The Role Of Inflammation In Beta-Cell Dedifferentiation

Chronic inflammation impairs insulin secretion and sensitivity. beta-cell dedifferentiation has recently been proposed as a mechanism underlying beta-cell failure in T2D. Yet the effect of inflammation on beta-cell identity in T2D has not been studied. Therefore, we investigated whether pro-inflammatory cytokines induce beta-cell dedifferentiation and whether anti-inflammatory treatments improve insulin secretion via beta-cell redifferentiation. We observed that IL-1 beta, IL-6 and TNF alpha promote beta-cell dedifferentiation in cultured human and mouse islets, with IL-1 beta being the most potent one of them. In particular, beta-cell identity maintaining transcription factor Foxo1 was downregulated upon IL-1 beta exposure. In vivo, anti-IL-1 beta, anti-TNF alpha or NF-kappa B inhibiting sodium salicylate treatment improved insulin secretion of isolated islets. However, only TNF alpha antagonism partially prevented the loss of beta-cell identity gene expression. Finally, the combination of IL-1 beta and TNF alpha antagonism improved insulin secretion of ex vivo isolated islets in a synergistic manner. Thus, while inflammation triggered beta-cell dedifferentiation and dysfunction in vitro, this mechanism seems to be only partly responsible for the observed in vivo improvements in insulin secretion.