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

Abstract

Syntaxin 4 (Stx4) enrichment in human and mouse islet grafts improves the success of transplants in reversing streptozotocin (STZ)-induced diabetes in mice, although the underlying molecular mechanisms remain elusive. Toward a further understanding of this, human islets and inducible transgenic mice that selectively overexpress Stx4 in islet β-cells (βTG-Stx4) were challenged with proinflammatory stressors in vitro and in vivo. Remarkably, βTG-Stx4 mice resisted the loss of β-cell mass and the glucose intolerance that multiple low doses of STZ induce. Under standard conditions, glucose tolerance was enhanced and mice maintained normal fasting glycemia and insulinemia. Conversely, Stx4 heterozygous knockout mice succumbed rapidly to STZ-induced glucose intolerance compared with their wild-type littermates. Human islet β-cells overexpressing Stx4 exhibited enhanced insulin secretory capability; resilience against proinflammatory cytokine–induced apoptosis; and reduced expression of the CXCL9, CXCL10, and CXCL11 genes coordinate with decreased activation/nuclear localization of nuclear factor-κB. Finding ways to boost Stx4 expression presents a novel potential therapeutic avenue for promoting islet function and preserving β-cell mass.

Advances in Knowledge of Candidate Genes Acting at the Beta-Cell Level in the Pathogenesis of T1DM

“…Furthermore, increased STX4 expression can downregulate the expression of chemokine genes associated with inflammation and the apoptosis of pancreatic islets, such as CXCL9, CXCL10, and CXCL11 (94). Additionally, increased STX4 expression leads to decreased apoptosis by decreasing the translocation and activation of NF-κB (94). In conclusion, STX4 can influence both insulin secretion and beta-cell apoptosis, and it may be a novel target for the treatment of T1DM.…”

“…Located on human chromosome 16, the STX4 (syntaxin 4) gene is situated within the T1DM susceptibility region, and similar to HIP14, the Stx4 protein encoded by STX4 was identified as a T1DM candidate protein by in silico phenomeinteractome network analysis (12,94). STX4, which localizes to the plasma membrane, is associated with insulin secretion (94). STX4 overexpression restricted to pancreatic beta-cells increases the capacity for insulin secretion, promotes glucose tolerance and protects STZ-treated mice from developing diabetes (94).…”

“…STX4, which localizes to the plasma membrane, is associated with insulin secretion (94). STX4 overexpression restricted to pancreatic beta-cells increases the capacity for insulin secretion, promotes glucose tolerance and protects STZ-treated mice from developing diabetes (94). Furthermore, increased STX4 expression can downregulate the expression of chemokine genes associated with inflammation and the apoptosis of pancreatic islets, such as CXCL9, CXCL10, and CXCL11 (94).…”

“…STX4 overexpression restricted to pancreatic beta-cells increases the capacity for insulin secretion, promotes glucose tolerance and protects STZ-treated mice from developing diabetes (94). Furthermore, increased STX4 expression can downregulate the expression of chemokine genes associated with inflammation and the apoptosis of pancreatic islets, such as CXCL9, CXCL10, and CXCL11 (94). Additionally, increased STX4 expression leads to decreased apoptosis by decreasing the translocation and activation of NF-κB (94).…”

Sphingolipids in Type 1 Diabetes: Focus on Beta-Cells

“…Another twist to SL effects on beta-cell function was added by demonstration that synthaxin 4 (Stx4) is required for aSMase activity [138]. Stx4 is a plasma membrane-localized exocytosis protein that is crucial for GSIS [139]. Interestingly, Stx4 is a T1DM candidate protein [140].…”