{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,19]],"date-time":"2026-10-19T21:06:53Z","timestamp":1792444013436,"version":"4.5.0"},"reference-count":52,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2025,3,15]],"date-time":"2025-03-15T00:00:00Z","timestamp":1741996800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Research Council of Lithuania","award":["S-MIP-22-37"],"award-info":[{"award-number":["S-MIP-22-37"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Medicina"],"abstract":"<jats:p>Background and Objectives: Neuropeptide Y (NPY) family peptides and dipeptidyl peptidase-4 (DPP-4) are involved in gastrointestinal regulation and may contribute to obesity and type 2 diabetes mellitus (T2DM) pathophysiology. This study investigates their expression in jejunal muscular tissue and associations with gastrointestinal symptoms in patients with obesity, with (OB+\/DM+) and without T2DM (OB+\/DM\u2212). Materials and Methods: This cross-sectional study includes forty-four patients undergoing laparoscopic Roux-en-Y gastric bypass divided based on T2DM status. Gastrointestinal symptoms were assessed using the Gastrointestinal Symptom Rating Scale (GSRS) questionnaire, and jejunal tissue samples were analyzed for DPP-4, NPY, peptide YY (PYY), and pancreatic polypeptide (PP) mRNA and protein levels. Results: DPP-4, NPY, PYY, and PP gene expression in jejunal muscular tissue was similar between groups. In the OB+\/DM+ group, PP protein was higher, while DPP-4 and PYY were lower compared to the OB+\/DM\u2212 group. Significant positive correlations between DPP-4 and NPY, PYY, and PP were found in the OB+\/DM\u2212 group, while only DPP-4 and PYY correlated in the OB+\/DM+ group. Gastrointestinal symptoms in the OB+\/DM\u2212 group showed positive correlations with PP (abdominal pain), DPP-4 (indigestion), and NPY (constipation). Conclusions: The study demonstrates significant differences in DPP-4, PYY, and PP protein expression between patients with obesity, with or without T2DM. Peptide correlations with gastrointestinal symptoms in non-diabetic patients suggest distinct regulatory mechanisms, warranting further research.<\/jats:p>","DOI":"10.3390\/medicina61030504","type":"journal-article","created":{"date-parts":[[2025,3,17]],"date-time":"2025-03-17T08:57:02Z","timestamp":1742201822000},"page":"504","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Role of DPP-4 and NPY Family Peptides in Gastrointestinal Symptoms Associated with Obesity and Type 2 Diabetes Mellitus"],"prefix":"10.3390","volume":"61","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9879-3130","authenticated-orcid":false,"given":"Mantas","family":"Malinauskas","sequence":"first","affiliation":[{"name":"Institute of Physiology and Pharmacology, Lithuanian University of Health Sciences, 44307 Kaunas, Lithuania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Deimante","family":"Paskeviciene","sequence":"additional","affiliation":[{"name":"Institute of Endocrinology, Medical Academy, Lithuanian University of Health Sciences, 50161 Kaunas, Lithuania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"R\u016bta","family":"Steponaitien\u0117","sequence":"additional","affiliation":[{"name":"Institute for Digestive Research, Lithuanian University of Health Sciences, 50161 Kaunas, Lithuania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7489-8069","authenticated-orcid":false,"given":"Rita","family":"Gudaityte","sequence":"additional","affiliation":[{"name":"Department of Surgery, Lithuanian University of Health Sciences, 50161 Kaunas, Lithuania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8689-9023","authenticated-orcid":false,"given":"Limas","family":"Kup\u010dinskas","sequence":"additional","affiliation":[{"name":"Institute for Digestive Research, Lithuanian University of Health Sciences, 50161 Kaunas, Lithuania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7514-7435","authenticated-orcid":false,"given":"Anna","family":"Casselbrant","sequence":"additional","affiliation":[{"name":"Department of Surgery, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, 413 45 Goteborg, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Almantas","family":"Maleckas","sequence":"additional","affiliation":[{"name":"Department of Surgery, Lithuanian University of Health Sciences, 50161 Kaunas, Lithuania"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,3,15]]},"reference":[{"key":"ref_1","unstructured":"(2025, March 02). Obesity Atlas 2024|World Obesity Federation Global Obesity Observatory. Available online: https:\/\/data.worldobesity.org\/publications\/?cat=22."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1016\/j.cmet.2021.12.012","article-title":"Why does obesity cause diabetes?","volume":"34","author":"Klein","year":"2022","journal-title":"Cell Metab."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1150","DOI":"10.1093\/aje\/kwh167","article-title":"Changes in body weight and body fat distribution as risk factors for clinical diabetes in US men","volume":"159","author":"Wang","year":"2004","journal-title":"Am. J. Epidemiol."},{"key":"ref_4","first-page":"421","article-title":"Medical Costs Associated with Type 2 Diabetes Complications and Comorbidities","volume":"19","author":"Li","year":"2013","journal-title":"Am. J. Manag. Care"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"627","DOI":"10.2337\/dc17-1536","article-title":"Gastrointestinal Symptoms in Diabetes: Prevalence, Assessment, Pathogenesis, and Management","volume":"41","author":"Du","year":"2018","journal-title":"Diabetes Care"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1111\/j.1572-0241.2001.03350.x","article-title":"Impact of chronic gastrointestinal symptoms in diabetes mellitus on health-related quality of life","volume":"96","author":"Talley","year":"2001","journal-title":"Am. J. Gastroenterol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"611","DOI":"10.1111\/nmo.12330","article-title":"Diabetic gastrointestinal motility disorders and the role of enteric nervous system: Current status and future directions","volume":"26","author":"Yarandi","year":"2014","journal-title":"Neurogastroenterol. Motil."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"e13846","DOI":"10.1111\/eci.13846","article-title":"Novel insights into the pathogenic impact of diabetes on the gastrointestinal tract","volume":"52","author":"Portincasa","year":"2022","journal-title":"Eur. J. Clin. Investig."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1097\/MED.0000000000000859","article-title":"Gut hormones and appetite regulation","volume":"31","author":"Hong","year":"2024","journal-title":"Curr. Opin. Endocrinol. Diabetes Obes."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"928","DOI":"10.1016\/j.coph.2013.09.002","article-title":"Gut motility and enteroendocrine secretion","volume":"13","author":"Wu","year":"2013","journal-title":"Curr. Opin. Pharmacol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"76","DOI":"10.1016\/j.autneu.2006.10.005","article-title":"Neuropeptide Y receptors, antisecretory control of intestinal epithelial function","volume":"133","author":"Cox","year":"2007","journal-title":"Auton. Neurosci."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"261","DOI":"10.1016\/j.npep.2012.08.005","article-title":"Neuropeptide Y, peptide YY and pancreatic polypeptide in the gut-brain axis","volume":"46","author":"Holzer","year":"2012","journal-title":"Neuropeptides"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"101973","DOI":"10.1016\/j.npep.2019.101973","article-title":"Possible role of peptide YY (PYY) in the pathophysiology of irritable bowel syndrome (IBS)","volume":"79","author":"Hatlebakk","year":"2020","journal-title":"Neuropeptides"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"137","DOI":"10.1016\/j.npep.2015.09.005","article-title":"The role of the neuropeptide Y (NPY) family in the pathophysiology of inflammatory bowel disease (IBD)","volume":"55","author":"Hausken","year":"2016","journal-title":"Neuropeptides"},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Hassan, A.M., Jain, P., Mayerhofer, R., Fr\u00f6hlich, E.E., Farzi, A., Reichmann, F., Herzog, H., and Holzer, P. (2017). Visceral hyperalgesia caused by peptide YY deletion and Y2 receptor antagonism. Sci. Rep., 7.","DOI":"10.1038\/srep40968"},{"key":"ref_16","first-page":"G71","article-title":"Intestinal peptide YY: Ontogeny of gene expression in rat bowel and trophic actions on rat and mouse bowel","volume":"268","author":"Gomez","year":"1995","journal-title":"Am. J. Physiol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"163","DOI":"10.1016\/j.regpep.2004.08.020","article-title":"Differential expression of Y receptors and signaling pathways in intestinal circular and longitudinal smooth muscle","volume":"125","author":"Misra","year":"2005","journal-title":"Regul. Pept."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"133","DOI":"10.1016\/0167-0115(93)90435-B","article-title":"Proteolytic processing of neuropeptide Y and peptide YY by dipeptidyl peptidase IV","volume":"49","author":"Mentlein","year":"1993","journal-title":"Regul. Pept."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1755","DOI":"10.1210\/en.2016-1827","article-title":"Degradation Paradigm of the Gut Hormone, Pancreatic Polypeptide, by Hepatic and Renal Peptidases","volume":"158","author":"Cuenco","year":"2017","journal-title":"Endocrinology"},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Sarkar, J., Nargis, T., Tantia, O., Ghosh, S., and Chakrabarti, P. (2019). Increased Plasma Dipeptidyl Peptidase-4 (DPP4) Activity Is an Obesity-Independent Parameter for Glycemic Deregulation in Type 2 Diabetes Patients. Front. Endocrinol., 10.","DOI":"10.3389\/fendo.2019.00505"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"485","DOI":"10.1016\/j.npep.2010.08.001","article-title":"Plasma neuropeptide Y levels differ in distinct diabetic conditions","volume":"44","author":"Ilhan","year":"2010","journal-title":"Neuropeptides"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"3160","DOI":"10.2337\/diacare.26.11.3160","article-title":"Follow-up report on the diagnosis of diabetes mellitus","volume":"26","author":"Genuth","year":"2003","journal-title":"Diabetes Care"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"653","DOI":"10.1093\/ajh\/hpv153","article-title":"Predictors of Hypertension Remission and Recurrence After Bariatric Surgery","volume":"29","author":"Benaiges","year":"2016","journal-title":"Am. J. Hypertens."},{"key":"ref_24","unstructured":"Hulley, S.B., Cummings, S.R., Browner, W.S., Grady, D.G., and Newman, T.B. (2013). Designing Clinical Research, 4e. Designing Clinical Research, Lippincott Williams & Wilkins."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1007\/BF01535722","article-title":"GSRS\u2014A clinical rating scale for gastrointestinal symptoms in patients with irritable bowel syndrome and peptic ulcer disease","volume":"33","author":"Svedlund","year":"1988","journal-title":"Dig. Dis. Sci."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1723","DOI":"10.1007\/s00262-009-0728-1","article-title":"On the origin of serum CD26 and its altered concentration in cancer patients","volume":"58","author":"Cordero","year":"2009","journal-title":"Cancer Immunol. Immunother."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1111\/all.12919","article-title":"Proteome analysis identifies L1CAM\/CD171 and DPP4\/CD26 as novel markers of human skin mast cells","volume":"72","author":"Gschwandtner","year":"2017","journal-title":"Allergy"},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Gomes, S.F., Valois, A., Estevinho, M.M., Santiago, M., and Magro, F. (2024). Association of Gut Microbiome and Dipeptidyl Peptidase 4 in Immune-Mediated Inflammatory Bowel Disease: A Rapid Literature Review. Int. J. Mol. Sci., 25.","DOI":"10.20944\/preprints202410.1079.v1"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"665","DOI":"10.1016\/j.ebiom.2019.03.057","article-title":"Alteration of gut microbiota induced by DPP-4i treatment improves glucose homeostasis","volume":"44","author":"Liao","year":"2019","journal-title":"EBioMedicine"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"172521","DOI":"10.1016\/j.ejphar.2019.172521","article-title":"Contribution of intestinal dipeptidyl peptidase-4 inhibition for incretin-dependent improved glucose tolerance in mice","volume":"859","author":"Yamashita","year":"2019","journal-title":"Eur. J. Pharmacol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1016\/j.peptides.2017.12.020","article-title":"Tissue expression of DPP-IV in obesity-diabetes and modulatory effects on peptide regulation of insulin secretion","volume":"100","author":"McKillop","year":"2018","journal-title":"Peptides"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"429","DOI":"10.1002\/emmm.201000100","article-title":"Therapeutic potential of neuropeptide Y (NPY) receptor ligands","volume":"2","author":"Brothers","year":"2010","journal-title":"EMBO Mol. Med."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"358","DOI":"10.1007\/s11894-010-0129-9","article-title":"Enteric Nervous System in the Small Intestine: Pathophysiology and Clinical Implications","volume":"12","author":"Nezami","year":"2010","journal-title":"Curr. Gastroenterol. Rep."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"143","DOI":"10.1046\/j.1365-2982.1997.d01-46.x","article-title":"Neuropeptides in idiopathic chronic constipation (slow transit constipation)","volume":"9","author":"Fasth","year":"1997","journal-title":"Neurogastroenterol. Motil."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"41921","DOI":"10.1074\/jbc.M110.164020","article-title":"Neuropeptide Y modulation of interleukin-1{beta} (IL-1{beta})-induced nitric oxide production in microglia","volume":"285","author":"Ferreira","year":"2010","journal-title":"J. Biol. Chem."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"137395","DOI":"10.1016\/j.neulet.2023.137395","article-title":"Mini-review: Enteric glial cell reactions to inflammation and potential therapeutic implications for GI diseases, motility disorders, and abdominal pain","volume":"812","author":"Schneider","year":"2023","journal-title":"Neurosci. Lett."},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Guida, C., Stephen, S.D., Watson, M., Dempster, N., Larraufie, P., Marjot, T., Cargill, T., Rickers, L., Pavlides, M., and Tomlinson, J. (2019). PYY plays a key role in the resolution of diabetes following bariatric surgery in humans. EBioMedicine, 40.","DOI":"10.1016\/j.ebiom.2018.12.040"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"370","DOI":"10.1136\/gut.46.3.370","article-title":"Pathways and receptors involved in peptide YY induced contraction of rat proximal colonic muscle in vitro","volume":"46","author":"Ferrier","year":"2000","journal-title":"Gut"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1111\/j.1365-2982.2010.01659.x","article-title":"Oxidative stress: Key player in gastrointestinal complications of diabetes","volume":"23","author":"Kashyap","year":"2011","journal-title":"Neurogastroenterol. Motil."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"400","DOI":"10.3109\/00365521.2015.1101780","article-title":"Peptide YY3-36 and glucagon-like peptide-1 in functional dyspepsia. Secretion and role in symptom generation","volume":"51","author":"Witte","year":"2016","journal-title":"Scand. J. Gastroenterol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"2613","DOI":"10.1111\/j.1572-0241.2008.02041.x","article-title":"Functional dyspepsia is associated with a greater symptomatic response to fat but not carbohydrate, increased fasting and postprandial CCK, and diminished PYY","volume":"103","author":"Pilichiewicz","year":"2008","journal-title":"Am. J. Gastroenterol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"5846","DOI":"10.1074\/jbc.M113.502021","article-title":"Pancreatic polypeptide is recognized by two hydrophobic domains of the human Y4 receptor binding pocket","volume":"289","author":"Sliwoski","year":"2014","journal-title":"J. Biol. Chem."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"4175","DOI":"10.1073\/pnas.78.7.4175","article-title":"X-ray analysis (1. 4-\u00c5 resolution) of avian pancreatic polypeptide: Small globular protein hormone","volume":"78","author":"Blundell","year":"1981","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"269","DOI":"10.1016\/S0196-9781(01)00608-8","article-title":"The origin and evolution of peptide YY (PYY) and pancreatic polypeptide (PP)","volume":"23","year":"2002","journal-title":"Peptides"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"1154","DOI":"10.1124\/jpet.104.071415","article-title":"Coexpression of Y1, Y2, and Y4 receptors in smooth muscle coupled to distinct signaling pathways","volume":"311","author":"Misra","year":"2004","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"170923","DOI":"10.1016\/j.peptides.2022.170923","article-title":"Pancreatic polypeptide revisited: Potential therapeutic effects in obesity-diabetes","volume":"160","author":"Zhu","year":"2023","journal-title":"Peptides"},{"key":"ref_47","unstructured":"(2025, January 12). Tissue Expression of PPY-Summary\u2014The Human Protein Atlas. Available online: https:\/\/www.proteinatlas.org\/ENSG00000108849-PPY\/tissue."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"e3829","DOI":"10.1002\/dmrr.3829","article-title":"Fasting pancreatic polypeptide predicts incident microvascular and macrovascular complications of type 2 diabetes: An observational study","volume":"40","author":"Sam","year":"2024","journal-title":"Diabetes Metab. Res. Rev."},{"key":"ref_49","doi-asserted-by":"crossref","unstructured":"Aggeletopoulou, I., and Triantos, C. (2024). Microbiome Shifts and Their Impact on Gut Physiology in Irritable Bowel Syndrome. Int. J. Mol. Sci., 25.","DOI":"10.3390\/ijms252212395"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"e13738","DOI":"10.1111\/nmo.13738","article-title":"The Glucagon-like peptide-1 receptor agonist, exendin-4, ameliorated gastrointestinal dysfunction in the Wistar Kyoto rat model of Irritable Bowel Syndrome","volume":"32","year":"2020","journal-title":"Neurogastroenterol. Motil."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"459","DOI":"10.1016\/j.clinre.2016.12.007","article-title":"Decreased glucagon-like peptide-1 correlates with abdominal pain in patients with constipation-predominant irritable bowel syndrome","volume":"41","author":"Li","year":"2017","journal-title":"Clin. Res. Hepatol. Gastroenterol."},{"key":"ref_52","doi-asserted-by":"crossref","unstructured":"Barton, J.R., Londregan, A.K., Alexander, T.D., Entezari, A.A., Covarrubias, M., and Waldman, S.A. (2023). Enteroendocrine cell regulation of the gut-brain axis. Front. Neurosci., 17.","DOI":"10.3389\/fnins.2023.1272955"}],"container-title":["Medicina"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1648-9144\/61\/3\/504\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T16:54:12Z","timestamp":1760028852000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1648-9144\/61\/3\/504"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,3,15]]},"references-count":52,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2025,3]]}},"alternative-id":["medicina61030504"],"URL":"https:\/\/doi.org\/10.3390\/medicina61030504","relation":{},"ISSN":["1648-9144"],"issn-type":[{"value":"1648-9144","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,3,15]]}}}