RESUMO
Syntaxin 4 (STX4), a plasma membrane-localized SNARE protein, regulates human islet ß-cell insulin secretion and preservation of ß-cell mass. We found that human type 1 diabetes (T1D) and NOD mouse islets show reduced ß-cell STX4 expression, consistent with decreased STX4 expression, as a potential driver of T1D phenotypes. To test this hypothesis, we generated inducible ß-cell-specific STX4-expressing NOD mice (NOD-ißSTX4). Of NOD-ißSTX4 mice, 73% had sustained normoglycemia vs. <20% of control NOD (NOD-Ctrl) mice by 25 weeks of age. At 12 weeks of age, before diabetes conversion, NOD-ißSTX4 mice demonstrated superior whole-body glucose tolerance and ß-cell glucose responsiveness than NOD-Ctrl mice. Higher ß-cell mass and reduced ß-cell apoptosis were also detected in NOD-ißSTX4 pancreata compared with pancreata of NOD-Ctrl mice. Single-cell RNA sequencing revealed that islets from NOD-ißSTX4 had markedly reduced interferon-γ signaling and tumor necrosis factor-α signaling via nuclear factor-κB in islet ß-cells, including reduced expression of the chemokine CCL5; CD4+ regulatory T cells were also enriched in NOD-ißSTX4 islets. These results provide a deeper mechanistic understanding of STX4 function in ß-cell protection and warrant further investigation of STX4 enrichment as a strategy to reverse or prevent T1D in humans or protect ß-cell grafts.
