Enhanced insulin signaling via circulating ATG7: A potential therapeutic strategy for diabetes

Yi Guan; Yang Yu; Mengdi Fu; Hongde Xu; Eunyoung Lee; Hanfeng Wang; José María Moreno-Navarrete; Chengsi Deng; Yuheng Li; Kangjing Song; Qiqiang Guo; Xiaoyou Jiang; Xiaoyu Song; Wendong Guo; Yanling Feng; Fei Yi; Ning Bai; Jiabin Li; Jingyang Chen; Wenjing Shen; Wan Yu; Difei Wang; Siru Hou; Jichun Tan; José Manuel Fernández-Real; Antonio Vidal-Puig; Liu Cao

doi:10.1073/pnas.2503783123

Enhanced insulin signaling via circulating ATG7: A potential therapeutic strategy for diabetes

Yi Guan
, Yang Yu
, Mengdi Fu
, Hongde Xu
, Eunyoung Lee
, Hanfeng Wang
, José María Moreno-Navarrete
, Chengsi Deng
, Yuheng Li
, Kangjing Song
, Qiqiang Guo
, Xiaoyou Jiang
, Xiaoyu Song
, Wendong Guo
, Yanling Feng
, Fei Yi
, Ning Bai
, Jiabin Li
, Jingyang Chen
, Wenjing Shen

Wan Yu, Difei Wang, Siru Hou, Jichun Tan, José Manuel Fernández-Real, Antonio Vidal-Puig, Liu Cao

Girona Biomedical Research Institute (IdiBGi)

China Medical University
Chiba University
University of Girona
Key Laboratory of Reproductive Dysfunction Disease and Fertility Remodeling of Liaoning Province
University of Cambridge
Centro de Investigación Biomédica en Red
Nanjing University

Research output: Contribution to journal › Scientific article › peer-review

2 Citations (Scopus)

Abstract

Diabetes and insulin resistance (IR) remain major global health challenges, underscoring the need for novel therapeutic strategies. Here, we identify an autophagy-independent role of circulating autophagy-related gene 7 (ATG7) in metabolic regulation. Circulating ATG7 enhances insulin sensitivity and glucose homeostasis by directly interacting with IRS1 and modulating insulin signaling (IS) through liver–muscle crosstalk. Mechanistically, ATG7 binds to IRS1, promoting its activation and the propagation of downstream IS. Notably, we identify an ATG7-derived peptide (Aap2) that recapitulates ATG7’s insulin-sensitizing effects and improves glycemic control in both Type 1 and Type 2 diabetic mouse models. These findings establish ATG7 as a key regulator of IS and suggest that targeting ATG7 may represent a promising therapeutic approach for IR and diabetes.

Original language	English
Article number	e2503783123
Journal	Proceedings of the National Academy of Sciences of the United States of America
Volume	123
Issue number	1
DOIs	https://doi.org/10.1073/pnas.2503783123
Publication status	Published - 6 Jan 2026

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Keywords

ATG7
IRS1
exosomes
glucose homeostasis
insulin resistance

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10.1073/pnas.2503783123

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Guan, Y., Yu, Y., Fu, M., Xu, H., Lee, E., Wang, H., Moreno-Navarrete, J. M., Deng, C., Li, Y., Song, K., Guo, Q., Jiang, X., Song, X., Guo, W., Feng, Y., Yi, F., Bai, N., Li, J., Chen, J., ... Cao, L. (2026). Enhanced insulin signaling via circulating ATG7: A potential therapeutic strategy for diabetes. Proceedings of the National Academy of Sciences of the United States of America, 123(1), Article e2503783123. https://doi.org/10.1073/pnas.2503783123

@article{f122c4b20e024eeeb3fc744a59a20a9a,

title = "Enhanced insulin signaling via circulating ATG7: A potential therapeutic strategy for diabetes",

abstract = "Diabetes and insulin resistance (IR) remain major global health challenges, underscoring the need for novel therapeutic strategies. Here, we identify an autophagy-independent role of circulating autophagy-related gene 7 (ATG7) in metabolic regulation. Circulating ATG7 enhances insulin sensitivity and glucose homeostasis by directly interacting with IRS1 and modulating insulin signaling (IS) through liver–muscle crosstalk. Mechanistically, ATG7 binds to IRS1, promoting its activation and the propagation of downstream IS. Notably, we identify an ATG7-derived peptide (Aap2) that recapitulates ATG7{\textquoteright}s insulin-sensitizing effects and improves glycemic control in both Type 1 and Type 2 diabetic mouse models. These findings establish ATG7 as a key regulator of IS and suggest that targeting ATG7 may represent a promising therapeutic approach for IR and diabetes.",

keywords = "ATG7, IRS1, exosomes, glucose homeostasis, insulin resistance",

author = "Yi Guan and Yang Yu and Mengdi Fu and Hongde Xu and Eunyoung Lee and Hanfeng Wang and Moreno-Navarrete, \{Jos{\'e} Mar{\'i}a\} and Chengsi Deng and Yuheng Li and Kangjing Song and Qiqiang Guo and Xiaoyou Jiang and Xiaoyu Song and Wendong Guo and Yanling Feng and Fei Yi and Ning Bai and Jiabin Li and Jingyang Chen and Wenjing Shen and Wan Yu and Difei Wang and Siru Hou and Jichun Tan and Fern{\'a}ndez-Real, \{Jos{\'e} Manuel\} and Antonio Vidal-Puig and Liu Cao",

note = "Publisher Copyright: Copyright {\textcopyright} 2025 the Author(s).",

year = "2026",

month = jan,

day = "6",

doi = "10.1073/pnas.2503783123",

language = "English",

volume = "123",

journal = "Proceedings of the National Academy of Sciences of the United States of America",

issn = "0027-8424",

publisher = "National Academy of Sciences",

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Guan, Y, Yu, Y, Fu, M, Xu, H, Lee, E, Wang, H, Moreno-Navarrete, JM, Deng, C, Li, Y, Song, K, Guo, Q, Jiang, X, Song, X, Guo, W, Feng, Y, Yi, F, Bai, N, Li, J, Chen, J, Shen, W, Yu, W, Wang, D, Hou, S, Tan, J, Fernández-Real, JM, Vidal-Puig, A & Cao, L 2026, 'Enhanced insulin signaling via circulating ATG7: A potential therapeutic strategy for diabetes', Proceedings of the National Academy of Sciences of the United States of America, vol. 123, no. 1, e2503783123. https://doi.org/10.1073/pnas.2503783123

TY - JOUR

T1 - Enhanced insulin signaling via circulating ATG7

T2 - A potential therapeutic strategy for diabetes

AU - Guan, Yi

AU - Yu, Yang

AU - Fu, Mengdi

AU - Xu, Hongde

AU - Lee, Eunyoung

AU - Wang, Hanfeng

AU - Moreno-Navarrete, José María

AU - Deng, Chengsi

AU - Li, Yuheng

AU - Song, Kangjing

AU - Guo, Qiqiang

AU - Jiang, Xiaoyou

AU - Song, Xiaoyu

AU - Guo, Wendong

AU - Feng, Yanling

AU - Yi, Fei

AU - Bai, Ning

AU - Li, Jiabin

AU - Chen, Jingyang

AU - Shen, Wenjing

AU - Yu, Wan

AU - Wang, Difei

AU - Hou, Siru

AU - Tan, Jichun

AU - Fernández-Real, José Manuel

AU - Vidal-Puig, Antonio

AU - Cao, Liu

PY - 2026/1/6

Y1 - 2026/1/6

N2 - Diabetes and insulin resistance (IR) remain major global health challenges, underscoring the need for novel therapeutic strategies. Here, we identify an autophagy-independent role of circulating autophagy-related gene 7 (ATG7) in metabolic regulation. Circulating ATG7 enhances insulin sensitivity and glucose homeostasis by directly interacting with IRS1 and modulating insulin signaling (IS) through liver–muscle crosstalk. Mechanistically, ATG7 binds to IRS1, promoting its activation and the propagation of downstream IS. Notably, we identify an ATG7-derived peptide (Aap2) that recapitulates ATG7’s insulin-sensitizing effects and improves glycemic control in both Type 1 and Type 2 diabetic mouse models. These findings establish ATG7 as a key regulator of IS and suggest that targeting ATG7 may represent a promising therapeutic approach for IR and diabetes.

AB - Diabetes and insulin resistance (IR) remain major global health challenges, underscoring the need for novel therapeutic strategies. Here, we identify an autophagy-independent role of circulating autophagy-related gene 7 (ATG7) in metabolic regulation. Circulating ATG7 enhances insulin sensitivity and glucose homeostasis by directly interacting with IRS1 and modulating insulin signaling (IS) through liver–muscle crosstalk. Mechanistically, ATG7 binds to IRS1, promoting its activation and the propagation of downstream IS. Notably, we identify an ATG7-derived peptide (Aap2) that recapitulates ATG7’s insulin-sensitizing effects and improves glycemic control in both Type 1 and Type 2 diabetic mouse models. These findings establish ATG7 as a key regulator of IS and suggest that targeting ATG7 may represent a promising therapeutic approach for IR and diabetes.

KW - ATG7

KW - IRS1

KW - exosomes

KW - glucose homeostasis

KW - insulin resistance

UR - https://www.scopus.com/pages/publications/105026323964

U2 - 10.1073/pnas.2503783123

DO - 10.1073/pnas.2503783123

M3 - Scientific article

C2 - 41461029

AN - SCOPUS:105026323964

SN - 0027-8424

VL - 123

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

IS - 1

M1 - e2503783123

ER -

Enhanced insulin signaling via circulating ATG7: A potential therapeutic strategy for diabetes

Abstract

UN SDGs

Keywords

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