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Syntaxin 4 Eenrichment in β-cells Prevents Conversion to Autoimmune Diabetes in Non-Obese Diabetic (NOD) Mice
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posted on 2021-09-23, 17:26 authored by Eunjin Oh, Erika M. McCown, Miwon Ahn, Pablo A. Garcia, Sergio Branciamore, Shanshan Tang, De-Fu Zeng, Bart O. Roep, Debbie C. ThurmondSyntaxin 4 (STX4), a plasma membrane-localized SNARE
protein, regulates human islet β-cell insulin secretion and preservation of β-cell
mass. We found that human type 1 diabetic (T1D) and non-obese diabetic (NOD)
mouse islets show reduced β-cell STX4 expression, consistent with decreased
STX4 expression as a potential driver of T1D phenotypes. To test this
hypothesis, we generated inducible β-cell-specific STX4-expressing NOD mice
(NOD-iβSTX4). Of NOD-iβSTX4 mice, 73% had sustained normoglycemia versus
<20% of control NOD (NOD-Ctrl) mice, by 25 weeks of age. At 12 weeks of age,
prior to diabetes conversion, NOD-iβSTX4 mice demonstrated superior whole-body
glucose tolerance and β-cell glucose responsiveness than NOD-Ctrl mice. Higher β-cell
mass and reduced β-cell apoptosis were also detected in NOD-iβSTX4 pancreata
compared with those of NOD-Ctrl mice. Single-cell RNA‐sequencing revealed that
islets from NOD-iβSTX4 had markedly reduced IFNƔ signaling and TNFα signaling via NF-ĸB in
islet β-cells, including reduced expression of the chemokine CCL5; CD4+
Treg cells were also enriched in NOD-iβSTX4 islets. These results provide a deeper
mechanistic understanding of STX4 function in β-cell protection and warrant further
investigation of STX4 enrichment as a strategy to reverse or prevent T1D in
humans or protect β-cell grafts.