Basic Study
Copyright ©The Author(s) 2024. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Diabetes. Feb 15, 2024; 15(2): 287-304
Published online Feb 15, 2024. doi: 10.4239/wjd.v15.i2.287
Duodenal-jejunal bypass improves hypothalamic oxidative stress and inflammation in diabetic rats via glucagon-like peptide 1-mediated Nrf2/HO-1 signaling
Huai-Jie Wang, Li-Bin Zhang, Si-Peng Sun, Qing-Tao Yan, Zhi-Qin Gao, Fang-Ming Fu, Mei-Hua Qu
Huai-Jie Wang, Si-Peng Sun, Mei-Hua Qu, Translational Medical Center, Weifang Second People's Hospital, Weifang 261041, Shandong Province, China
Li-Bin Zhang, Department of Endocrinology, Weifang Second People's Hospital, Weifang 261041, Shandong Province, China
Qing-Tao Yan, Department of Pediatric Surgery, Weifang People’s Hospital, Weifang 261041, Shandong Province, China
Zhi-Qin Gao, School of Bioscience and Technology, Weifang Medical University, Weifang 261053, Shandong Province, China
Fang-Ming Fu, Department of Endocrinology, Jinan Central Hospital Affiliated to Shandong First Medical University, Jinan 250013, Shandong Province, China
Co-corresponding authors: Fang-Ming Fu and Mei-Hua Qu.
Author contributions: Qu MH and Fu FM had equal contribution to this paper; Qu MH and Fu FM designed the research scheme and directed the relevant experimental techniques and methods; Wang HJ, Zhang LB, Sun SP, Yan QT, Gao ZQ performed the research and data analysis; Wang HJ, Qu MH analyzed the data and wrote the manuscript; All authors have read and approve the final manuscript. Qu MH and Fu FM contributed to the experimental design. Qu primarily developed the research direction and experimental hypothesis based on literature and previous research. Fu FM participated in the design of the experimental verification scheme. Qu MH and Fu FM jointly supervised the modeling and duodenal jejunal bypass surgery-related experiments. They are co-corresponding authors of this study, and there is no conflict of interest between them.
Supported by the Natural Science Foundation of China, No. 82070856; the Science and Technology Development Plan of Shandong Medical and Health Science, No. 202102040075; Scientific Research Plan of Weifang Health Commission, No. WFWSJK-2022-010 and No. WFWSJK-2022-008; and Weifang Science and Technology Development Plan, No. 2021YX071 and No. 2021YX070.
Institutional review board statement: This study was carried out following the recommendations of Weifang Medical University, China. The experimental protocol was approved by the Research Ethics Committee of Weifang Medical University, China, Approval No. 2020SDL074.
Institutional animal care and use committee statement: The experimental protocols were approved by the Institutional Animal Care and Use Committee, No. 2021SDL574.
Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article.
Data sharing statement: No additional data are available.
ARRIVE guidelines statement: The authors have read the ARRIVE guidelines, and the manuscript was prepared and revised according to the ARRIVE guidelines.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: https://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Mei-Hua Qu, PhD, Professor, Translational Medical Center, Weifang Second People's Hospital, No. 7 Yuanxiao Street, Weifang 261041, Shandong Province, China. qumeihua2016@163.com
Received: October 10, 2023
Peer-review started: October 10, 2023
First decision: November 17, 2023
Revised: December 12, 2023
Accepted: January 12, 2024
Article in press: January 12, 2024
Published online: February 15, 2024
Processing time: 117 Days and 2.4 Hours
Abstract
BACKGROUND

Type 2 diabetes mellitus (T2DM) is often accompanied by impaired glucose utilization in the brain, leading to oxidative stress, neuronal cell injury and infla-mmation. Previous studies have shown that duodenal jejunal bypass (DJB) surgery significantly improves brain glucose metabolism in T2DM rats, the role and the metabolism of DJB in improving brain oxidative stress and inflammation condition in T2DM rats remain unclear.

AIM

To investigate the role and metabolism of DJB in improving hypothalamic oxidative stress and inflammation condition in T2DM rats.

METHODS

A T2DM rat model was induced via a high-glucose and high-fat diet, combined with a low-dose streptozotocin injection. T2DM rats were divided into DJB operation and Sham operation groups. DJB surgical intervention was carried out on T2DM rats. The differential expression of hypothalamic proteins was analyzed using quantitative proteomics analysis. Proteins related to oxidative stress, inflammation, and neuronal injury in the hypothalamus of T2DM rats were analyzed by flow cytometry, quantitative real-time PCR, Western blotting, and immunofluorescence.

RESULTS

Quantitative proteomics analysis showed significant differences in proteins related to oxidative stress, inflammation, and neuronal injury in the hypothalamus of rats with T2DM-DJB after DJB surgery, compared to the T2DM-Sham groups of rats. Oxidative stress-related proteins (glucagon-like peptide 1 receptor, Nrf2, and HO-1) were significantly increased (P < 0.05) in the hypothalamus of rats with T2DM after DJB surgery. DJB surgery significantly reduced (P < 0.05) hypothalamic inflammation in T2DM rats by inhibiting the activation of NF-κB and decreasing the expression of interleukin (IL)-1β and IL-6. DJB surgery significantly reduced (P < 0.05) the expression of factors related to neuronal injury (glial fibrillary acidic protein and Caspase-3) in the hypothalamus of T2DM rats and upregulated (P < 0.05) the expression of neuroprotective factors (C-fos, Ki67, Bcl-2, and BDNF), thereby reducing hypothalamic injury in T2DM rats.

CONCLUSION

DJB surgery improve oxidative stress and inflammation in the hypothalamus of T2DM rats and reduce neuronal cell injury by activating the glucagon-like peptide 1 receptor-mediated Nrf2/HO-1 signaling pathway.

Keywords: Duodenal jejunal bypass surgery; Type 2 diabetes mellitus; Neuron apoptosis; Inflammatory; Oxidative stress; Hypothalamic injury

Core Tip: Duodenal jejunal bypass (DJB) increases serum glucagon-like peptide 1 (GLP-1) Levels and enhances brain glucose utilization, playing a positive role in the treatment of diabetes. The GLP-1 signal may play a significant role after DJB surgery in brain injury related to type 2 diabetes mellitus (T2DM). In the current study, DJB surgery increased the serum levels of GLP-1 and upregulated the expression of GLP-1 receptor and antioxidant signaling proteins (Nrf2 and HO-1) in the hypothalamic tissue of T2DM rats. DJB reduced the expression of hypothalamic inflammatory and nerve cell injury-related factors. Therefore, DJB surgery improve oxidative stress and inflammation in the hypothalamus of T2DM rats and reduce neuronal cell injury by activating the GLP-1-mediated Nrf2/HO-1 signaling pathway.