Impaired insulin exocytosis in NCAM-/- mice due to defective reorganization of the submembrane F-actin network.

In English Neural cell adhesion molecule (NCAM) is required for cell type segregation during pancreatic islet organogenesis. We have investigated the functional consequences of ablating NCAM on pancreatic beta-cell function. In vivo, NCAM(-/-) mice exhibit impaired glucose tolerance and basal hyperinsulinemia. Insulin secretion from isolated NCAM(-/-) islets is enhanced at glucose concentrations below 15 mM but inhibited at higher concentrations. Glucagon secretion from pancreatic alpha-cells evoked by low glucose was also severely impaired in NCAM(-/-) islets. The diminution of insulin secretion is not attributable to defective glucose metabolism or glucose-sensing (documented as glucose-induced changes in Ca(2+)i and KATP-channel activity). Resting KATP-conductance was lower in NCAM(-/-) beta-cells than in wildtype cells and this difference was abolished when F-actin was disrupted by cytochalasin D (1 microM). In wildtype beta-cells, the submembrane actin network disassembles within 10 min during glucose stimulation (30 mM), an effect not seen in NCAM(-/-) beta-cells. Cytochalasin D eliminated this difference and normalized insulin and glucagon secretion in NCAM(-/-) islets. Capacitance measurements of exocytosis indicate that replenishment of the readily releasable granule pool (RRP) is suppressed in NCAM(-/-) alpha- and beta-cells. Our data suggest that remodelling of the submembrane actin network is critical to normal glucose regulation of both insulin and glucagon secretion.