In Vivo Role of Focal Adhesion Kinase in Regulating Pancreatic β-Cell Mass and Function Through Insulin Signaling, Actin Dynamics, and Granule Trafficking

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