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Sweet signal: glucose–GK binding shuts KATP channels for GLP-1 secretion

Terytty Yang Li , Johan Auwerx

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Vita > Cutting Edge > DOI: 10.15302/vita.2026.08.0065
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Sweet signal: glucose–GK binding shuts KATP channels for GLP-1 secretion

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In a recent study published in Vita, Li et al.1 show that glucose itself acts as a direct ligand for glucokinase (GK), and that glucose-bound GK inhibits the ATP-sensitive potassium channels (KATP) to trigger postprandial GLP-1 secretion without altering intracellular ATP level. This work uncovers a ligand-sensing function of GK separable from its catalytic activity, providing a promising strategy to enhance endogenous GLP-1 release for the treatment of type 2 diabetes and related metabolic disorders.

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Glucagon-like peptide-1 (GLP-1) is secreted from intestinal enteroendocrine L cells and has emerged as a cornerstone of the management of type 2 diabetes (T2DM) and obesity2. Yet the molecular mechanism linking postprandial luminal glucose to incretin release has remained incompletely understood. The prevailing model posits that glucose triggers GLP-1 secretion through a metabolic coupling pathway analogous to that established in pancreatic β cells: glucose uptake, glycolysis, ATP production, KATP channel inhibition, membrane depolarization, and exocytosis3,4. However, this model has been challenged by the observation that patients with maturity-onset diabetes of the young type 2 (MODY2) who carry catalytically defective glucokinase (GK) mutations exhibit impaired insulin secretion but retain robust postprandial GLP-1 responses5. An additional layer of complexity involves sodium-glucose cotransporter 1 (SGLT1), which co-transports sodium ions with glucose into L cells and directly induces membrane depolarization to trigger GLP-1 release6. However, SGLT1 reaches full substrate saturation at luminal glucose concentrations no higher than 8 mM7, whereas postprandial intestinal glucose routinely peaks above 20 mM, a level at which GLP-1 secretion remains unsaturated7. These observations suggest that additional SGLT1-independent glucose-sensing mechanisms probably exist and account for the robust GLP-1 secretion elicited by high post-prandial glucose.
In a recent study published in Vita1, Li and colleagues demonstrate that it is the physical binding of glucose itself to GK that directly triggers the major portion of postprandial GLP-1 secretion. Using in vivo refeeding, ex vivo intestinal preparations, primary L cells, and multiple intestinal cell lines, they show that high glucose stimulates GLP-1 secretion without raising intracellular ATP, ADP or AMP levels, as measured using a targeted ATP:ADP biosensor. In line with these observations, metabolic tracing with [U-13C]glucose revealed that less than 20% of intracellular glucose enters glycolysis in L cells, and ATP-linked oxygen consumption does not increase upon glucose stimulation. Thus, GLP-1 secretion, unlike insulin release from β cells, proceeds through an ATP-independent route.
In support of the model that glucose serves as a ligand and GK as its receptor, they showed that the nonmetabolizable glucose analog methyl-α-d-glucopyranoside (MDGP), which binds GK but cannot be metabolized, stimulates GLP-1 secretion in mice and cultured L cells8. By contrast, 2-deoxy-d-glucose (2-DG), which is phosphorylated by GK but fails to stabilize the glucose-bound conformation of GK, does not8. Steady-state fluorescence binding assays further revealed that MDGP binds GK with saturable kinetics (Kd ~25 mM), whereas 2-DG does not. This finding of structure-dependent requirement for glucose binding is reinforced by experiments using MODY2-associated GK mutants: G80A, which severely reduces glucose binding affinity, impairs high glucose-induced GLP-1 secretion; L309P, which adopts the glucose-bound conformation due to a catalytic defect, constitutively triggers GLP-1 secretion even under low glucose condition. Meanwhile, neither mutant alters ATP levels in L cells, underscoring the separation of GK's ligand-sensing and catalytic functions.
Mechanistically, glucose-occupied GK binds directly to the Kir6.2 subunit of the KATP channel. High glucose enhances GK–Kir6.2 association, whereas the interaction between GK and SUR1, another KATP subunit, was constitutive. Fluorescence lifetime imaging-Förster resonance energy transfer (FLIM-FRET) analyses in living cells further confirmed a glucose-induced decrease in GK–Kir6.2 distance (from ~4.8 nm to ~4.7 nm), corresponding to increased FRET efficiency. Domain mapping identified amino acids 205–228 of Kir6.2 as the GK-binding region; alanine substitution of this segment (Kir6.2-205–228A) abolished GK-mediated KATP inhibition and blocked high glucose-induced GLP-1 secretion both in cells and in intestine-specific knock-in mice. Finally, whole-cell and inside-out patch-clamping experiments demonstrated that glucose-bound GK directly reduces KATP channel open probability multiplied by the number of channels (NPo) by roughly 40% in the presence of physiologically relevant ATP and ADP concentrations, which is also recapitulated with purified GK in a cell-free system.
Finally, this work clarifies the distinct contributions of SGLT1 and GLUT2. SGLT1, with its low Km for glucose, drives GLP-1 release at basal glucose levels through sodium-coupled depolarization. However, SGLT1 saturates above ~8 mM and contributes little to the robust postprandial secretion triggered by luminal glucose that can exceed 20 mM. Instead, GLUT2, the high-Km facilitative transporter, mediates glucose uptake during the postprandial state, delivering glucose to intracellular GK for ligand sensing. This dual-transporter, dual-sensor model reconciles the contributions of SGLT1 and GK across the physiological range of glucose concentrations (Fig. 1).
This study reemphasizes our understanding of glucose as a signaling molecule and may carry broader implications. Glucose can function as a bona fide ligand, not merely via its metabolic products, conveys information. GK furthermore joins a growing list of glucose-binding proteins (DDX21, NSUN2, and IRF6) that mediate non-metabolic glucose signaling9. The GK-KATP axis may represent a conserved glucose-sensing mechanism in other endocrine cells that co-express these proteins, including pancreatic δ cells, pituitary corticotrophs, hypothalamic glucose-excited neurons, and enteroendocrine K cells.
Therapeutically, the work offers a rationale for rethinking GK activator design. Conventional GK activators that boost catalytic activity have faced challenges including loss of efficacy over time, hepatic steatosis, and impaired β-cell function10. These off-target effects likely stem from enhanced glycolysis. Strategies aimed at stabilizing the glucose-bound conformation of GK, rather than simply increasing its catalytic turnover, might more safely stimulate endogenous GLP-1 secretion.
Overall, Li and colleagues greatly broaden our understanding of glucose-stimulated GLP-1 secretion, establishing that glucose acts as a ligand and GK as its receptor to directly inhibit KATP channels through protein–protein interaction, independent of ATP generation. This work thus resolves long-standing paradoxes in incretin physiology and may thereby open new avenues for therapeutic development targeting metabolic diseases.

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The Author(s) 2026. Published by Higher Education Press. This is an Open Access article distributed under the terms of the CC BY license (https://creativecommons.org/licenses/by/4.0/).

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Li, T., Auwerx, J.  Sweet signal: glucose–GK binding shuts KATP channels for GLP-1 secretion  Vita https://doi.org/10.15302/vita.2026.08.0065 ()
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