Incretin‐dependent acute and chronic gut responses to fructose exposure in glycaemic control

Fructose consumption has increased markedly over recent decades and has been consistently associated with the development of non-communicable chronic diseases, including impaired glycaemic homeostasis, type 2 diabetes and metabolic dysfunction-associated steatotic liver disease (MASLD). Although the liver has historically been viewed as the primary organ mediating these effects, more recent evidence identifies the intestine as a central site for fructose sensing and metabolism. In this context, the study by Murao et al. (2025), recently published in The Journal of Physiology, provides elegant and important mechanistic insight into how intestinal fructose metabolism contributes to postprandial glycaemia control. Murao et al. (2025) demonstrated in adult mice that oral fructose administration activates a gut–pancreas axis dependent on glucagon-like peptide-1 (GLP-1). In their main experimental protocol, fructose was administered ad libitum in drinking water over 24 h, which resulted in sustained elevations in circulating GLP-1 and insulin, as well as maintenance of normoglycaemia. To confirm that these effects were not due to direct stimulation of pancreatic β-cells by fructose, the authors also examined circulating insulin levels, which fell well below the threshold required to stimulate insulin secretion on its own. From a mechanistic perspective, the experiments indicate that this incretin response depends strictly on intestinal fructolysis. Pharmacological inhibition or genetic disruption of key metabolic pathways in the intestinal epithelium abolished fructose-induced GLP-1 secretion (Murao et al., 2025). Physiologically, this process involves stimulation of secretion coupling in enteroendocrine L cells, whereby fructose metabolism increases the ATP/ADP ratio and promotes closure of KATP channels, membrane depolarisation and Ca2+ influx, ultimately leading to GLP-1 release (Murao et al., 2025). The functional relevance of this axis was confirmed by pharmacological blockade of the GLP-1 receptor or induction of pancreatic β-cell dysfunction, both of which resulted in marked hyperglycaemia following fructose administration (Murao et al., 2025). Together, these findings position the intestine as an active metabolic sensor that is essential for the immediate maintenance of glycaemic homeostasis after fructose intake. As the experimental protocols used by Murao et al. (2025) focus exclusively on acute exposure, how this system behaves under chronic fructose consumption remains unresolved. While GLP-1 primarily acts to acutely potentiate insulin secretion, other proglucagon-derived peptides, such as glucagon-like peptide-2 (GLP-2), are co-secreted by L-cells and exert distinct physiological actions (Ali et al., 2024; Drucker, 2007; Holst, 2007). Unlike GLP-1, GLP-2 has predominantly trophic effects on the intestinal epithelium, modulating nutrient absorption and mucosal integrity, with more gradual and indirect effects on glycaemic regulation (Ali et al., 2024; Holst, 2007). Considering these functional differences, it may be cautiously hypothesised that the relative contribution of GLP-1 and GLP-2 to metabolic adaptation to fructose varies with the duration of nutrient exposure. Notably, evidence from mouse models of prolonged fructose intake over several weeks indicates sustained activation of GLP-2 signalling, associated with increased expression of intestinal glucose transporters and expansion of the absorptive surface area, without a concomitant increase in circulating GLP-1 levels (Sellami et al., 2025). It is important to note that chronic fructose exposure may render the GLP-1–β-cell axis no longer operational, due to the loss of β-cell responsiveness to GLP-1 under sustained fructose stimulation (Murao et al., 2025). These observations raise the possibility that, under chronic fructose consumption, GLP-2 may become the predominant proglucagon-derived signal, potentially shifting the balance away from GLP-1-mediated insulinotropic actions. Within this hypothetical framework, the GLP-1–β-cell axis described by Murao et al. (2025) may represent an immediate and protective response to acute fructose intake, whereas more gradual, GLP-2-associated intestinal adaptations may emerge only with sustained exposure (Figure 1). Taken together, the work of Murao et al. (2025) clearly defines an intestinal physiological mechanism that protects against fructose-induced hyperglycaemia under acute conditions. When considered within a broader temporal context, these findings raise the possibility that the metabolic impact of fructose reflects a dynamic balance between GLP-1 and GLP-2 signalling. This perspective highlights the importance of future studies aimed at understanding how acute hormonal responses and longer-term intestinal adaptations are integrated in the regulation of nutrient handling and metabolic homeostasis. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article. The author declares he has no competing interests. Sole author. This work was supported by Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) grant #2024/17868-8.