Intestinal fructose metabolism/GLP-1/β-cell axis counteracts hyperglycemia after short-term fructose ingestion

Fructose ingestion increases circulating 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-Ay/a) mice, fructose elevated plasma insulin, glucagon-like peptide 1 (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-/-), GLUTag L-cell line, and metabolic tracing of 13C-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 KATP 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. KEY POINTS SUMMARYO_LIFructose ingestion acutely increases plasma insulin levels, but the underlying mechanisms and physiological significance remain elusive. C_LIO_LIOur study demonstrates that short-term (24h) 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. C_LIO_LIWe found that fructose metabolism in intestinal L-cells triggered GLP-1 secretion by increasing the ATP/ADP ratio and closing ATP-sensitive K+ channels (KATP channels). C_LIO_LIThis intestinal fructose metabolism/GLP-1/{beta}-cell axis plays a crucial role in preventing fructose-induced hyperglycaemia, an effect that is compromised in obese diabetic mice. C_LIO_LIThese insights highlight the previously unclear metabolic responses following short-term fructose ingestion and their importance in glucose homeostasis. C_LI 1. ABSTRACT FIGURE LEGENDThis study investigated the hormonal effects of short-term fructose consumption in mice, allowing them ad-lib access to fructose solution for 24 h. Fructose metabolism in intestinal L-cells increases the intracellular ATP/ADP ratio, leading to GLP-1 secretion via KATP channel closure and Ca2+ influx. GLP-1 promotes insulin secretion from pancreatic {beta}-cells. The fructose metabolism/GLP-1/insulin pathway is essential for mitigation of fructose-induced hyperglycaemia. Figures were drawn using BioRender.com.