1/1
2 files

Syntaxin 4 Eenrichment in β-cells Prevents Conversion to Autoimmune Diabetes in Non-Obese Diabetic (NOD) Mice

figure
posted on 23.09.2021, 17:26 by Eunjin Oh, Erika M. McCown, Miwon Ahn, Pablo A. Garcia, Sergio Branciamore, Shanshan Tang, De-Fu Zeng, Bart O. Roep, Debbie C. Thurmond
Syntaxin 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.

Funding

This study was supported by grants from the National Institutes of Health (DK067912, DK112917 and DK102233 to D.C.T.) and the Wanek Family Project for Type 1 Diabetes (to D.C.T. and E.O.) Human islets were supplied by the Southern California Islet Cell Resource Center (City of Hope), and the Integrated Islet Distribution Program (IIDP). Research reported in this publication also includes work performed in the City of Hope Islet Core supported by the National Cancer Institute of the National Institutes of Health under award number P30CA33572.

History