Impaired insulin exocytosis in NCAM-/- mice due to defective reorganization of the submembrane F-actin network.
Nummer: Feb 12
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.
- Medicine and Health Sciences
- ISSN: 1945-7170