL-6 levels between major and minor resections.

    “Resections were stratified by resection extent (major or minor per Brisbane 2000 criteria), with no difference in postoperative day 5 IL-6 levels between the two groups, indicating that the resection volume does not necessarily lead to sustained IL-6 levels after the immediate postoperative period [31].”

    From The Role of Perioperative Interleukin-6 Serum Levels on Liver Dysfunction and Infectious Complications After Hepatectomy—A Systematic Review (2025) · cites this paper as [31]

    The Results report no postoperative IL-6 difference by resection extent, which supports the major-versus-minor comparison at POD5. However, that analysis excluded patients with postoperative liver failure or morbidity ≥ 3; the citing sentence does not state this restriction and could be read as applying to all resections. (LLM, conf=0.84)

    Experimental — accuracy not yet measured

  • Impaired liver regeneration accounts for sustained IL-6 elevation.

    “After excluding cases with PHLF or major morbidity, no IL-6 differences between minor and major resections were observed, indicating that impaired liver regeneration accounts for sustained IL-6 elevation [31].”

    From The Role of Perioperative Interleukin-6 Serum Levels on Liver Dysfunction and Infectious Complications After Hepatectomy—A Systematic Review (2025) · cites this paper as [31]

    The Results subsection on postoperative GLP concentrations (page not supplied) reports that IL-6 remained elevated in patients with PHLF but declined in those without it. After excluding patients with PHLF or major morbidity, IL-6 did not differ by resection extent. The authors conclude that impaired regeneration is associated with elevated postoperative IL-6; they do not establish that it causes the sustained elevation. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • Resection volume does not necessarily lead to sustained IL-6 levels after the immediate postoperative period.

    “Resections were stratified by resection extent (major or minor per Brisbane 2000 criteria), with no difference in postoperative day 5 IL-6 levels between the two groups, indicating that the resection volume does not necessarily lead to sustained IL-6 levels after the immediate postoperative period [31].”

    From The Role of Perioperative Interleukin-6 Serum Levels on Liver Dysfunction and Infectious Complications After Hepatectomy—A Systematic Review (2025) · cites this paper as [31]

    The Methods section defines major and minor resections using Brisbane 2000 criteria. The Results report no difference in postoperative IL-6 by resection extent, but only after excluding patients with post-hepatectomy liver failure or severe morbidity. The citing sentence omits that restriction when describing the day-5 comparison. (LLM, conf=0.83)

    Experimental — accuracy not yet measured

  • This heterogeneity precluded a meta-analysis, specifically in relation to a specific cut-off for early postoperative IL-6 levels to predict ISGLS-CR-PHLF in pre-defined cohorts (e.g., minor versus major resections).

    “This precluded a meta-analysis, specifically in relation to a specific cut-off for early postoperative IL-6 levels to predict ISGLS-CR-PHLF in pre-defined cohorts (e.g., minor versus major resections) [31,40].”

    From The Role of Perioperative Interleukin-6 Serum Levels on Liver Dysfunction and Infectious Complications After Hepatectomy—A Systematic Review (2025) · cites this paper as [31]

    The Results report that early postoperative IL-6 did not differ by PHLF status, although levels diverged by postoperative day 5. The Methods use the ISGLS definition of PHLF, and the Discussion notes that no patients with minor resections developed PHLF. These findings are relevant to the proposed cohort distinction, but this paper does not establish an early IL-6 cut-off for clinically relevant PHLF or state that heterogeneity precluded a meta-analysis. (LLM, conf=0.78)

    Experimental — accuracy not yet measured

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Research works printed but not linked: 48

  1. [1]Sparrelid E Olthof PB Dasari BVM Erdmann JI Santol J Starlinger P Current evidence on posthepatectomy liver failure: Comprehensive review BJS Open 2022 6 6 142 PMC9681670 36415029
  2. [2]Huang J Rudnick DA Elucidating the metabolic regulation of liver regeneration Am. J. Pathol. 2014 184 2 309 321 24139945 PMC3906487
  3. [4]Crumm S Cofan M Juskeviciute E Hoek JB Adenine nucleotide changes in the remnant liver: An early signal for regeneration after partial hepatectomy Hepatology 2008 48 3 898 908 18697206 PMC3348855
  4. [5]Nauck MA Homberger E Siegel EG Allen RC Eaton RP Ebert R Incretin effects of increasing glucose loads in man calculated from venous insulin and C-peptide responses J. Clin. Endocrinol. Metab. 1986 63 2 492 498 3522621
  5. [6]Jeppesen PB Gilroy R Pertkiewicz M Allard JP Messing B O'Keefe SJ Randomised placebo-controlled trial of teduglutide in reducing parenteral nutrition and/or intravenous fluid requirements in patients with short bowel syndrome Gut 2011 60 7 902 914 21317170 PMC3112364
  6. [7]Taher J Baker C Alvares D Ijaz L Hussain M Adeli K GLP-2 dysregulates hepatic lipoprotein metabolism, inducing fatty liver and VLDL overproduction in male hamsters and mice Endocrinology 2018 159 9 3340 3350 30052880
  7. [8]Wong C Lee MH Yaow CYL Chin YH Goh XL Ng CH Glucagon-like peptide-1 receptor agonists for non-alcoholic fatty liver disease in type 2 diabetes: A meta-analysis Front. Endocrinol. 2021 12 609110 PMC8063104 33897616
  8. [9]Pi-Sunyer X Astrup A Fujioka K Greenway F Halpern A Krempf M A randomized, controlled trial of 3.0 mg of liraglutide in weight management N. Engl. J. Med. 2015 373 1 11 22 26132939
  9. [10]El-Jamal N Erdual E Neunlist M Koriche D Dubuquoy C Maggiotto F Glugacon-like peptide-2: Broad receptor expression, limited therapeutic effect on intestinal inflammation and novel role in liver regeneration Am. J. Physiol. Gastrointest. Liver Physiol. 2014 307 3 G274 G285 24875097
  10. [11]Fontana J Kucera O Mezera V Andel M Cervinkova Z Glucagon-like peptide-1 analogues exenatide and liraglutide exert inhibitory effect on the early phase of liver regeneration after partial hepatectomy in rats Physiol. Res. 2017 66 5 833 844 28730824
  11. [12]Drucker DJ Shi Q Crivici A Sumner-Smith M Tavares W Hill M Regulation of the biological activity of glucagon-like peptide 2 in vivo by dipeptidyl peptidase IV Nat. Biotechnol. 1997 15 7 673 677 9219272
  12. [13]Ellingsgaard H Seelig E Timper K Coslovsky M Soederlund L Lyngbaek MP GLP-1 secretion is regulated by IL-6 signalling: A randomised, placebo-controlled study Diabetologia 2020 63 2 362 373 31796986
  13. [14]Ipharraguerre IR Tedo G Menoyo D de Diego Cabero N Holst JJ Nofrarias M Bile acids induce glucagon-like peptide 2 secretion with limited effects on intestinal adaptation in early weaned pigs J. Nutr. 2013 143 12 1899 1905 24047704
  14. [15]Holst JJ The physiology of glucagon-like peptide 1 Physiol. Rev. 2007 87 4 1409 1439 17928588
  15. [16]Perl SH Bloch O Zelnic-Yuval D Love I Mendel-Cohen L Flor H Sepsis-induced activation of endogenous GLP-1 system is enhanced in type 2 diabetes Diabetes Metab. Res. Rev. 2018 34 4 e2982 29334697
  16. [17]Barchetta I Ceccarelli V Cimini FA Barone E Sentinelli F Coluzzi M Circulating dipeptidyl peptidase-4 is independently associated with the presence and severity of NAFLD/NASH in individuals with and without obesity and metabolic disease J Endocrinol. Invest. 2021 44 5 979 988 32852705 PMC8049937
  17. [18]Barchetta I Cimini FA Dule S Cavallo MG Dipeptidyl peptidase 4 (DPP4) as a novel adipokine: Role in metabolism and fat homeostasis Biomedicines 2022 10 9 2306 36140405 PMC9496088
  18. [19]Parker HE Wallis K le Roux CW Wong KY Reimann F Gribble FM Molecular mechanisms underlying bile acid-stimulated glucagon-like peptide-1 secretion Br. J. Pharmacol. 2012 165 2 414 423 21718300 PMC3268195
  19. [20]Fan M Wang X Xu G Yan Q Huang W Bile acid signaling and liver regeneration Biochim. Biophys. Acta 2015 1849 2 196 200 24878541 PMC4246016
  20. [21]Panzitt K Wagner M FXR in liver physiology: Multiple faces to regulate liver metabolism Biochim. Biophys. Acta Mol. Basis Di.s 2021 1867 7 166133 33771667
  21. [22]Lim DW Wales PW Mi S Yap JY Curtis JM Mager DR Glucagon-like peptide-2 alters bile acid metabolism in parenteral nutrition-associated liver disease JPEN J Parenter. Enteral Nutr. 2016 40 1 22 35 26220199
  22. [23]Green RM Gollan JL Hagenbuch B Meier PJ Beier DR Regulation of hepatocyte bile salt transporters during hepatic regeneration Am. J. Physiol. 1997 273 3 Pt 1 G621 G627 9316464
  23. [24]Ellingsgaard H Hauselmann I Schuler B Habib AM Baggio LL Meier DT Interleukin-6 enhances insulin secretion by increasing glucagon-like peptide-1 secretion from L cells and alpha cells Nat. Med. 2011 17 11 1481 1489 22037645 PMC4286294
  24. [25]Kang LI Mars WM Michalopoulos GK Signals and cells involved in regulating liver regeneration Cells 2012 1 4 1261 1292 24710554 PMC3901148
  25. [26]Kishimoto T IL-6: from its discovery to clinical applications Int. Immunol. 2010 22 5 347 352 20410258
  26. [27]Taub R Liver regeneration: From myth to mechanism Nat. Rev. Mol. Cell Biol. 2004 5 10 836 847 15459664
  27. [29]Lebrun LJ Lenaerts K Kiers D de Barros JP Le Guern N Plesnik J Enteroendocrine L cells sense LPS after gut barrier injury to enhance GLP-1 secretion Cell Rep. 2017 21 5 1160 1168 29091756
  28. [30]Kouris GJ Liu Q Rossi H Djuricin G Gattuso P Nathan C The effect of glucagon-like peptide 2 on intestinal permeability and bacterial translocation in acute necrotizing pancreatitis Am. J. Surg. 2001 181 6 571 575 11513789
  29. [31]Hein GJ Baker C Hsieh J Farr S Adeli K GLP-1 and GLP-2 as yin and yang of intestinal lipoprotein production: evidence for predominance of GLP-2-stimulated postprandial lipemia in normal and insulin-resistant states Diabetes 2013 62 2 373 381 23028139 PMC3554391
  30. [32]Koehler JA Kain T Drucker DJ Glucagon-like peptide-1 receptor activation inhibits growth and augments apoptosis in murine CT26 colon cancer cells Endocrinology 2011 152 9 3362 3372 21771884
  31. [33]Hsieh J Longuet C Maida A Bahrami J Xu E Baker CL Glucagon-like peptide-2 increases intestinal lipid absorption and chylomicron production via CD36 Gastroenterology 2009 137 3 997 1005 19482026
  32. [34]Dash S Xiao C Morgantini C Connelly PW Patterson BW Lewis GF Glucagon-like peptide-2 regulates release of chylomicrons from the intestine Gastroenterology 2014 147 6 1275 1284 25173752 PMC4316201
  33. [36]Ejarque M Sabadell-Basallote J Beiroa D Calvo E Keiran N Nunez-Roa C Adipose tissue is a key organ for the beneficial effects of GLP-2 metabolic function Br. J. Pharmacol. 2021 178 10 2131 2145 32986861
  34. [37]Ioannidis JPA The proposal to lower p value thresholds to.005 JAMA 2018 319 14 1429 1430 29566133
  35. [38]Li Y Glotfelty EJ Karlsson T Fortuno LV Harvey BK Greig NH The metabolite GLP-1 (9–36) is neuroprotective and anti-inflammatory in cellular models of neurodegeneration J. Neurochem. 2021 159 5 867 886 34569615 PMC8627453
  36. [39]Thulesen J Knudsen LB Hartmann B Hastrup S Kissow H Jeppesen PB The truncated metabolite GLP-2 (3–33) interacts with the GLP-2 receptor as a partial agonist Regul. Pept. 2002 103 1 9 15 11738243
  37. [40]Psichas A Larraufie PF Goldspink DA Gribble FM Reimann F Chylomicrons stimulate incretin secretion in mouse and human cells Diabetologia 2017 60 12 2475 2485 28866808 PMC5850988
  38. [41]Guan X Stoll B Lu X Tappenden KA Holst JJ Hartmann B GLP-2-mediated up-regulation of intestinal blood flow and glucose uptake is nitric oxide-dependent in TPN-fed piglets 1 Gastroenterology 2003 125 1 136 147 12851879
  39. [42]Xie S Liu B Fu S Wang W Yin Y Li N GLP-2 suppresses LPS-induced inflammation in macrophages by inhibiting ERK phosphorylation and NF-kappaB activation Cell Physiol. Biochem. 2014 34 2 590 602 25116357
  40. [43]Strasberg SM Nomenclature of hepatic anatomy and resections: A review of the Brisbane 2000 system J Hepatobiliary Pancreat Surg 2005 12 5 351 355 16258801
  41. [44]Rahbari NN Garden OJ Padbury R Brooke-Smith M Crawford M Adam R Posthepatectomy liver failure: A definition and grading by the international study group of liver surgery (ISGLS) Surgery 2011 149 5 713 724 21236455
  42. [45]Dindo D Demartines N Clavien PA Classification of surgical complications: A new proposal with evaluation in a cohort of 6336 patients and results of a survey Ann. Surg. 2004 240 2 205 213 15273542 PMC1360123
  43. [46]Ryskjaer J Deacon CF Carr RD Krarup T Madsbad S Holst J Plasma dipeptidyl peptidase-IV activity in patients with type-2 diabetes mellitus correlates positively with HbAlc levels, but is not acutely affected by food intake Eur. J. Endocrinol. 2006 155 3 485 493 16914604
  44. [47]Starlinger P Haegele S Wanek D Zikeli S Schauer D Alidzanovic L Plasma thrombospondin 1 as a predictor of postoperative liver dysfunction Br. J. Surg. 2015 102 7 826 836 25871570
  45. [48]Brunt EM Janney CG Di Bisceglie AM Neuschwander-Tetri BA Bacon BR Nonalcoholic steatohepatitis: A proposal for grading and staging the histological lesions Am. J. Gastroenterol. 1999 94 9 2467 2474 10484010
  46. [49]Rinella ME Lazarus JV Ratziu V Francque SM Sanyal AJ Kanwal F A multi-society Delphi consensus statement on new fatty liver disease nomenclature Hepatology 2023 10.1097/HEP.0000000000000520 37983810 · DOI · Paper page
  47. [50]Kleiner DE Brunt EM Van Natta M Behling C Contos MJ Cummings OW Design and validation of a histological scoring system for nonalcoholic fatty liver disease Hepatology 2005 41 6 1313 1321 15915461
  48. [51]Bedossa P Poynard T An algorithm for the grading of activity in chronic hepatitis C. The METAVIR Cooperative Study Group Hepatology 1996 24 2 289 293 8690394

Cited by

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Authors
Ammann, M., Santol, J., Pereyra, D., Kalchbrenner, T., Wuerger, T., Laengle, J., Smoot, R. L., Hulla, W., Laengle, F., & Starlinger, P.
Affiliations
  • Medical University of Vienna (AT)
  • Sigmund Freud Privatuniversität Wien (AT)
  • Mayo Clinic (US)
Corresponding author
Starlinger, Patrick
ORCID
Venue
Scientific Reports
Publisher
Springer Science and Business Media LLC
Published
2023-09-25
Volume
13
Issue
1
Pages
15980-15980
ISSN
2045-2322 (ISSN-L)
DOI
10.1038/s41598-023-43283-8
PMC
PMC10519971
OpenAlex
W4387019476
Cited by
8
References
3
Citations by year
2026: 3 · 2025: 4 · 2024: 1
FWCI
1.34
Type
journal article
Language
en
Open access
Licence
Locations
  • Scientific Reports (publishedVersion, cc-by)
  • Research Square (acceptedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Topics
  • Health Sciences › Medicine › Hepatology › Liver physiology and pathology
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
  • Health Sciences › Medicine › Surgery › Pancreatic function and diabetes
Keywords
glucagon-like peptide-1, glucagon-like peptide-2, liver regeneration, hepatectomy, post-hepatectomy liver failure, interleukin-6, lipid metabolism, dipeptidyl peptidase IV, inflammation, plasma biomarkers
MeSH terms
Hepatectomy, Humans, Liver Regeneration, Interleukin-6, Liver Failure, Hepatic Insufficiency, Glucagon-Like Peptide 1, Glucagon-Like Peptide 2

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