Reply to Huang et al.: ‘Segmental fructose handling may refine the temporal glucagon‐like peptide‐1/glucagon‐like peptide‐2 framework during chronic fructose exposure’

I thank Huang and colleagues for their interest in our recent article (Murao et al., 2025), and welcome the opportunity to clarify the current question, evidence and remaining uncertainties.

Building upon our previous work (Murao et al., 2025) and the study by Sellami et al. (2025), the recent Journal Club by Evangelista‐Silva (2026) proposed that the relative physiological contribution of proglucagon‐derived peptides may change during chronic fructose intake, with acute GLP‐1‐dependent protection giving way to GLP‐2‐associated intestinal adaptation. Huang and colleagues further refine this temporal framework by highlighting spatial factors, proposing that the site at which fructose is handled along the intestine may influence the balance between GLP‐1‐ and GLP‐2‐associated actions.

I agree that intestinal geography is likely to modify GLP‐1/GLP‐2 responses during prolonged fructose intake. However, it remains unclear whether this spatial component can be explained simply by a proximal‐to‐distal redistribution of fructose handling. Jang et al. (2018) demonstrated that an acute high fructose load exceeds the small‐intestinal clearance capacity and allows fructose to reach the liver and colonic microbiota. Subsequent studies have shown that intestinal fructolysis can be enhanced during chronic sucrose exposure (Jang et al., 2020). Nevertheless, whether chronic fructose exposure redistributes the anatomical site of fructose absorption or L‐cell stimulation along the intestine remains unclear.

In addition to possible distal recruitment, I suggest that fructose‐induced small‐intestinal remodelling should be considered as another spatial factor that may shape GLP‐1/GLP‐2 physiology. Taylor et al. (2021) demonstrated that dietary fructose increases villus length and absorptive surface area in the small intestine through fructolysis‐dependent enhancement of epithelial cell survival. Furthermore, GLP‐2 has long been recognised as an intestinotrophic hormone that promotes intestinal epithelial proliferation (Drucker et al., 1996). Sellami et al. (2025) showed that GLP‐2R inhibition prevents high‐fructose‐induced increases in gut glucose absorption and gut surface enlargement. Because intestinal GLP‐2R is localised mainly to enteric neurones and lamina propria stromal cells (Yusta et al., 2019), chronic fructose may create a local feed‐forward context in the remodelled intestine, in which GLP‐2R‐dependent signalling becomes more physiologically influential.

Because GLP‐1 and GLP‐2 are generated from the same proglucagon precursor, I do not think that chronic fructose exposure should be interpreted as necessarily shifting the molar ratio of secreted GLP‐2 to GLP‐1, a point that is also consistent with the Letter by Huang and colleagues. However, intestinal remodelling could alter the local bioavailability of co‐secreted peptides by changing the degradative environment in which they act. In particular, expansion of differentiated absorptive and vascular compartments may modify local DPP‐4 activity. Since intact GLP‐1 is a short‐lived insulinotropic signal, whereas GLP‐2 appears relatively more stable in vivo despite also being a DPP‐4 substrate (Hartmann et al., 2000), such remodelling could make GLP‐2‐associated intestinal actions more apparent. This remains a testable hypothesis rather than a demonstrated mechanism.

In summary, I agree with Huang et al. that spatial factors should be incorporated into the temporal framework of fructose‐induced GLP‐1 and GLP‐2 activity. I would further propose that small‐intestinal remodelling induced by chronic fructose intake may be a physiologically relevant spatial alteration, in addition to any proximal‐to‐distal redistribution of fructose handling. In this view, temporal and spatial aspects of chronic fructose exposure are difficult to separate because remodelling is itself a time‐dependent change in intestinal architecture and function. As Huang and colleagues point out, integrating time‐resolved and segment‐resolved analyses will be crucial to understand the interplay between proglucagon‐derived peptide secretion, peptide stability and target‐tissue responsiveness during prolonged fructose exposure.

Additional information

Competing interests

None declared.

Author contributions

N.M.: writing – original draft, review, and editing. Other authors of the focus article (Murao et al., 2025) did not contribute to this reply.

Funding

None.

Supporting information

Peer Review History