{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,12]],"date-time":"2026-06-12T15:34:52Z","timestamp":1781278492051,"version":"3.54.1"},"reference-count":48,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,12,19]],"date-time":"2025-12-19T00:00:00Z","timestamp":1766102400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Endocrinol."],"abstract":"<jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>Most patients with insulinoma are overweight or obese. Ghrelin levels in insulinoma have been linked to both obesity and hyperinsulinemia. Liver-expressed antimicrobial peptide 2 (LEAP2), a novel hormone and endogenous antagonist of the ghrelin receptor, is associated with obesity; however, its relationship with obesity and hyperinsulinemia in insulinoma, and its expression within tumor tissue, remains unknown.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Serum LEAP2, insulin, and ghrelin levels were measured by ELISA in patients with insulinoma and in age-, sex-, and BMI-matched controls. LEAP2 expression was examined in insulinoma tissue and paired adjacent pancreatic specimens by immunohistochemical staining.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Serum LEAP2 levels were significantly higher in patients with insulinoma than in controls (P = 0.028) and positively correlated with serum insulin levels (r = 0.408, P &amp;lt; 0.001) while negatively correlated with ghrelin levels (r = \u22120.551, P &amp;lt; 0.01). In controls, serum LEAP2 levels were significantly associated with BMI (P = 0.047), whereas in patients, the correlation did not reach statistical significance (P = 0.067). Immunostaining showed that LEAP2 peptide was expressed in insulinoma tissue.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Serum LEAP2 levels are elevated in insulinoma and correlate with hyperinsulinemia and BMI. LEAP2 is expressed in insulinoma tissue, suggesting a potential role in the metabolic profile of these patients.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fendo.2025.1685806","type":"journal-article","created":{"date-parts":[[2025,12,19]],"date-time":"2025-12-19T05:17:13Z","timestamp":1766121433000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["Elevated blood levels of liver-expressed antimicrobial peptide 2 in patients with insulinoma and its expression in insulinomas"],"prefix":"10.3389","volume":"16","author":[{"given":"Jia-Lei","family":"Zhang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"An-Li","family":"Tong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yun-Lu","family":"Feng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Da-Chun","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ling","family":"Zhong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yin-Jie","family":"Gao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu-Li","family":"Song","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tai-Ping","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ming","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuan-Jia","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2025,12,19]]},"reference":[{"key":"B1","unstructured":"Obesity and Overweight"},{"key":"B2","doi-asserted-by":"publisher","first-page":"e2124750","DOI":"10.1001\/jamanetworkopen.2021.24750","article-title":"Epidemiologic trends of and factors associated with overall survival for patients with gastroenteropancreatic neuroendocrine tumors in the United States","volume":"4","author":"Xu","year":"2021","journal-title":"JAMA Netw Open"},{"key":"B3","doi-asserted-by":"publisher","first-page":"e2515798","DOI":"10.1001\/jamanetworkopen.2025.15798","article-title":"Epidemiology of neuroendocrine neoplasms in the US","volume":"8","author":"Dasari","year":"2025","journal-title":"JAMA Netw Open"},{"key":"B4","doi-asserted-by":"publisher","first-page":"e13343","DOI":"10.1111\/jne.13343","article-title":"European Neuroendocrine Tumour Society (ENETS) 2023 guidance paper for nonfunctioning pancreatic neuroendocrine tumours","volume":"35","author":"Kos\u2013Kud\u0142a","year":"2023","journal-title":"J Neuroendocrinol"},{"key":"B5","doi-asserted-by":"publisher","first-page":"303","DOI":"10.3390\/biomedicines11020303","article-title":"An insight on functioning pancreatic neuroendocrine neoplasms","volume":"11","author":"Bevere","year":"2023","journal-title":"Biomedicines"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1016\/j.eprac.2021.02.016","article-title":"Mutation and expression of gene YY1 in pancreatic neuroendocrine tumors and its clinical significance","volume":"27","author":"Song","year":"2021","journal-title":"Endocrine Pract"},{"key":"B7","doi-asserted-by":"publisher","first-page":"48","DOI":"10.1097\/MPA.0000000000000718","article-title":"A clinicopathological study of Malignant insulinoma in a contemporary series","volume":"46","author":"Yu","year":"2017","journal-title":"Pancreas"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.18632\/oncotarget.17599","article-title":"A nation\u2013wide retrospective epidemiological study of gastroenteropancreatic neuroendocrine neoplasms in China","volume":"8","author":"Fan","year":"2017","journal-title":"Oncotarget"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1016\/j.suc.2009.06.009","article-title":"Insulinoma","volume":"89","author":"Mathur","year":"2009","journal-title":"Surg Clinics North America"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1007\/s12020-020-02233-4","article-title":"Plasma levels of acylated ghrelin in patients with insulinoma and expression of ghrelin and its receptor in insulinomas","volume":"68","author":"Wu","year":"2020","journal-title":"Endocrine"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2003-031118","article-title":"Elevated fasting plasma ghrelin in prader\u2013willi syndrome adults is not solely explained by their reduced visceral adiposity and insulin resistance","volume":"89","author":"Goldstone","year":"2004","journal-title":"J Clin Endocrinol Metab"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1038\/45230","article-title":"Ghrelin is a growth\u2013hormone\u2013releasing acylated peptide from stomach","volume":"402","author":"Kojima","year":"1999","journal-title":"Nature"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1016\/j.molmet.2015.03.005","article-title":"Ghrelin","volume":"4","author":"M\u00fcller","year":"2015","journal-title":"Mol Metab"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1038\/s42255-024-00995-z","article-title":"Gastric mechanosensitive channel Piezo1 regulates ghrelin production and food intake","volume":"6","author":"Zhao","year":"2024","journal-title":"Nat Metab"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1210\/er.2002-0029","article-title":"Biological, physiological, pathophysiological, and pharmacological aspects of ghrelin","volume":"25","author":"van der Lely","year":"2004","journal-title":"Endocrine Rev"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1530\/EC-17-0212","article-title":"Ghrelin stimulation by hypothalamic\u2013pituitary\u2013adrenal axis activation depends on increasing cortisol levels","volume":"6","author":"Azzam","year":"2017","journal-title":"Endocrine Connect"},{"key":"B17","doi-asserted-by":"publisher","first-page":"13","DOI":"10.1530\/JOE-19-0102","article-title":"Liver\u2013expressed antimicrobial peptide 2 antagonizes the effect of ghrelin in rodents","volume":"244","author":"Islam","year":"2020","journal-title":"J Endocrinol"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1016\/j.molmet.2016.04.007","article-title":"Comprehensive alpha, beta and delta cell transcriptomes reveal that ghrelin selectively activates delta cells and promotes somatostatin release from pancreatic islets","volume":"5","author":"DiGruccio","year":"2016","journal-title":"Mol Metab"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1016\/j.peptides.2011.10.006","article-title":"Ghrelin in neuroendocrine tumors","volume":"32","author":"Vu","year":"2011","journal-title":"Peptides"},{"key":"B20","doi-asserted-by":"publisher","first-page":"461","DOI":"10.1016\/j.cmet.2017.10.016","article-title":"LEAP2 is an endogenous antagonist of the ghrelin receptor","volume":"27","author":"Ge","year":"2018","journal-title":"Cell Metab"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1172\/JCI125332","article-title":"LEAP2 changes with body mass and food intake in humans and mice","volume":"129","author":"Mani","year":"2019","journal-title":"J Clin Invest"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.3389\/fendo.2021.717544","article-title":"LEAP\u20132: an emerging endogenous ghrelin receptor antagonist in the pathophysiology of obesity","volume":"12","author":"Lu","year":"2021","journal-title":"Front Endocrinol"},{"key":"B23","doi-asserted-by":"publisher","first-page":"100582","DOI":"10.1016\/j.xcrm.2022.100582","article-title":"LEAP2 reduces postprandial glucose excursions and ad libitum food intake in healthy men","volume":"3","author":"Hagemann","year":"2022","journal-title":"Cell Rep Med"},{"key":"B24","doi-asserted-by":"publisher","first-page":"bvad061","DOI":"10.1210\/jendso\/bvad061","article-title":"Postprandial increases in liver\u2013gut hormone LEAP2 correlate with attenuated eating behavior in adults without obesity","volume":"7","author":"Bhargava","year":"2023","journal-title":"J Endocrine Soc"},{"key":"B25","doi-asserted-by":"publisher","first-page":"bqac038","DOI":"10.1210\/endocr\/bqac038","article-title":"Beta\u2013hydroxybutyrate suppresses hepatic production of the ghrelin receptor antagonist LEAP2","volume":"163","author":"Holm","year":"2022","journal-title":"Endocrinology"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1210\/clinem\/dgaa803","article-title":"Identification and metabolic profiling of a novel human gut\u2013derived LEAP2 fragment","volume":"106","author":"Hagemann","year":"2021","journal-title":"J Clin Endocrinol Metab"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2013-2874","article-title":"\u03b1\u2013Internexin: a novel biomarker for pancreatic neuroendocrine tumor aggressiveness","volume":"99","author":"Liu","year":"2014","journal-title":"J Clin Endocrinol Metab"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1007\/s12020-023-03546-w","article-title":"SQSTM1\/p62 is a prognostic molecular marker and potential therapeutic target for pancreatic neuroendocrine tumours","volume":"85","author":"Song","year":"2024","journal-title":"Endocrine"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1007\/s12022-022-09708-2","article-title":"Overview of the 2022 WHO classification of neuroendocrine neoplasms","volume":"33","author":"Rindi","year":"2022","journal-title":"Endocrine Pathol"},{"key":"B30","article-title":"Development and preliminary application of enzyme\u2013linked immunosorbent assay for human net insulin in serum","volume":"13","author":"Li","year":"1997","journal-title":"Chin J Endocrinol Metab"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1530\/EC-16-0021","article-title":"Plasma acylated and plasma unacylated ghrelin: useful new biomarkers in patients with neuroendocrine tumors","volume":"5","author":"van Adrichem","year":"2016","journal-title":"Endocrine Connect"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.3389\/fendo.2020.563267","article-title":"Interplay between diabetes and pancreatic ductal adenocarcinoma and insulinoma: the role of aging, genetic factors, and obesity","volume":"11","author":"Duvilli\u00e9","year":"2020","journal-title":"Front Endocrinol"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2002-021450","article-title":"Modulation of hunger by plasma glucose and metformin","volume":"88","author":"Schultes","year":"2003","journal-title":"J Clin Endocrinol Metab"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1080\/00365521.2017.1335768","article-title":"Surgery in overweight patients with insulinoma: effects on weight loss","volume":"52","author":"Dai","year":"2017","journal-title":"Scand J Gastroenterol"},{"key":"B35","doi-asserted-by":"publisher","first-page":"101996","DOI":"10.1016\/j.xcrm.2025.101996","article-title":"Regulation of LEAP2 by insulin and glucagon in mice and humans","volume":"6","author":"Johansen","year":"2025","journal-title":"Cell Rep Med"},{"key":"B36","doi-asserted-by":"publisher","first-page":"102615","DOI":"10.1016\/j.pneurobio.2024.102615","article-title":"Decoding the influence of central LEAP2 on food intake and its effect on accumbal dopamine release","volume":"236","author":"Tufvesson\u2013Alm","year":"2024","journal-title":"Prog Neurobiol"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1016\/j.febslet.2010.02.069","article-title":"Ghrelin inhibits insulin secretion through the AMPK\u2013UCP2 pathway in beta cells","volume":"584","author":"Wang","year":"2010","journal-title":"FEBS Lett"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.17925\/EE.2015.11.02.90","article-title":"Ghrelin \u2013 physiological functions and regulation","volume":"11","author":"Ibrahim Abdalla","year":"2015","journal-title":"Eur Endocrinol"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1111\/dom.12344","article-title":"Ghrelin signalling in \u03b2\u2013cells regulates insulin secretion and blood glucose","author":"Yada","year":"2014","journal-title":"Diabetes Obes Metab"},{"key":"B40","doi-asserted-by":"publisher","first-page":"110835","DOI":"10.1016\/j.mce.2020.110835","article-title":"Ghrelin suppresses insulin secretion in human islets and type 2 diabetes patients have diminished islet ghrelin cell number and lower plasma ghrelin levels","volume":"511","author":"Lindqvist","year":"2020","journal-title":"Mol Cell Endocrinol"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.33549\/physiolres.935189","article-title":"High\u2013fat diet induces resistance to ghrelin and LEAP2 peptide analogs in mice","volume":"72","author":"Hol\u00e1","year":"2023","journal-title":"Physiol Res"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.1038\/s41575-019-0224-9","article-title":"LEAP2: A novel regulator of food intake and body weight","volume":"16","author":"Schalla","year":"2019","journal-title":"Nat Rev Gastroenterol Hepatol"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2265.2006.02695.x","article-title":"Co\u2013expression of ghrelin and its receptor in pancreatic endocrine tumours","volume":"66","author":"Ekeblad","year":"2007","journal-title":"Clin Endocrinol"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.1210\/jcem.87.3.8279","article-title":"Expression of ghrelin and of the GH secretagogue receptor by pancreatic islet cells and related endocrine tumors","volume":"87","author":"Volante","year":"2002","journal-title":"J Clin Endocrinol Metab"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.1530\/JME-13-0122","article-title":"The islet ghrelin cell","volume":"52","author":"Wierup","year":"2014","journal-title":"J Mol Endocrinol"},{"key":"B46","doi-asserted-by":"publisher","first-page":"4","DOI":"10.2337\/db11-1483","article-title":"Banting lecture 2011: hyperinsulinemia: cause or consequence","volume":"61","author":"Corkey","year":"2012","journal-title":"Diabetes"},{"key":"B47","doi-asserted-by":"publisher","DOI":"10.1530\/JOE-24-0135","article-title":"The GHSR1a antagonist LEAP2 regulates islet hormone release in a sex\u2013specific manner","volume":"263","author":"Hewawasam","year":"2024","journal-title":"J Endocrinol"},{"key":"B48","doi-asserted-by":"publisher","DOI":"10.1097\/CM9.0000000000003215","article-title":"LEAP2 ameliorates high fat diet\u2013impaired glucose tolerance and enhances glucose\u2013stimulated insulin secretion from \u03b2 cells through PPAR\u03b3 signal pathway","volume":"137","author":"Li","year":"2024","journal-title":"Chin Med J. (Engl)"}],"container-title":["Frontiers in Endocrinology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fendo.2025.1685806\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,12,19]],"date-time":"2025-12-19T05:17:15Z","timestamp":1766121435000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fendo.2025.1685806\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,12,19]]},"references-count":48,"alternative-id":["10.3389\/fendo.2025.1685806"],"URL":"https:\/\/doi.org\/10.3389\/fendo.2025.1685806","relation":{},"ISSN":["1664-2392"],"issn-type":[{"value":"1664-2392","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,12,19]]},"article-number":"1685806"}}