In this study, Zhang and colleagues show that drinking-water supplementation of D-mannose serves as an effective and potential therapeutic of type 2 diabetes, with improvement of both liver health and bone mass. The effect is exerted through suppressing macrophage release of extracellular vesicles based on metabolic control of CD36 expression. These findings shed light on translational pharmaceutical strategies of type 2 diabetes.
Abstract:
Type 2 diabetes (T2D) is a prevalent metabolic disease inducing alterations of multiple organ systems with currently no cure. Extracellular vesicles (EVs) have been increasingly noticed as one critical paracrine communicator inducing insulin resistance and metabolic disorders in T2D, but clinically available pharmaceuticals for controlling pathological EV release is lacking. Here, we discover that the natural monosaccharide D-mannose exists with an altered level in the db/db mouse T2D model. Intriguingly, oral administration of D-mannose with the drinking water safely ameliorates diabetic symptoms in db/db mice. D-mannose administration does not critically regulate the gut microbiome and circulatory T lymphocytes in treating T2D, while administrated D-mannose rapidly accumulates in the liver, alleviates hepatic steatosis and rescues insulin resistance. Regarding the mechanism, the T2D pathological EVs released by macrophages are targeted and reduced by D-mannose, which metabolically inhibits CD36 expression and restores function of hepatocytes. Importantly, by regulating macrophage EV release, D-mannose administration reveals extra-hepatic benefits and retards diabetic bone loss. Taken together, our findings unveil D-mannose as a candidate T2D therapeutic and highlight sugars governing intercellular EV crosstalk, paving an avenue for pharmaceutical T2D approaches with amelioration of multi-organ deteriorations.
Author list:
Sha Zhang†, Kai Zhang†, Chen-Xi Zheng†*, Ying-Feng Gao†, Guo-Rong Deng, Xu Zhang, Yuan Yuan, Ting Jia, Si-Yuan Tang, Guang-Xiang He, Zhen Gong, Na Zhao, Bo Ma, Hua Tian, Hong Zhang, Zhe Li, Yong-Chang Di-Wu, Yi-Han Liu, Liang Kong, Jing Ma*, Yan Jin*, Bing-Dong Sui*
How to cite:
S. Zhang, K. Zhang, C.-X. Zheng, Y.-F. Gao, G.-R. Deng, X. Zhang, Y. Yuan, T. Jia, S.-Y. Tang, G.-X. He, Z. Gong, N. Zhao, B. Ma, H. Tian, H. Zhang, Z. Li, Y.-C. Di-Wu, Y.-H. Liu, L. Kong, J. Ma, Y. Jin, B.-D. Sui, Exploration 2025, 5, 20240133.
https://doi.org/10.1002/EXP.20240133