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Abstract

Objective: Glucose tolerance (GT) is a major effector for adipose tissue (AT) remodeling in obesity, yet its molecular mechanisms remain incompletely defined. We hypothesized that the biophysical and molecular profiles of AT-derived small extracellular vesicles (sEVAT) change in response to glucose availability and differ by GT status.

Methods: sEVAT were isolated from plasma of individuals with normal GT (NGT) and impaired GT (IGT) (n = 5/group) at fasting (0 h) and 1 h post glucose challenge during oral glucose tolerance test (OGTT). sEVAT were characterized for size, concentration, surface expression of insulin receptor-α (INSRα), proteome, and insulin signaling-related miRNAs. C2C12 myotubes were treated with sEVAT for 48 h, followed by quantification of 84 insulin signaling-related genes.

Result: The size and concentration of sEVAT did not differ between groups. At fasting, INSRα expression on sEVAT was comparable; however, groups exhibited opposite directional changes at 1-h OGTT. LC–MS/MS identified significant proteomic differences between NGT and IGT sEVAT. miR-27a-5p and miR-145a-5p levels in sEVAT also differed significantly by GT status. Notably, treatment with sEVAT (IGT-0 h) significantly downregulated insulin signaling-related genes in myotubes.

Conclusions: Distinct molecular signatures in sEVAT offer a unique insight into AT dysfunction during IGT and offer novel diagnostic and therapeutic targets.

Document Type

Article

Publication Date

2026

Notes/Citation Information

This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non- commercial and no modifications or adaptations are made. © 2026 The Author(s). Obesity published by Wiley Periodicals LLC on behalf of The Obesity Society.

Digital Object Identifier (DOI)

https://doi.org/10.1002/oby.70157

Funding Information

This work was supported by the Office of Extramural Research, National Institutes of Health (RF1AG068629, AG061805, P30CA012197, R01 DK080327, UL1 TR001998).

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