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- Title
Syntaxin 4 Enrichment in β-Cells Prevents Conversion to Autoimmune Diabetes in Non-Obese Diabetic (NOD) Mice.
- Authors
Oh, Eunjin; McCown, Erika M.; Ahn, Miwon; Garcia, Pablo A.; Branciamore, Sergio; Tang, Shanshan; Zeng, De-Fu; Roep, Bart O.; Thurmond, Debbie C.
- Abstract
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 diabetes (T1D) and 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 vs. <20% of control NOD (NOD-Ctrl) mice by 25 weeks of age. At 12 weeks of age, before 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 pancreata of NOD-Ctrl mice. Single-cell RNA sequencing revealed that islets from NOD-iβSTX4 had markedly reduced interferon-γ signaling and tumor necrosis factor-α signaling via nuclear factor-κB in islet β-cells, including reduced expression of the chemokine CCL5; CD4+ regulatory T 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.
- Subjects
REGULATORY T cells; TYPE 1 diabetes; SNARE proteins; MICE; RNA sequencing; RESEARCH; CELL culture; ANIMAL experimentation; RESEARCH methodology; MEDICAL cooperation; EVALUATION research; ISLANDS of Langerhans; COMPARATIVE studies; IMMUNITY; MEMBRANE proteins; PREDIABETIC state
- Publication
Diabetes, 2021, Vol 70, Issue 12, p2837
- ISSN
0012-1797
- Publication type
journal article
- DOI
10.2337/db21-0170