Intestinal Nogo-B reduces GLP1 levels by binding to proglucagon on the endoplasmic reticulum to inhibit PCSK1 cleavage
Glucagon-like peptide 1 (GLP1), which is mainly processed and cleaved from proglucagon in enteroendocrine cells (EECs) of the intestinal tract, acts on the GLP1 receptor in pancreatic cells to stimulate insulin secretion and to inhibit glucagon secretion. However, GLP1 processing is not fully understood. Here, we show that reticulon 4B (Nogo-B), an endoplasmic reticulum (ER)-resident protein, interacts with the major proglucagon fragment of proglucagon to retain proglucagon on the ER, thereby inhibiting PCSK1-mediated cleavage of proglucagon in the Golgi. Intestinal Nogo-B knockout in male type 2 diabetes mellitus (T2DM) mice increases GLP1 and insulin levels and decreases glucagon levels, thereby alleviating pancreatic injury and insulin resistance. Finally, we identify aberrantly elevated Nogo-B expression and inhibited proglucagon cleavage in EECs from diabetic patients. Our study reveals the subcellular regulatory processes involving Nogo-B during GLP1 production and suggests intestinal Nogo-B as a potential therapeutic target for T2DM.
Authors
- Jun‐Ming Tang (ORCID: https://orcid.org/0000-0002-1591-7626)
- Yajun Duan (ORCID: https://orcid.org/0000-0002-3880-9070)
- Shasha Chen (ORCID: https://orcid.org/0000-0002-1446-7678)
- Ke Gong (ORCID: https://orcid.org/0000-0001-7025-4864)
- Liwei Jiang (ORCID: https://orcid.org/0000-0001-6313-6026)
- Zequn Yin
- Hou‐Zao Chen (ORCID: https://orcid.org/0000-0001-6805-3182)
- Yuanli Chen (ORCID: https://orcid.org/0000-0003-0813-3847)
- Likun Ma (ORCID: https://orcid.org/0000-0002-9680-1472)
- Zian Feng (ORCID: https://orcid.org/0000-0001-7780-2229)
- Yudong Guan
- Yasuko Iwakiri (ORCID: https://orcid.org/0000-0001-8032-5654)
- Bei Wang (ORCID: https://orcid.org/0000-0002-3898-6974)
- Lingyun Dai (ORCID: https://orcid.org/0000-0001-9386-5967)
- Ling Li (ORCID: https://orcid.org/0000-0002-5839-3033)
- Chenzhong Liao
- Ruru Pan
- Chao Xue
- Mengyao Wang (ORCID: https://orcid.org/0009-0005-5135-0224)
- Shuang Zhang (ORCID: https://orcid.org/0000-0003-4927-7230)
Institutions
- University of Science and Technology of China (CN)
- Hubei University of Medicine (CN)
- Hefei University of Technology (CN)
- Chinese Academy of Sciences (CN)
- Chinese Academy of Medical Sciences & Peking Union Medical College (CN)
- Nankai University (CN)
- China-Japan Friendship Hospital (CN)
- Hefei Institutes of Physical Science (CN)
- Southern University of Science and Technology (CN)
- Yale University (US)
Publication Details
- Journal
- Nature Communications
- Published
- 2024-08-09
- DOI
- https://doi.org/10.1038/s41467-024-51352-3
- Citations
- 4
- Primary Topic
- Diabetes Treatment and Management
- Type
- article
- Field-Weighted Citation Impact
- 1.43