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

Forskningsoutput: TidskriftsbidragArtikel i vetenskaplig tidskrift

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)

Detaljer

Författare
  • 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
Enheter & grupper
Forskningsområden

Ämnesklassifikation (UKÄ) – OBLIGATORISK

  • Endokrinologi och diabetes
Originalspråkengelska
Sidor (från-till)3067-3075
TidskriftEndocrinology
Volym150
Utgåva nummer7
StatusPublished - 2009
PublikationskategoriForskning
Peer review utfördJa