Glucose acts as a ligand for glucokinase to trigger GLP-1 secretion
image: Model of glucose sensing in intestinal L cells for GLP-1 secretion. In the postprandial state, high glucose is transported into L cells via GLUT2 and binds glucokinase (GK). The glucose-bound GK then interacts with and inhibits KATP channels, causing plasma membrane depolarization and robust GLP-1 secretion (upper). Under low glucose conditions, SGLT1 co-transports Na⁺ and glucose into L cells, leading to membrane depolarization that mediates basal GLP-1 secretion (lower).
Credit: HIGHER EDUCATION PRESS
The classical model of glucose-stimulated GLP-1 secretion posits that glucose must be metabolized to ATP to close KATP channels and trigger vesicle release. However, this model has not been directly proven in L cells. The authors found that high glucose stimulates GLP-1 secretion without changing intracellular ATP levels. Using non-metabolizable glucose analogs, they showed that MDGP, which binds GK but cannot produce ATP, effectively stimulates GLP-1 release, whereas 2-DG, which is phosphorylated but does not stably bind GK, fails to do so. These results suggest that glucose itself, rather than its metabolic products, triggers GLP-1 release.
Further evidence came from GK mutants identified in MODY2 patients. The L309P mutant, which constitutively binds glucose but lacks catalytic activity, triggered GLP-1 secretion even at low glucose. In contrast, the G80A mutant, which cannot bind glucose, failed to stimulate secretion even at high glucose. Clinical validation in two MODY2 patients carrying R397L (glucose-binding) or Δ92-CT (binding-deficient) mutations confirmed that glucose binding to GK, not catalysis, drives GLP-1 secretion.
Mechanistically, the authors demonstrated that glucose-bound GK directly interacts with the Kir6.2 subunit of KATP channels, inhibiting channel activity and causing membrane depolarization. This interaction is independent of ATP and is mediated by a specific region (aa 205–228) on Kir6.2 (Fig. 1). The study also revealed that SGLT1, which co-transports Na⁺ and glucose, mediates basal GLP-1 secretion at low glucose concentrations, while the GK-KATP axis dominates at postprandial glucose levels (Fig. 1). Together, these two pathways provide a safety mechanism: GLP-1 secretion is strictly glucose-dependent, and insulin release from β-cells only occurs when blood glucose is already high, preventing hypoglycemia.
This study provides two key conceptual advances. First, it redefines glucose as a ligand and GK as its receptor, establishing a paradigm of “ligand-receptor” signaling for nutrient sensing. Second, it shows that GK’s glucose-sensing function can be separated from its catalytic activity, offering a new strategy for drug development: stabilizing the glucose-bound conformation of GK may promote endogenous GLP-1 secretion with fewer side effects than current long-acting GLP-1 receptor agonists.