Messages From the Small Intestine Carried by Extracellular Vesicles in Prediabetes: a Proteomic Portrait

Extracellular vesicles (EVs) mediate cell-cell communication in a variety of physiological and pathological conditions. In the pathogenesis of type 2 diabetes, inter-organ communication plays an important role in its progress and metabolic surgery leads to its remission. Gut dysbiosis is emerging as a diabetogenic factor. However, it remains unclear how gut senses metabolic alterations and whether this is transmitted to other tissues via EVs content. In this study, using a diet induced-prediabetic mouse model, we observed that protein packaging in gut derived extracellular vesicles (GDE), specifically at the small intestine, is increased in prediabetes compared to GDE from healthy mice. Moreover, there were significant differences in GDE proteins between the two conditions. Proteins related to lipid metabolism and to oxidative stress management were more abundant in prediabetic GDE compared to those of healthy mice. On the other hand, proteins related to glycolytic activity, as well as those responsible for the degradation of polyubiquitinated composites in the proteasome, were depleted in prediabetic GDE compared to those of healthy mice. Together, our findings show that protein packaging in GDE is markedly modified during prediabetes pathogenesis. Thus, suggesting that prediabetes alterations in small intestine are translated into GDE with a modified protein cargo which are dispersed into the circulation where they can interact with and influence the metabolic status of other tissues. This study highlights the importance of the small intestine as a tissue that can propagate the metabolic dysfunctions of prediabetes throughout the body and the importance of GDE as the messenger.