D-mannose suppresses macrophage release of extracellular vesicles and ameliorates type 2 diabetes

The monosaccharide D-mannose exists naturally in low abundance in human blood, while an increased plasma mannose level is associated with insulin resistance and the incidence of type 2 diabetes (T2D) in patients. However, whether and how D-mannose may regulate T2D development remains elusive. Here, we show that despite the altered mannose metabolism in T2D, drinking-water supplementation of supraphysiological D-mannose safely ameliorates T2D in genetically obese db/db mice. Interestingly, D-mannose therapy exerts limited effects on the gut microbiome and peripheral blood T cells, whereas D-mannose after administration is enriched in the liver and alleviates hepatic steatosis and insulin resistance. Mechanistically, D-mannose suppresses macrophage release of pathological extracellular vesicles (EVs) for improving hepatocyte function through metabolic control of CD36 expression. Collectively, these findings reveal D-mannose as an effective and potential T2D therapeutic, which add to the current knowledge of sugars regulating EV-based intercellular communication and inspire translational pharmaceutical strategies of T2D. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=200 SRC="FIGDIR/small/580856v1_ufig1.gif" ALT="Figure 1"> View larger version (65K): org.highwire.dtl.DTLVardef@604ddcorg.highwire.dtl.DTLVardef@97ca9corg.highwire.dtl.DTLVardef@176f741org.highwire.dtl.DTLVardef@1630699_HPS_FORMAT_FIGEXP M_FIG C_FIG Drinking-water supplementation of D-mannose serves as an effective therapeutic of type 2 diabetes, which rescued hepatocyte steatosis through suppressing macrophage release of extracellular vesicles based on metabolic control of CD36 expression.