D‐Mannose Alleviates Type 2 Diabetes and Rescues Multi‐Organ Deteriorations by Controlling Release of Pathological Extracellular Vesicles

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.