Syntaxin 4 Enrichment in b-Cells Prevents Conversion to Autoimmune Diabetes in Non-Obese Diabetic (NOD) Mice

Abstract

Syntaxin 4 (STX4), a plasma membrane–localized SNARE protein, regulates human islet b-cell insulin secretion and preservation of b-cell mass. We found that human type 1 diabetes (T1D) and NOD mouse islets show reduced b-cell STX4 expression, consistent with decreased STX4 expression, as a potential driver of T1D phenotypes. To test this hypothesis, we generated inducible b-cell–specific STX4-expressing NOD mice (NOD-ibSTX4). Of NOD-ibSTX4 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-ibSTX4 mice demonstrated superior whole-body glucose tolerance and b-cell glucose responsiveness than NOD-Ctrl mice. Higher b-cell mass and reduced b-cell apoptosis were also detected in NOD-ibSTX4 pancreata compared with pancreata of NOD-Ctrl mice. Single-cell RNA sequencing revealed that islets from NOD-ibSTX4 had markedly reduced interferon-g signaling and tumor necrosis factor-a signaling via nuclear factor-kB inisletb-cells, including reduced expression of the chemokine CCL5; CD4+ regulatory T cells were also enriched in NOD-ibSTX4 islets. These results provide a deeper mechanistic understanding of STX4 function in b-cell protection and warrant further investigation of STX4 enrichment as a strategy to reverse or prevent T1D in humans or protect b-cell grafts.