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Abstract

Glucose sensing and signaling are central to cellular metabolic machinery for the regulation of metabolic homeostasis. Glucose sensing has been almost always assumed to be coupled with glucose metabolism; however, recent findings have unraveled metabolism-independent sensing mechanisms. Here, we discuss whether glucose transporters (GLUTs) and sodium-glucose co-transporters (SGLTs) may also function as glucose sensors independent of their roles in transporting glucose. Moreover, we review the emerging roles of G protein-coupled receptors (GPCRs) in sensing glucose and, consequently, initiating its signaling pathways in a cell-specific manner. Altogether, this review offers insights into the newly identified glucose sensing mechanisms and highlights the therapeutic potential of targeting the downstream glucose signaling pathways for more efficient treatment of diabetes, obesity, and their complications.

Document Type

Article

Publication Date

2026

Notes/Citation Information

© 2025 Elsevier Ltd. All rights are reserved, including those for text and data mining, AI training, and similar technologies.

Digital Object Identifier (DOI)

https://doi.org/10.1016/j.tem.2025.08.008

Funding Information

NIH awards DK124619 and DK140148 and University of Kentucky start-up funds to K.H.C. The Del Monte Institute for Neuroscience Pilot Research Award, University of Rochester to K.H.C.

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