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Impaired Insulin Exocytosis in Neural Cell Adhesion Molecule^–/– Mice Due to Defective Reorganization of the Submembrane F-Actin Network

Lund University Diabetes Centre (C.S.O., A.S., L.E., I.L.), Clinical Research Centre, SE20502 Malmö, Sweden; Departments of Biomedicine (J.H.) and Neuroscience and Physiology (C.S.O.), University of Gothenburg, SE41390 Göteborg, Sweden; Oxford Centre for Diabetes, Endocrinology and Metabolism (M.B., J.G., C.P., P.R.), Churchill Hospital, Oxford OX3 7LJ, United Kingdom; and Stem Cell Center (J.H., X.X., H.S.) and Department of Clinical Sciences (M.S.), Lund University, Biomedical Center, SE-22184 Lund, Sweden

Address all correspondence and requests for reprints to: Charlotta Olofsson, Department of Neuroscience and Physiology, University of Gothenburg, Medicinaregatan 11, SE41390 Göteborg, Sweden. E-mail: charlotta.olofsson{at}physiol.gu.se.

The 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 β-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 -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 intracellular Ca²⁺ and K_ATP-channel activity). Resting K_ATP conductance was lower in NCAM^–/– β-cells than wild-type cells, and this difference was abolished when F-actin was disrupted by cytochalasin D (1 µM). In wild-type β-cells, the submembrane actin network disassembles within 10 min during glucose stimulation (30 mM), an effect not seen in NCAM^–/– β-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 is suppressed in NCAM^–/– - and β-cells. Our data suggest that remodeling of the submembrane actin network is critical to normal glucose regulation of both insulin and glucagon secretion.