The contribution of macrophages to islet inflammation and β-cell dysfunction in the context of Type 2 diabetes is increasingly accepted, but remains poorly understood. Deletion of PKCε in mice fed a high fat diet (HFD) improves β-cell function in vivo. PKCε is important in macrophage function, therefore we hypothesise that deletion of PKCε in macrophages could alleviate macrophage-mediated β-cell dysfunction in HFD mice.
PKCε floxed mice were crossed with Pdx-cre mice for β-cell specific deletion and LysMcre mice for macrophage specific deletion. Mice were fed normal chow or HFD and glucose tolerance tests (GTTs) and insulin tolerance tests (ITTs) were performed. Insulin excursions were monitored during GTTs. Circulating cytokines and islet gene expression were also characterised. The role of PKCε in macrophage function in vitro was characterised in primary PKCε WT and null macrophages. Islet cell suspensions were sorted by fluorescence-activated cell sorting in to macrophage and β-cell fractions, which were lysed for gene expression analysis.
β-cell specific PKCε deletion did not improve β-cell function in HFD mice. At 12 weeks of HFD, LysMcrePKCεf mice exhibited significantly improved glucose tolerance, and enhanced insulin secretion during the GTT. Insulin resistance was not altered, and no changes in circulating cytokines or islet inflammatory gene expression were observed. In vitro activation of primary PKCε WT and null macrophages showed no alteration in macrophage activation as measured by common signalling pathways and release of common cytokines. However there was a remodelling of expression of four growth factor receptors, suggesting acquisition of a more specialized phenotype. Islet cell sorting experiments revealed macrophages as the major source of inflammatory gene expression for all genes measured, except for MCP-1.
These results suggest that a subtle alteration in macrophage biology independently of currently known mediators can preserve β-cell function under a HFD stress.