期刊
DIABETES
卷 61, 期 7, 页码 1708-1718出版社
AMER DIABETES ASSOC
DOI: 10.2337/db11-1344
关键词
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资金
- Canadian Institutes of Health Research (CIHR) [MOP-201188, MOP-191501]
- Canadian Diabetes Association (CDA)
- Alberta Innovates-Health Solutions (AI-HS)
- Eliot Phillipson Clinician Scientist Training program
- Banting and Best Diabetes Centre (BBDC)
- Natural Sciences and Engineering Research Council Alexander Graham Bell Canada Graduate Scholarship
Focal adhesion kinase (FAX) acts as an adaptor at the focal contacts serving as a junction between the extracellular matrix and actin cytoskeleton. Actin dynamics is known as a determinant step in insulin secretion. Additionally, FAX has been shown to regulate insulin signaling. To investigate the essential physiological role of FAX in pancreatic beta-cells in vivo, we generated a transgenic mouse model using rat insulin promoter (RIP)-driven Cre-loxP recombination system to specifically delete FAX in pancreatic beta-cells. These RIPcre(+)fak(fl/ft) mice exhibited glucose intolerance without changes in insulin sensitivity. Reduced beta-cell viability and proliferation resulting in decreased beta-cell mass was observed in these mice, which was associated with attenuated insulin/Akt (also known as protein kinase B) and extracellular signal-related kiinase 1/2 signaling and increased caspase 3 activation. FAK-deficient beta-cells exhibited impaired insulin secretion with normal glucose sensing and preserved Ca2+ influx in response to glucose, but a reduced number of docked insulin granules and insulin exocytosis were found, which was associated with a decrease in focal proteins, paxillin and talin, and an impairment in actin depolymerization. This study is the first to show in vivo that FAX is critical for pancreatic beta-cell viability and function through regulation in insulin signaling, actin dynamics, and granule trafficking. Diabetes 61:1708-1718,2012
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