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Diabetes. 2018 Dec;67(12):2626-2639. doi: 10.2337/db18-0259. Epub 2018 Oct 10.

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

Author information

1
Department of Molecular and Cellular Endocrinology, Diabetes and Metabolism Research Institute of City of Hope, Duarte, CA.
2
Department of Surgery/Division of Transplantation, University of Illinois at Chicago, Chicago, IL.
3
Department of Internal Medicine, Duke Molecular Physiology Institute, Duke University, Durham, NC.
4
Department of Diabetes Immunology, Diabetes and Metabolism Research Institute of City of Hope, Duarte, CA.
5
Department of Molecular and Cellular Endocrinology, Diabetes and Metabolism Research Institute of City of Hope, Duarte, CA dthurmond@coh.org.

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.

PMID:
30305365
PMCID:
PMC6245223
[Available on 2019-12-01]
DOI:
10.2337/db18-0259
[Indexed for MEDLINE]

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