Type 2 diabetes (T2D) is associated with low-grade inflammation. Here we investigate if the anti-inflammatory cytokine interleukin-4 (IL-4) affects glucose-stimulated insulin secretion (GSIS) in human islets from non-diabetic (ND) and type-2 diabetic (T2D) donors. We first confirmed that GSIS is reduced in islets from T2D donors. Treatment with IL-4 for 48 h had no further effect on GSIS in these islets but significantly reduced secretion in ND islets. Acute treatment with IL-4 for 1 h had no effect on GSIS in ND islets which led us to suspect that IL-4 affects a slow cellular mechanism such as gene transcription. IL-4 has been reported to regulate miR-378a-3p and, indeed, we found that this microRNA was increased with IL-4 treatment. However, overexpression of miR-378a-3p in the human beta cell line EndoC-βH1 did not affect GSIS. MiR-378a-3p is transcribed from the same gene as peroxisome proliferator-activated receptor gamma co-activator 1 beta (PCG-1β) and we found that IL-4 treatment showed a clear tendency to increased gene expression of PCG-1β. PCG-1β is a co-activator of peroxisome proliferator-activated receptor gamma (PPARγ) and, the gene expression of PPARγ was also increased with IL-4 treatment. Our data suggests that the protective role of IL-4 on beta cell survival comes at the cost of lowered insulin secretion, presumably involving the PPARγ-pathway.
Keywords: Beta cell; Diabetes; IL-4; Insulin secretion; PPARγ; microRNA.
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