Pancreatic β-cell identity and metabolic consequences following anti-inflammatory therapy in type 2 diabetes

Type 2 diabetes mellitus (T2DM) is a metabolic disorder, characterized by the inability of the insulin secreting β-cells to compensate for insulin resistance. Increasing evidence points towards a role of the immune system in this development. Furthermore, ß-cell dedifferentiation has recently been proposed as a mechanism underlying β-cell failure in T2DM. Therefore we investigated whether cytokines may induce ß-cell dedifferentiation and whether anti-inflammatory drugs, alone or in combination, may improve insulin secretion.
We observed that IL-1ß drives ß-cell dedifferentiation in both human and mouse pancreatic islets. Interestingly, ß-cell identity maintaining transcription factor FoxO1 was downregulated upon IL-1ß exposure. To test the relevance of IL-1ß induced dedifferentiation in vivo, 3 animal models of T2DM were investigated for the presence of ß-cell dedifferentiation and the impact of IL-1ß antagonism. All 3 models showed signs of islet-inflammation and ß-cell dedifferentiation. However, IL-1ß antagonism failed to restore reduced expression of key ß-cell identity markers, while partially improving glycemia. Thus, while IL-1ß triggers dedifferentiation and dysfunction in vitro, glycemic improvement through IL-1ß antagonism appears not to be related to ß-cell redifferentiation in vivo. In addition, while separate treatment of anti-IL-1ß, anti-TNFα and NF-κB suppressing salicylate showed favorable effects on glycemia, our data do not show a meaningful additive effect of IL-1ß inhibition together with TNFα antagonism or with salicylate.
Finally, focusing on the adaptive side of inflammation, we tested whether the physiological, exercise-induced and muscle-derived IL–6 is regulated by the IL–1 system. In a double blind, crossover study in humans, we could show that the beneficial effect of muscle-induced IL–6 is not meaningfully affected by IL–1 antagonism.