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This study examines how glucagon in the pancreatic microenvironment regulates pancreatic neuroendocrine tumour (pNET) cell features and metabolic remodelling under glucose presence versus absence. BON-1 and QGP-1 pNET cells and non-malignant α-TC1 cells show distinct responses to glucose deprivation. Glucagon modulates signalling, exometabolome profiles, metabolic gene expression, and glucose production, linking GCGR expression with malignancy and suggesting glucose-related therapeutic strategies.","Article  \nGlucagon and Glucose Availability Influence Metabolic Heterogeneity and Malignancy in Pancreatic Neuroendocrine Tumour (pNET) Cells: Novel Routes for Therapeutic Targeting  \nBárbara Ferreira 1,2, Isabel Lemos 1,2, Cindy Mendes 1,2, Beatriz Chumbinho 3, Fernanda Silva 1, Daniela Pereira 2, Emanuel Vigia 1,3, Luís G. Gonçalves 4, António Figueiredo 3, Daniela Cavaco 2 and Jacinta Serpa 1,2, *  \nAcademic Editors: Arduino  \nA. Mangoni, Jiuming He, Maria de Fátima Monginho Baltazar and Julieta Alexandra Pereira Afonso  \nReceived: 7 May 2025  \nRevised: 1 June 2025  \nAccepted: 18 June 2025  \nPublished: 25 June 2025  \nCitation: Ferreira, B.; Lemos, I.; Mendes, C.; Chumbinho, B.; Silva, F.; Pereira, D.; Vigia, E.; Gonçalves, L.G.; Figueiredo, A.; Cavaco, D.; et al. Glucagon and Glucose Availability Influence Metabolic Heterogeneity and Malignancy in Pancreatic Neuroendocrine Tumour (pNET) Cells: Novel Routes for Therapeutic Targeting. Molecules 2025, 30, 2736 . [https://doi.org/10.3390/](https://doi.org/10.3390/)[ ](https://doi.org/10.3390/)molecules30132736  \nCopyright: © 2025 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ([https://creativecommons.org/](https://creativecommons.org/)[ ](https://creativecommons.org/)[licenses/by/4.0/](licenses/by/4.0/)) .  \n1 iNOVA4Health, NOVA Medical School, Campo dos Mártires da Pátria, 130, 1169-056 Lisboa, Portugal; [a2021084@nms.unl.pt](a2021084@nms.unl.pt) (B.F.); [a2022507@nms.unl.pt](a2022507@nms.unl.pt) (I.L.); [cindy.mendes@nms.unl.pt](cindy.mendes@nms.unl.pt) (C.M.); [fernanda.silva@nms.unl.pt](fernanda.silva@nms.unl.pt) (F.S.); [emanuel.duarte@chlc.min-saude.pt](emanuel.duarte@chlc.min-saude.pt) (E.V.)  \n2 Portuguese Institute of Oncology of Lisbon Francisco Gentil (IPOLFG), Rua Prof Lima Basto, 1099-023 Lisboa, Portugal; [dcpereira@ipolisboa.min-saude.pt](dcpereira@ipolisboa.min-saude.pt) (D.P.); [daniela.rcavaco@gmail.com](daniela.rcavaco@gmail.com) (D.C.)  \n3 Universitary Center and Hospital of Central Lisbon, Hospital Curry Cabral, Rua da Beneficência, 1069-166 Lisboa, Portugal; [beatriz.chumbinho@gmail.com](beatriz.chumbinho@gmail.com) (B.C.); [antonio.figueiredo@chlc.min-saude.pt](antonio.figueiredo@chlc.min-saude.pt) (A.F.)  \n4 Institute of Chemical and Biological Tecnology António Xavier (ITQB NOVA), Avenida da República (EAN), 2780-157 Oeiras, Portugal; [lgafeira@itqb.unl.pt](lgafeira@itqb.unl.pt)  \n* [Correspondence: jacinta.serpa@nms.unl.pt](Correspondence: jacinta.serpa@nms.unl.pt)  \nAbstract  \nCancer metabolism is a hallmark of cancer. However, the impact of systemic metabolism and diet on tumour evolution is less understood. This study delves into the role of glucagon, as a component of the pancreatic microenvironment, in regulating features of pancreatic neuroendocrine tumour (pNET) cells and the metabolic remodelling occurring in the presence and absence of glucose. pNET cell lines (BON-1 and QGP-1) and the non-malignant pancreatic α-TC1 cell line were used as models. Results showed that pNET cells responded differently to glucose deprivation than α-TC1 cells. Specifically, pNET cells upregulated the GCGR in the absence of glucose, while α-TC1 cells did so in high-glucose conditions, allowing the glucagon-related pERK1/2 activation under these conditions in pNET cells. Glucagon enhanced cancerous features in pNET BON-1 cells under glucose-deprived and hyperglucagonemia-compatible concentrations. In the α-TC1 cell line, glucagon modulated cell features under high-glucose and physiological glucagon levels. NMR exometabolome analysis revealed differences in metabolic processes based on glucose availability and glucagon stimulation across cell lines, highlighting amino acid metabolism, glycolysis, and gluconeogenesis. The expression of metabolic genes was consistent with these findings. Interestingly, QGP-1 and α-TC1 cells produced ","cbCaiqoFucVAEc9b","https://ap.wps.com/l/cbCaiqoFucVAEc9b","pdf",6185723,32,"English","en",105,"# Abstract\n# Introduction","[{\"question\":\"How do pNET cells respond differently to glucose deprivation compared with non-malignant α-TC1 cells?\",\"answer\":\"pNET cells upregulate the glucagon receptor GCGR under glucose deprivation, while α-TC1 cells show this response in high-glucose conditions.\"},{\"question\":\"What role does glucagon play in malignancy-related features of pNET BON-1 cells?\",\"answer\":\"Glucagon enhances cancerous features in pNET BON-1 cells under glucose-deprived conditions and at hyperglucagonemia-compatible concentrations.\"},{\"question\":\"Which metabolic pathways were highlighted by NMR exometabolome analysis?\",\"answer\":\"NMR exometabolome analysis revealed differences in amino acid metabolism, glycolysis, and gluconeogenesis depending on glucose availability and glucagon stimulation.\"}]","Glucagon and Glucose Availability Influence Metabolic Heterogeneity and Malignancy in Pancreatic Neuroendocrine Tumour (pNET) Cells - Novel Routes for Therapeutic Targeting | PDF",1790183990,81,{"code":4,"msg":82,"data":83},"ok",{"site_id":75,"language":74,"slug":84,"title":65,"keywords":85,"description":66,"schema_data":86,"social_meta":140,"head_meta":142,"extra_data":144,"updated_unix":145},"glucagon-and-glucose-availability-influence-metabolic-heterogeneity-and-malignancy-in-pancreatic-neuroendocrine-tumour-pnet-cells-novel-routes-for-therapeutic-targeting","",{"@graph":87,"@context":139},[88,102,122],{"@type":89,"itemListElement":90},"BreadcrumbList",[91,95,97,100],{"item":92,"name":93,"@type":94,"position":8},"https://docshare.wps.com","Home","ListItem",{"item":96,"name":9,"@type":94,"position":14},"https://docshare.wps.com/document/",{"item":98,"name":35,"@type":94,"position":99},"https://docshare.wps.com/document/healthcare/",3,{"item":101,"name":65,"@type":94,"position":19},"https://docshare.wps.com/document/glucagon-and-glucose-availability-influence-metabolic-heterogeneity-and-malignancy-in-pancreatic-neuroendocrine-tumour-pnet-cells-novel-routes-for-therapeutic-targeting/369666/",{"url":101,"name":65,"@type":103,"image":104,"author":109,"headline":65,"publisher":111,"fileFormat":114,"inLanguage":74,"description":66,"dateModified":115,"datePublished":116,"encodingFormat":114,"isAccessibleForFree":117,"interactionStatistic":118},"DigitalDocument",{"url":105,"@type":106,"width":107,"height":108},"https://docshare.wps.com/thumbnails/glucagon-and-glucose-availability-influence-metabolic-heterogeneity-and-malignancy-in-pancreatic-neuroendocrine-tumour-pnet-cells-novel-routes-for-therapeutic-targeting/369666.png","ImageObject",300,407,{"name":63,"@type":110},"Person",{"url":92,"name":112,"@type":113},"DocShare","Organization","application/pdf","2026-10-24","2026-09-23",true,{"@type":119,"interactionType":120,"userInteractionCount":19},"InteractionCounter",{"@type":121},"ViewAction",{"@type":123,"mainEntity":124},"FAQPage",[125,131,135],{"name":126,"@type":127,"acceptedAnswer":128},"How do pNET cells respond differently to glucose deprivation compared with non-malignant α-TC1 cells?","Question",{"text":129,"@type":130},"pNET cells upregulate the glucagon receptor GCGR under glucose deprivation, while α-TC1 cells show this response in high-glucose conditions.","Answer",{"name":132,"@type":127,"acceptedAnswer":133},"What role does glucagon play in malignancy-related features of pNET BON-1 cells?",{"text":134,"@type":130},"Glucagon enhances cancerous features in pNET BON-1 cells under glucose-deprived conditions and at hyperglucagonemia-compatible concentrations.",{"name":136,"@type":127,"acceptedAnswer":137},"Which metabolic pathways were highlighted by NMR exometabolome analysis?",{"text":138,"@type":130},"NMR exometabolome analysis revealed differences in amino acid metabolism, glycolysis, and gluconeogenesis depending on glucose availability and glucagon stimulation.","https://schema.org",{"og:url":101,"og:type":141,"og:title":65,"og:site_name":112,"og:description":66},"article",{"robots":143,"canonical":101},"index,follow",{"doc_id":61,"site_id":75},1790398724]