Hepatic AMPK signaling activation in response to dynamic REDOX balance is a biomarker of exercise to improve blood glucose control

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Abstract

Antioxidant intervention is considered to inhibit reactive oxygen species (ROS) and alleviates hyperglycemia. Paradoxically, moderate exercise can produce ROS to improve diabetes. The exact redox mechanism of these two different approaches remains largely unclear. Here, by comparing exercise and antioxidants intervention on type 2 diabetic rats, we found moderate exercise upregulated compensatory antioxidant capability and reached a higher level of redox balance in the liver. In contrast, antioxidant intervention achieved a low-level redox balance by inhibiting oxidative stress. Both of these two interventions could promote glucose catabolism and inhibit gluconeogenesis through activation of hepatic AMPK signaling, therefore ameliorating diabetes. During exercise, different levels of ROS generated by exercise have differential regulations on the activity and expression of hepatic AMPK. Moderate exercise-derived ROS promoted hepatic AMPK glutathionylation activation. However, excessive exercise increased oxidative damage and inhibited the activity and expression of AMPK. Overall, our results illustrate that both exercise and antioxidant intervention improve blood glucose in diabetes by promoting redox balance, despite different levels of redox balance. These results indicate that the AMPK signaling activation, combined with oxidative damage markers, could act as a sensitive biomarker, reflecting the threshold of redox balance defining effective treatment in diabetes. These findings provide theoretical evidence for the precise treatment of diabetes by antioxidants and exercise.

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Figure 1 - Source Data 1, Source Data 2; Figure 2 - Source Data 1; Figure 3 - Source Data 1, Source Data 2; Figure 4 - Source Data 1, Source Data 2; Figure 5 - Source Data 1, Source Data 2; Figure 6 - Source Data 1, Source Data 2 contain the numerical data used to generate the figures.

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Meiling Wu

Department of Biochemistry and Molecular Biology, Fudan University, Shanghai, China

Competing interests
The authors declare that no competing interests exist.
Anda Zhao

Department of Biochemistry and Molecular Biology, Fudan University, Shanghai, China

Competing interests
The authors declare that no competing interests exist.
Xingchen Yan

Department of Biochemistry and Molecular Biology, Fudan University, Shanghai, China

Competing interests
The authors declare that no competing interests exist.
Hongyang Gao

Department of Biochemistry and Molecular Biology, Fudan University, Shanghai, China

Competing interests
The authors declare that no competing interests exist.
Chunwang Zhang

Department of Biochemistry and Molecular Biology, Fudan University, Shanghai, China

Competing interests
The authors declare that no competing interests exist.
Xiaomin Liu

Department of Biochemistry and Molecular Biology, Fudan University, Shanghai, China

Competing interests
The authors declare that no competing interests exist.
Qiwen Luo

Department of Biochemistry and Molecular Biology, Fudan University, Shanghai, China

Competing interests
The authors declare that no competing interests exist.
Feizhou Xie

Shanghai Changning Maternity and Infant Health Hospital, Shanghai, China

Competing interests
The authors declare that no competing interests exist.
Shanlin Liu

Free Radical Regulation and Application Research Center, Fudan University, Shanghai, China

For correspondence
slliu@shmu.edu.cn

Competing interests
The authors declare that no competing interests exist.
Dongyun Shi

Department of Biochemistry and Molecular Biology, Fudan University, Shanghai, China

For correspondence
dyshi@fudan.edu.cn

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0003-4179-1913

Funding

National Natural Science Foundation of China (31770916)

Dongyun Shi

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: All animal care and experimental procedures were approved by the Fudan University Institutional Laboratory Animal Ethics Committee (NO. 20170223-123).

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This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.