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

Objective

The endocrine mechanisms linking fructose ingestion to glycemia remain unclear. This study revisited the mechanisms of fructose-induced incretin and insulin secretion to contextualize their roles in glycemic regulation following short-term fructose administration.

Methods

Mice were administered 20% fructose water ad libitum for 24 h. Plasma insulin and GLP-1 levels were compared with those of the water-administered controls. The mouse models included lean mice (C57BL/6J and NSY.B6- a / a ), obese diabetic mice (NSY.B6- A ^y / a ), proglucagon-deficient mice ( Gcg ^-/- ), glucose-dependent insulinotropic polypeptide (GIP) receptor-deficient mice ( Gipr ^-/- ), and ATP-sensitive potassium channel (K _ATP channel)-deficient mice ( Kcnj11 ^-/- ). The involvement of intracellular fructose metabolism in GLP-1 secretion was investigated using GLUTag cells (a mouse L-cell line) and freshly isolated intestinal crypts.

Results

Fructose ingestion increased insulin, GLP-1, and GIP levels in lean mice. This insulin response was maintained in Gipr ^-/- mice but was eliminated in Gcg ^-/- mice or upon administration of the GLP-1 receptor antagonist exendin [9-39], indicating the requirement of GLP-1. Notably, multiple mouse strains deficient in fructose-induced insulin responses exhibit hyperglycemia following fructose ingestion, suggesting that insulin responses are essential for suppressing glycemia. Characterization of Kcnj11 ^-/- mice and GLUTag cells corroborated the hypothesis that intestinal fructose metabolism regulates GLP-1 secretion through the ATP/ADP ratio and K _ATP channels. Metabolic tracing of the isolated intestinal crypts further suggested that fructolysis activity is coupled to the ATP/ADP ratio in the L-cell-resident niche.

Conclusion

Fructose ingestion stimulates GLP-1 secretion through intestinal fructose metabolism, which is required for the potentiation of insulin secretion. This pathway constitutes a counter-regulatory response to fructose-induced hyperglycemia.

GRAPHICAL ABSTRACT

This 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 K _ATP channel closure and Ca ²⁺ influx. GLP-1 promotes insulin secretion from pancreatic β-cells. The fructose metabolism/GLP-1/insulin pathway is essential for mitigation of fructose-induced hyperglycemia.

Parts of the figure were drawn using pictures from Servier Medical Art by Servier licensed under a CC-BY 4.0 with color modification.