Glucose is a ligand-like trigger for secretion of postprandial GLP-1

Li, C.; Li, M.; Yang, H.-y.; Tian, X.; Zhang, C.-S.; Zhao, L.; Wu, J.; Zhang, C.; Liu, S.; Yang, X.; Sun, X.; Chen, J.; Zhang, B.; Yun, C.; Lin, J.; Ma, W.; Ma, T.; Zhu, Q.; Zheng, Z.-Z.; Hong, X.; Deng, X.; Wang, K.; Jiang, C.; Hu, M.; Li, X.; Xu, H.; Lin, S.-C.

doi:10.64898/2026.01.04.697549

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bioRxiv · 10.64898/2026.01.04.697549

Glucose is a ligand-like trigger for secretion of postprandial GLP-1

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Abstract

Glucagon-like peptide 1 (GLP-1) is secreted from the intestinal L cells in a glucose-dependent manner. However, the mechanism underlying how glucose stimulates the secretion remains unclear. Here, we found that glucose at postprandial concentrations near the Km of GK for glucose ([~]10 mM), as well as nonmetabolizable glucose analogs, triggers GLP-1 secretion by intestinal L cells through directly binding to glucokinase (GK), without increasing intracellular ATP levels. We also show that in postprandially high glucose, glucose-bound GK interacts and inhibits KATP, as assessed by immunoprecipitation and FRET-FLIM analyses, as well as patch clamping. In addition, we have utilized GK mutants identified in diabetics, demonstrating that those mutants defective in binding to glucose impair GLP-1 secretion in however high glucose, whereas mutants constitutively bound to glucose with defects in catalysis, promote GLP-1 secretion even in low glucose. Furthermore, the KATP mutant unable to bind to GK blocks GLP-1 secretion in high glucose. We have also provided evidence showing that sodium-glucose cotransporter 1 (SGLT1) plays an important role in the basal secretion of GLP-1, but not in high glucose. We have thus revealed that glucose the molecule itself and GK act as a ligand and the receptor, respectively, to induce GLP-1 secretion in response to high glucose, providing new therapeutic avenues targeting metabolic diseases.

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Li, C., Li, M., Yang, H.-y., Tian, X., Zhang, C.-S., Zhao, L., Wu, J., Zhang, C., Liu, S., Yang, X., Sun, X., Chen, J., Zhang, B., Yun, C., Lin, J., Ma, W., Ma, T., Zhu, Q., Zheng, Z.-Z., Hong, X., Deng, X., Wang, K., Jiang, C., Hu, M., Li, X., Xu, H., Lin, S.-C.. 2026-01-04. Glucose is a ligand-like trigger for secretion of postprandial GLP-1. https://doi.org/10.64898/2026.01.04.697549

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