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  3. Buckwheat protein-derived peptide ameliorates insulin resistance by directing O-linked N-acetylglucosamine transferase to regulate the SIRT1/PGC1α pathway

Buckwheat protein-derived peptide ameliorates insulin resistance by directing O-linked N-acetylglucosamine transferase to regulate the SIRT1/PGC1α pathway

  • Int J Biol Macromol. 2025 Apr;304(Pt 2):140925. doi: 10.1016/j.ijbiomac.2025.140925.
Jiajun Yang 1,  Siyu Hou 2,  Yuhui Zhao 2,  Zhaoyang Sun 2,  Lilin Zhang 2,  Yan Deng 2,  Xiaoli Shang 3,  Hanjie Yu 4,  Zheng Li 5,  Hongmei Li 6
Affiliations

Affiliations

  • 1 Department of Biochemistry and Molecular Biology, School of Basic Medical Science, Guizhou Medical University, Guiyang 561113, China; Key Laboratory of Endemic and Ethenic Diseases, Ministry of Education & Key Laboratory of Medical Molecular Biology of Guizhou Province, Guizhou Medical University, Guiyang 550004, Guizhou, China.
  • 2 Department of Biochemistry and Molecular Biology, School of Basic Medical Science, Guizhou Medical University, Guiyang 561113, China.
  • 3 School of Biology and Engineering (School of Modern Industry of Health Medicine), Guizhou Medical University, Guizhou, Guiyang 561113, China.
  • 4 Laboratory for Functional Glycomics, College of Life Sciences, Northwest University, Xi'an 710069, China.
  • 5 Laboratory for Functional Glycomics, College of Life Sciences, Northwest University, Xi'an 710069, China. Electronic address: zhengli@nwu.edu.cn.
  • 6 Department of Biochemistry and Molecular Biology, School of Basic Medical Science, Guizhou Medical University, Guiyang 561113, China; Key Laboratory of Endemic and Ethenic Diseases, Ministry of Education & Key Laboratory of Medical Molecular Biology of Guizhou Province, Guizhou Medical University, Guiyang 550004, Guizhou, China. Electronic address: gylhm@gmc.edu.cn.
PMID: 39947565 DOI: 10.1016/j.ijbiomac.2025.140925
Abstract

The antidiabetic activity of the novel Buckwheat protein-derived peptide (Ala-Phe-Tyr-Arg-Trp, AFYRW) and its associated protein glycosylation have been verified. Our preliminary study demonstrates the potential of AFYRW as a therapeutic agent for diabetes, but the mechanism needs further investigation. Given the vital role of O-linked N-acetylglucosamine transferase (OGT) in diabetes mellitus and Insulin resistance (IR), we focused on the underlying molecular mechanisms of them in ameliorating IR. We found AFYRW protects against hyperglycemia in diabetic mice and improves glucose metabolism in an IR cell model. Mechanistically, we demonstrated that AFYRW decreases glutamine-fructose-6-phosphate amidotransferase (GFAT) expression via X-box binding protein 1 (XBP1) in the hexosamine biosynthesis pathway (HBP), consequently decreasing OGT and stimulating the SIRT1/PGC1α pathway. Of note, the overlapping roles of increased SIRT1 and decreased OGT caused by AFYRW ameliorated IR. The data presented here show that AFYRW contributes to metabolism by directly controlling glucose homeostasis. Taken together, our study unveils that AFYRW protects against both Insulin resistance and diabetes mellitus-induced hyperglycemia through OGT to regulate the SIRT1/PGC1α pathway, which provides a mechanistic basis for novel AFYRW to be a potential therapeutic agent.

Keywords

AFYRW; Hexosamine biosynthesis pathway; Insulin resistance; OGT; SIRT1/PGC1α pathway.

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