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

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Abstract

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 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 intracellular Ca2+ and K-ATP-channel activity). Resting K-ATP conductance was lower in NCAM(-/-) beta-cells than wild-type cells, and this difference was abolished when F-actin was disrupted by cytochalasin D (1 mu M). In wild-type 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 is suppressed in NCAM(-/-) alpha- and beta-cells. Our data suggest that remodeling of the submembrane actin network is critical to normal glucose regulation of both insulin and glucagon secretion. (Endocrinology 150: 3067-3075, 2009)

Details

Authors
  • Charlotta S. Olofsson
  • Joakim Hakansson
  • Albert Salehi
  • Martin Bengtsson
  • Juris Galvanovskis
  • Chris Partridge
  • Maria Sörhede Winzell
  • Xiaojie Xian
  • Lena Eliasson
  • Ingmar Lundquist
  • Henrik Semb
  • Patrik Rorsman
Organisations
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Endocrinology and Diabetes
Original languageEnglish
Pages (from-to)3067-3075
JournalEndocrinology
Volume150
Issue number7
Publication statusPublished - 2009
Publication categoryResearch
Peer-reviewedYes