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We hypothesised that fructose metabolism in intestinal L\u2010cells triggers GLP\u20101 secretion, which then potentiates insulin secretion and counteracts fructose\u2010induced hyperglycaemia. To test this hypothesis, we systematically characterised metabolic responses across multiple mouse strains after 24\u00a0h\n ad libitum<\/jats:italic>\n fructose ingestion. In both lean (NSY.B6\u2010\n a<\/jats:italic>\n \/\n a<\/jats:italic>\n ) and obese diabetic (NSY.B6\u2010\n \n A\n y<\/jats:sup>\n <\/jats:italic>\n \/\n a<\/jats:italic>\n ) mice, fructose elevated plasma insulin, GLP\u20101 and glucose\u2010dependent insulinotropic polypeptide (GIP). The insulin response was preserved in GIP receptor\u2010deficient mice (\n Gipr<\/jats:italic>\n \u2212\/\u2212<\/jats:sup>\n ) but was abolished in proglucagon\u2010deficient mice (\n Gcg<\/jats:italic>\n \u2212\/\u2212<\/jats:sup>\n ) by pharmacological GLP\u20101 receptor antagonism, indicating a requirement for GLP\u20101, but not GIP. Across strains, fructose\u2010induced insulin response correlated with attenuation of post\u2010fructose glycaemia, consistent with insulin being essential for suppressing fructose\u2010induced hyperglycaemia. To explore the mechanism underlying fructose\u2010induced GLP\u20101 secretion, we combined ATP\u2010sensitive potassium channel\u2010deficient mice (\n Kcnj11<\/jats:italic>\n \u2212\/\u2212<\/jats:sup>\n ), the GLUTag L\u2010cell line, and metabolic tracing of\n 13<\/jats:sup>\n C\u2010labelled fructose in freshly isolated intestinal crypts. These complementary approaches support a model in which fructolysis increases the ATP\/ADP ratio in L\u2010cells, closes K\n ATP<\/jats:sub>\n channels and stimulates GLP\u20101 secretion. In obese diabetic mice, increased fructolytic flux and a higher ATP\/ADP ratio were associated with elevated GLP\u20101 levels, further corroborating this model. Collectively, our findings indicate that intestinal fructose metabolism drives GLP\u20101 secretion required to potentiate insulin secretion, thereby establishing a gut\u2013pancreas axis that counter\u2010regulates fructose\u2010induced hyperglycaemia.\n \n \n image<\/jats:alt-text>\n <\/jats:graphic>\n <\/jats:boxed-text>\n <\/jats:p>\n <\/jats:sec>\n \n Key points<\/jats:title>\n \n \n \n Fructose ingestion acutely increases plasma insulin levels, but the underlying mechanisms and physiological significance remain elusive.<\/jats:p>\n <\/jats:list-item>\n \n Our study demonstrates that short\u2010term (24\u00a0h) fructose ingestion in mice elevates both insulin and glucagon\u2010like peptide 1 (GLP\u20101) levels in the blood, with the plasma insulin response being GLP\u20101\u2010dependent.<\/jats:p>\n <\/jats:list-item>\n \n \n We found that fructose metabolism in intestinal L\u2010cells triggered GLP\u20101 secretion by increasing the ATP\/ADP ratio and closing ATP\u2010sensitive K\n +<\/jats:sup>\n (K\n ATP<\/jats:sub>\n ) channels.\n <\/jats:p>\n <\/jats:list-item>\n \n This intestinal fructose metabolism\u2013GLP\u20101\u2013\u03b2\u2010cell axis plays a crucial role in preventing fructose\u2010induced hyperglycaemia, an effect that is compromised in obese diabetic mice.<\/jats:p>\n <\/jats:list-item>\n \n These insights highlight the previously unclear metabolic responses following short\u2010term fructose ingestion and their importance in glucose homeostasis.<\/jats:p>\n <\/jats:list-item>\n <\/jats:list>\n <\/jats:p>\n <\/jats:sec>","DOI":"10.1113\/jp289067","type":"journal-article","created":{"date-parts":[[2025,10,23]],"date-time":"2025-10-23T17:15:36Z","timestamp":1761239736000},"page":"6833-6858","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Intestinal fructose metabolism triggers a glucagon\u2010like peptide\u20101\u2013\u03b2\u2010cell axis to prevent post\u2010fructose 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