{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,24]],"date-time":"2026-08-24T14:19:31Z","timestamp":1787581171448,"version":"build-2736575974"},"reference-count":36,"publisher":"MDPI AG","issue":"17","license":[{"start":{"date-parts":[[2026,8,23]],"date-time":"2026-08-23T00:00:00Z","timestamp":1787443200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004281","name":"National Science Centre","doi-asserted-by":"publisher","award":["2021\/41\/B\/NZ5\/00446"],"award-info":[{"award-number":["2021\/41\/B\/NZ5\/00446"]}],"id":[{"id":"10.13039\/501100004281","id-type":"DOI","asserted-by":"publisher"}]},{"award":["2021\/41\/B\/NZ5\/00446"],"award-info":[{"award-number":["2021\/41\/B\/NZ5\/00446"]}],"id":[{"id":"https:\/\/ror.org\/03ha2q922","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Int. J. Mol. Sci.","IJMS"],"abstract":"<jats:p>LEAP2 is an endogenous antagonist and inverse agonist of GHSR-1a, the receptor for acyl-ghrelin. Although LEAP2 is increasingly recognized as a regulator of appetite and glucose homeostasis, its direct effects on pancreatic endocrine cells remain incompletely understood. The present in vitro study evaluated whether LEAP2 modulates insulin secretion and the expression of insulin-related genes in INS-1E beta cells and isolated rat pancreatic islets. LEAP2 treatment altered selected components of the insulin-related expression profile in a model- and time-dependent manner. In INS-1E cells, LEAP2 increased insulin protein expression after 6 h and IRSII protein expression after 24 h, whereas effects on mRNA expression were variable. In isolated rat islets, LEAP2 increased INS2 mRNA expression and decreased GHSR-1a and preproghrelin mRNA expression under the tested conditions. Acute exposure to 100 nM LEAP2 increased basal insulin release from both INS-1E cells and isolated islets. Immunofluorescence and Western blot analyses detected LEAP2- and GHSR-1a-related immunoreactivity in pancreatic models. LEAP2 did not adversely affect INS-1E cell metabolic activity, proliferation, or apoptosis. Overall, these data suggest that LEAP2 can modulate pancreatic endocrine cell function under in vitro conditions, but further studies using standard glucose-stimulated insulin secretion protocols and in vivo models are required to define its physiological relevance.<\/jats:p>","DOI":"10.3390\/ijms27177536","type":"journal-article","created":{"date-parts":[[2026,8,24]],"date-time":"2026-08-24T11:47:19Z","timestamp":1787572039000},"page":"7536","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["LEAP2 Regulates Insulin Secretion from INS-1E Beta Cells and Rat Pancreatic Islets: An In Vitro Study"],"prefix":"10.3390","volume":"27","author":[{"given":"Oskar","family":"Sosi\u0144ski","sequence":"first","affiliation":[{"name":"Department of Animal Physiology and Biochemistry, Poznan University of Life Sciences, Wolynska 35, 60-637 Poznan, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7182-6905","authenticated-orcid":false,"given":"Ewa","family":"Pruszy\u0144ska-Oszma\u0142ek","sequence":"additional","affiliation":[{"name":"Department of Animal Physiology and Biochemistry, Poznan University of Life Sciences, Wolynska 35, 60-637 Poznan, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maciej","family":"Sassek","sequence":"additional","affiliation":[{"name":"Department of Animal Physiology and Biochemistry, Poznan University of Life Sciences, Wolynska 35, 60-637 Poznan, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0081-7585","authenticated-orcid":false,"given":"Natalia","family":"Leciejewska","sequence":"additional","affiliation":[{"name":"Department of Animal Physiology and Biochemistry, Poznan University of Life Sciences, Wolynska 35, 60-637 Poznan, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3489-1684","authenticated-orcid":false,"given":"Piotr","family":"Pawlak","sequence":"additional","affiliation":[{"name":"Department of Genetics and Animal Breeding, Poznan University of Life Sciences, Wolynska 33, 60-637 Poznan, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0715-0223","authenticated-orcid":false,"given":"Pawe\u0142 Antoni","family":"Ko\u0142odziejski","sequence":"additional","affiliation":[{"name":"Department of Animal Physiology and Biochemistry, Poznan University of Life Sciences, Wolynska 35, 60-637 Poznan, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,8,23]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"143","DOI":"10.1110\/ps.0213603","article-title":"Isolation and Biochemical Characterization of LEAP-2, a Novel Blood Peptide Expressed in the Liver","volume":"12","author":"Krause","year":"2003","journal-title":"Protein Sci."},{"key":"ref_2","doi-asserted-by":"crossref","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":"ref_3","doi-asserted-by":"crossref","first-page":"24782","DOI":"10.1038\/s41598-024-74048-6","article-title":"Liver-Expressed Antimicrobial Peptide 2 Is a Hepatokine Regulated by Ghrelin, Nutrients, and Body Weight","volume":"14","author":"Islam","year":"2024","journal-title":"Sci. Rep."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"965","DOI":"10.1021\/acs.jmedchem.8b01644","article-title":"N-Terminal Liver-Expressed Antimicrobial Peptide 2 (LEAP2) Region Exhibits Inverse Agonist Activity toward the Ghrelin Receptor","volume":"62","author":"Cabral","year":"2019","journal-title":"J. Med. Chem."},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Mustaf\u00e1, E.R., Cordisco Gonz\u00e1lez, S., Damian, M., Cantel, S., Denoyelle, S., Wagner, R., Schi\u00f6th, H.B., Fehrentz, J.A., Ban\u00e8res, J.L., and Perell\u00f3, M. (2021). LEAP2 Impairs the Capability of the Growth Hormone Secretagogue Receptor to Regulate the Dopamine 2 Receptor Signaling. Front. Pharmacol., 12.","DOI":"10.3389\/fphar.2021.712437"},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Lugilde, J., Casado, S., Beiroa, D., Cu\u00f1arro, J., Garcia-Lavandeira, M., \u00c1lvarez, C.V., Nogueiras, R., Di\u00e9guez, C., and Tovar, S. (2022). LEAP-2 Counteracts Ghrelin-Induced Food Intake in a Nutrient Growth Hormone and Age Independent Manner. Cells, 11.","DOI":"10.3390\/cells11030324"},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Sosinski, O., Pruszynska-Oszmalek, E., Leciejewska, N., Sassek, M., and Kolodziejski, P.A. (2025). LEAP2 in Physiology\u2014A Narrative Review. Int. J. Mol. Sci., 26.","DOI":"10.3390\/ijms26010377"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"113573","DOI":"10.1016\/j.isci.2025.113573","article-title":"Ghrelin-GHSR-LEAP2 System in the Pathophysiology of Type 2 Diabetes","volume":"28","author":"Pu","year":"2025","journal-title":"iScience"},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Lu, X., Huang, L., Huang, Z., Feng, D., Clark, R.J., and Chen, C. (2021). LEAP-2: An Emerging Endogenous Ghrelin Receptor Antagonist in the Pathophysiology of Obesity. Front. Endocrinol., 12.","DOI":"10.3389\/fendo.2021.717544"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"135","DOI":"10.4161\/isl.2.3.11815","article-title":"Pancreatic Islet Plasticity: Interspecies Comparison of Islet Architecture and Composition","volume":"2","author":"Steiner","year":"2010","journal-title":"Islets"},{"key":"ref_11","first-page":"629","article-title":"An Immunocytochemical and Morphometric Study of the Rat Pancreatic Islets","volume":"186","author":"Elayat","year":"1995","journal-title":"J. Anat."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"167","DOI":"10.1210\/endo.130.1.1370150","article-title":"Establishment of 2-Mercaptoethanol-Dependent Differentiated Insulin-Secreting Cell Lines","volume":"130","author":"Asfari","year":"1992","journal-title":"Endocrinology"},{"key":"ref_13","doi-asserted-by":"crossref","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":"ref_14","doi-asserted-by":"crossref","first-page":"1332","DOI":"10.1111\/febs.14763","article-title":"Identifying the Binding Mechanism of LEAP2 to Receptor GHSR1a","volume":"286","author":"Wang","year":"2019","journal-title":"FEBS J."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"171227","DOI":"10.1016\/j.peptides.2024.171227","article-title":"Intestinal Expression Profiles and Hepatic Expression of LEAP2, Ghrelin and Their Common Receptor, GHSR, in Humans","volume":"177","author":"Englund","year":"2024","journal-title":"Peptides"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"2156","DOI":"10.1007\/s00125-016-4033-1","article-title":"Transcriptomic Profiling of Pancreatic Alpha, Beta and Delta Cell Populations Identifies Delta Cells as a Principal Target for Ghrelin in Mouse Islets","volume":"59","author":"Adriaenssens","year":"2016","journal-title":"Diabetologia"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"423","DOI":"10.2337\/db20-0231","article-title":"Acyl-Ghrelin Influences Pancreatic \u03b2-Cell Function by Interference with KATP Channels","volume":"70","author":"Kaiser","year":"2021","journal-title":"Diabetes"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1600","DOI":"10.1210\/me.2011-1001","article-title":"Ghrelin Directly Stimulates Glucagon Secretion from Pancreatic \u03b1-Cells","volume":"25","author":"Chuang","year":"2011","journal-title":"Mol. Endocrinol."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Pradhan, G., Wu, C.-S., Villarreal, D., Lee, J.H., Han, H.W., Gaharwar, A., Tian, Y., Fu, W., Guo, S., and Smith, R.G. (2021). \u03b2 Cell GHS-R Regulates Insulin Secretion and Sensitivity. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22083950"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"2266","DOI":"10.1097\/CM9.0000000000003215","article-title":"LEAP2 Ameliorates High Fat Diet-Impaired Glucose Tolerance and Enhances Glucose-Stimulated Insulin Secretion from \u03b2 Cells through PPAR\u03b3 Signal Pathway","volume":"137","author":"Li","year":"2024","journal-title":"Chin. Med. J."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"e126742","DOI":"10.1172\/jci.insight.126742","article-title":"\u03b2 Cell Tone Is Defined by Proglucagon Peptides through CAMP Signaling","volume":"4","author":"Capozzi","year":"2019","journal-title":"JCI Insight"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1843","DOI":"10.1007\/s00125-008-1103-z","article-title":"Insulin Secretion from Human Beta Cells Is Heterogeneous and Dependent on Cell-to-Cell Contacts","volume":"51","author":"Wojtusciszyn","year":"2008","journal-title":"Diabetologia"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"e240135","DOI":"10.1530\/JOE-24-0135","article-title":"The GHSR1a Antagonist LEAP2 Regulates Islet Hormone Release in a Sex-Specific Manner","volume":"263","author":"Hewawasam","year":"2024","journal-title":"J. Endocrinol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"E966","DOI":"10.1210\/clinem\/dgaa803","article-title":"Identification and Metabolic Profiling of a Novel Human Gut-Derived LEAP2 Fragment","volume":"106","author":"Hagemann","year":"2021","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"101950","DOI":"10.1016\/j.molmet.2024.101950","article-title":"A Long-Acting LEAP2 Analog Reduces Hepatic Steatosis and Inflammation and Causes Marked Weight Loss in Mice","volume":"84","author":"Shankar","year":"2024","journal-title":"Mol. Metab."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"375","DOI":"10.1111\/fcp.12722","article-title":"Liver-Expressed Antimicrobial Peptide 2 Antagonizes the Insulinostatic Effect of Ghrelin in Rat Isolated Pancreatic Islets","volume":"36","author":"Bayle","year":"2022","journal-title":"Fundam. Clin. Pharmacol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1751","DOI":"10.2337\/diabetes.49.11.1751","article-title":"Triggering and Amplifying Pathways of Regulation of Insulin Secretion by Glucose","volume":"49","author":"Henquin","year":"2000","journal-title":"Diabetes"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"128","DOI":"10.1016\/j.cellimm.2009.11.010","article-title":"Expression and Functional Analyses of Liver Expressed Antimicrobial Peptide-2 (LEAP-2) Variant Forms in Human Tissues","volume":"261","author":"Howard","year":"2010","journal-title":"Cell. Immunol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"195","DOI":"10.1016\/j.cyto.2011.04.002","article-title":"Differential Effects of Proinflammatory Cytokines on Cell Death and ER Stress in Insulin-Secreting INS1E Cells and the Involvement of Nitric Oxide","volume":"55","author":"Kacheva","year":"2011","journal-title":"Cytokine"},{"key":"ref_30","first-page":"99","article-title":"Adropin Suppresses Insulin Expression and Secretion in INS-1E Cells and Rat Pancreatic Islets","volume":"71","author":"Billert","year":"2020","journal-title":"J. Physiol. Pharmacol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"925","DOI":"10.2337\/db25-1132","article-title":"LEAP2 Reduces Ad Libitum Food Intake and Attenuates Postprandial Glucose Excursions in Men with Obesity","volume":"75","author":"Englund","year":"2026","journal-title":"Diabetes"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"64","DOI":"10.1007\/s00418-025-02391-4","article-title":"MOTS-c Modulates Pancreatic Islet Function in Rats and Pigs in Vitro","volume":"163","author":"Kolodziejski","year":"2025","journal-title":"Histochem. Cell Biol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"156","DOI":"10.1016\/0003-2697(87)90021-2","article-title":"Single-Step Method of RNA Isolation by Acid Guanidinium Thiocyanate-Phenol-Chloroform Extraction","volume":"162","author":"Chomczynski","year":"1987","journal-title":"Anal. Biochem."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"402","DOI":"10.1006\/meth.2001.1262","article-title":"Analysis of Relative Gene Expression Data Using Real-Time Quantitative PCR and the 2\u2212\u0394\u0394CT Method","volume":"25","author":"Livak","year":"2001","journal-title":"Methods"},{"key":"ref_35","first-page":"1228","article-title":"Spexin: A Novel Regulator of Adipogenesis and Fat Tissue Metabolism","volume":"1863","author":"Kolodziejski","year":"2018","journal-title":"Biochim. Biophys. Acta (BBA)-Mol. Cell Biol. Lipids"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"177","DOI":"10.1080\/19382014.2016.1251538","article-title":"Resistin Is Produced by Rat Pancreatic Islets and Regulates Insulin and Glucagon in Vitro Secretion","volume":"8","author":"Sassek","year":"2016","journal-title":"Islets"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/17\/7536\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,24]],"date-time":"2026-08-24T13:21:11Z","timestamp":1787577671000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/17\/7536"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,23]]},"references-count":36,"journal-issue":{"issue":"17","published-online":{"date-parts":[[2026,9]]}},"alternative-id":["ijms27177536"],"URL":"https:\/\/doi.org\/10.3390\/ijms27177536","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,23]]}}}