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Updated: Sep 11, 2025
High-resolution Respirometry to Measure Mitochondrial Function of Intact Beta Cells in the Presence of Natural Compounds
Published on: January 23, 2018
Ramulus Mori (Sangzhi) alkaloids enhance pancreatic β-Cell maturation and function by targeting the CD81/endoplasmic
Nan Wu1, Wenjing Zhang1, Sunyue He1
1Department of Endocrinology and Metabolism, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China.
Background:
β-cell dedifferentiation and impaired maturation are crucial contributors to β-cell dysfunction in type 2 diabetes mellitus (T2DM), yet targeted therapies remain limited.
Objective:
To investigate the protective effects of Ramulus Mori (Sangzhi) Alkaloids (SZ-A) on β-cell function and maturation in T2DM.
Methods:
A T2DM mouse model was induced by high-fat diet and streptozotocin, followed by SZ-A treatment. Single-cell RNA sequencing (scRNA-seq) was used to profile β-cell subpopulations, identifying Cd81 as a marker of β-cell immaturity. Cd81-overexpressing diabetic mice, as well as β-TC-6 cells with either Cd81 overexpression or knockdown, were employed to explore the role of CD81 in SZ-A-mediated β-cell maturation. Western blotting was performed to evaluate the effects of SZ-A on endoplasmic reticulum (ER) stress. The potential interactions between SZ-A components-1-deoxynojirimycin (DNJ), fagomine (FAG), and 1,4-dideoxy-1,4-imino-D-arabinitol (DAB)-and CD81 were investigated using molecular docking.
Results:
SZ-A treatment improved glucose metabolism in T2DM mice in a dose-dependent manner. ScRNA-seq revealed an increased proportion of Cd81high β-cells with reduced expression of mature β-cell markers in diabetic islets, which was reversed by SZ-A. CD81 overexpression attenuated the metabolic benefits of SZ-A both in vivo and in vitro. Mechanistically, SZ-A alleviates CD81-mediated ER stress, at least in part via its active components DNJ and FAG, which may bind to CD81, suppress its expression, and thereby promote insulin secretion.
Conclusion:
SZ-A promotes β-cell maturation and function by suppressing CD81-mediated ER stress. These findings reveal a novel therapeutic mechanism of SZ-A and identify CD81 as a potential target for T2DM intervention.
Insights
Ramulus Mori Alkaloids (SZ-A) improve glucose metabolism in type 2 diabetes by promoting beta-cell maturation. SZ-A suppresses CD81, reducing ER stress and enhancing insulin secretion, offering a new therapeutic target.
Area of Science:
- Endocrinology
- Molecular Biology
- Pharmacology
Background:
- Beta-cell dysfunction, characterized by dedifferentiation and impaired maturation, is central to type 2 diabetes mellitus (T2DM).
- Current therapeutic strategies targeting beta-cell function in T2DM are limited.
Purpose of the Study:
- To investigate the protective effects of Ramulus Mori (Sangzhi) Alkaloids (SZ-A) on beta-cell function and maturation in a T2DM model.
- To elucidate the underlying molecular mechanisms, focusing on the role of CD81 and endoplasmic reticulum (ER) stress.
Main Methods:
- Induced T2DM in mice using high-fat diet and streptozotocin, followed by SZ-A treatment.
- Utilized single-cell RNA sequencing (scRNA-seq) to profile beta-cell subpopulations and identify CD81 as a marker of immaturity.
- Investigated CD81's role in SZ-A-mediated maturation using overexpression/knockdown models and assessed ER stress via Western blotting.
Main Results:
- SZ-A treatment dose-dependently improved glucose metabolism in T2DM mice.
- ScRNA-seq identified increased CD81 expression in immature beta-cells in T2DM, a state reversed by SZ-A.
- CD81 overexpression diminished SZ-A's metabolic benefits; SZ-A alleviated CD81-mediated ER stress, partly via components DNJ and FAG, promoting insulin secretion.
Conclusions:
- SZ-A promotes beta-cell maturation and function by suppressing CD81-mediated ER stress.
- These findings highlight a novel therapeutic mechanism for SZ-A in T2DM.
- CD81 emerges as a potential therapeutic target for T2DM intervention.
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