Syntaxin 4 Expression in Pancreatic β-Cells Promotes and Protects Functional β-Cell Mass.

Syntaxin 4 (Stx4) enrichment in human and mouse islet grafts improves transplant success in reversing STZ-induced diabetes in mice, although the underlying molecular mechanisms remain elusive. Toward further understanding this, human islets and inducible transgenic mice over-expressing Stx4 selectively in the islet β-cells (βTG-Stx4) were challenged with pro-inflammatory stressors in vitro and in vivo. Remarkably, βTG-Stx4 mice resisted multiple-low dose streptozotocin (STZ)-induced loss of β-cell mass and glucose intolerance; under standard conditions glucose tolerance was enhanced, maintaining normal fasting glycemia and insulinemia. Conversely, Stx4 heterozygous knockout mice succumbed rapidly to STZ-induced glucose intolerance compared with wild-type littermates. Human islet β-cells over-expressing Stx4 exhibited enhanced insulin secretory capacity, resilience against pro-inflammatory cytokine-induced apoptosis, and reduced expression of CXCL9, CXCL10 and CXCL11 genes coordinate with decreased activation/nuclear localization of NF-ĸB. Taken together, finding ways to boost Stx4 expression presents a novel potential therapeutic avenue for promoting islet function and preserving β-cell mass.