Intestinal fructose metabolism triggers a glucagon‐like peptide‐1–β‐cell axis to prevent post‐fructose hyperglycaemia

Abstract Fructose ingestion increases circulating glucagon‐like peptide‐1 (GLP‐1) and insulin, yet the specific contributions of these hormonal responses to glycaemic control remain incompletely defined. We hypothesised that fructose metabolism in intestinal L‐cells triggers GLP‐1 secretion, which then potentiates insulin secretion and counteracts fructose‐induced hyperglycaemia. To test this hypothesis, we systematically characterised metabolic responses across multiple mouse strains after 24 h ad libitum fructose ingestion. In both lean (NSY.B6‐ a / a ) and obese diabetic (NSY.B6‐ A y / a ) mice, fructose elevated plasma insulin, GLP‐1 and glucose‐dependent insulinotropic polypeptide (GIP). The insulin response was preserved in GIP receptor‐deficient mice ( Gipr −/− ) but was abolished in proglucagon‐deficient mice ( Gcg −/− ) by pharmacological GLP‐1 receptor antagonism, indicating a requirement for GLP‐1, but not GIP. Across strains, fructose‐induced insulin response correlated with attenuation of post‐fructose glycaemia, consistent with insulin being essential for suppressing fructose‐induced hyperglycaemia. To explore the mechanism underlying fructose‐induced GLP‐1 secretion, we combined ATP‐sensitive potassium channel‐deficient mice ( Kcnj11 −/− ), the GLUTag L‐cell line, and metabolic tracing of 13 C‐labelled fructose in freshly isolated intestinal crypts. These complementary approaches support a model in which fructolysis increases the ATP/ADP ratio in L‐cells, closes K ATP channels and stimulates GLP‐1 secretion. In obese diabetic mice, increased fructolytic flux and a higher ATP/ADP ratio were associated with elevated GLP‐1 levels, further corroborating this model. Collectively, our findings indicate that intestinal fructose metabolism drives GLP‐1 secretion required to potentiate insulin secretion, thereby establishing a gut–pancreas axis that counter‐regulates fructose‐induced hyperglycaemia. image Key points Fructose ingestion acutely increases plasma insulin levels, but the underlying mechanisms and physiological significance remain elusive. Our study demonstrates that short‐term (24 h) fructose ingestion in mice elevates both insulin and glucagon‐like peptide 1 (GLP‐1) levels in the blood, with the plasma insulin response being GLP‐1‐dependent. We found that fructose metabolism in intestinal L‐cells triggered GLP‐1 secretion by increasing the ATP/ADP ratio and closing ATP‐sensitive K + (K ATP ) channels. This intestinal fructose metabolism–GLP‐1–β‐cell axis plays a crucial role in preventing fructose‐induced hyperglycaemia, an effect that is compromised in obese diabetic mice. These insights highlight the previously unclear metabolic responses following short‐term fructose ingestion and their importance in glucose homeostasis.