{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,9]],"date-time":"2026-06-09T11:43:19Z","timestamp":1781005399486,"version":"3.54.1"},"reference-count":96,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2025,8,14]],"date-time":"2025-08-14T00:00:00Z","timestamp":1755129600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["CIMB"],"abstract":"<jats:p>Type 2 diabetes mellitus (T2DM) is a multifactorial disorder defined by insulin resistance, \u03b2-cell dysfunction, and chronic hyperglycemia. Although peripheral mechanisms have been extensively studied, increasing evidence implicates the gastrointestinal tract in disease onset. Insights from bariatric surgery, gut hormone signaling, and incretin-based therapies suggest that the gut contributes actively beyond nutrient absorption. Yet, a cohesive framework integrating these observations remains absent, leaving a critical gap in our understanding of T2DM\u2019s upstream pathophysiology. This work builds upon the anti-incretin theory, which posits that nutrient-stimulated neurohormonal signals\u2014termed \u201canti-incretins\u201d\u2014arise from the proximal intestine to counteract incretin effects and regulate glycemic homeostasis. The excess of anti-incretin signals, perhaps stimulated by macronutrient composition or chemical additives of modern diets, disrupts this balance and may cause insulin resistance and \u03b2-cell depletion, leading to T2D. We hypothesize that the neuroendocrine signals produced by cholecystokinin (CCK)-I and secretin-S cells, both located in the proximal intestine, function as endogenous anti-incretins. In this context, we hypothesize a novel model centered on the chronic overstimulation of I and S cells by high-fat, high glycemic index modern diets. This drives what we term \u201camplified digestion\u201d\u2014a state marked by heightened vagal and hormonal stimulation of biliary and pancreatic secretions, increased enzymatic and bile acid activity, and alterations in bile acid composition. This condition leads to an extended breakdown of carbohydrates, lipids, and proteins into absorbable units, thereby promoting excessive nutrient absorption and ultimately contributing to insulin resistance and progressive \u03b2-cell failure. Multiple lines of clinical, surgical, and experimental evidence converge to support our model, rooted in the physiology of digestion and absorption. Western dietary patterns appear to induce an over-digestive adaptation\u2014marked by excessive vagal and hormonal stimulation of biliary and pancreatic secretion\u2014which amplifies digestive signaling. This heightened state correlates with increased nutrient absorption, insulin resistance, and \u03b2-cell dysfunction. Interventions that disrupt this maladaptive signaling\u2014such as truncal vagotomy combined with duodenal bypass\u2014may offer novel, physiology-based strategies for T2DM treatment. This hypothesis outlines a potential upstream contributor to insulin resistance and T2DM, grounded in digestive tract-derived neurohormonal dysregulation. This gut-centered model may provide insight into early, potentially reversible stages of the disease and identify a conceptual therapeutic target. Nonetheless, both the hypothesis and the accompanying surgical strategy\u2014truncal vagotomy combined with proximal intestinal bypass\u2014remain highly exploratory and require systematic validation through mechanistic and clinical studies. Further investigation is warranted to clarify the molecular regulation of I and S enteroendocrine cells, including the genetic and epigenetic factors that may drive hypersecretion. While speculative, interventions\u2014surgical or pharmacologic\u2014designed to modulate these digestive signals could represent a future avenue for research into T2DM prevention or remission, pending rigorous evidence.<\/jats:p>","DOI":"10.3390\/cimb47080657","type":"journal-article","created":{"date-parts":[[2025,8,14]],"date-time":"2025-08-14T15:44:21Z","timestamp":1755186261000},"page":"657","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["The Duodenum-Centered Neurohormonal Hypothesis of Type 2 Diabetes: A Mechanistic Review and Therapeutic Perspective"],"prefix":"10.3390","volume":"47","author":[{"given":"Athena N.","family":"Kapralou","sequence":"first","affiliation":[{"name":"General Surgery Department, Euroclinic Hospital, 115 21 Athens, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6695-186X","authenticated-orcid":false,"given":"Christos","family":"Yapijakis","sequence":"additional","affiliation":[{"name":"Unit of Orofacial Genetics, 1st Department of Pediatrics, School of Medicine, National Kapodistrian University of Athens, 115 27 Athens, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3098-5264","authenticated-orcid":false,"given":"George P.","family":"Chrousos","sequence":"additional","affiliation":[{"name":"Endocrine Unit, UNESCO Chair on Adolescent Health Care, University Research Institute of Maternal and Child Health and Precision Medicine, National and Kapodistrian University of Athens, 115 27 Athens, Greece"},{"name":"Hellenic Pasteur Institute, 115 21 Athens, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,8,14]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1016\/j.ijbiomac.2017.05.190","article-title":"Studies on glycoxidatively modified human IgG: Implications in immuno-pathology of type 2 diabetes mellitus","volume":"104","author":"Islam","year":"2017","journal-title":"Int. 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