Impaired insulin exocytosis in neural cell adhesion molecule-/- mice due to defective reorganization of the submembrane F-actin network.
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 Ca(2+) 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 muM). 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.
Olofsson
Charlotta S
CS
Lund University Diabetes Centre, Clinical Research Centre, SE20502 Malmö, Sweden. charlotta.olofsson@physiol.gu.se
Håkansson
Joakim
J
Salehi
Albert
A
Bengtsson
Martin
M
Galvanovskis
Juris
J
Partridge
Chris
C
SörhedeWinzell
Maria
M
Xian
Xiaojie
X
Eliasson
Lena
L
Lundquist
Ingmar
I
Semb
Henrik
H
Rorsman
Patrik
P
D000199:Actins / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D005089:Exocytosis / Q000502:physiology; D005260:Female; D005934:Glucagon / Q000378:metabolism; D005947:Glucose / Q000502:physiology; D018149:Glucose Intolerance / Q000235:genetics*; D007328:Insulin / Q000378:metabolism* / Q000502:physiology; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D019006:Neural Cell Adhesion Molecules / Q000172:deficiency*; D018408:Patch-Clamp Techniques; D024661:Potassium Channels, Inwardly Rectifying / Q000378:metabolism
D000199:Actins; D007328:Insulin; D019006:Neural Cell Adhesion Molecules; D024661:Potassium Channels, Inwardly Rectifying; D000255:Adenosine Triphosphate; D005934:Glucagon; D005947:Glucose