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

Olofsson, Charlotta S.; Hakansson, Joakim; Salehi, Albert; Bengtsson, Martin; Galvanovskis, Juris; Partridge, Chris; Sörhede Winzell, Maria LU ; Xian, Xiaojie LU ; Eliasson, Lena and Lundquist, Ingmar, et al. (2009) In Endocrinology 150(7). p.3067-3075
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... (More)
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) (Less)
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published
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Endocrinology
volume
150
issue
7
pages
3067 - 3075
publisher
Endocrine Society
external identifiers
  • wos:000267781300013
  • pmid:19213846
  • scopus:67649670129
ISSN
0013-7227
DOI
10.1210/en.2008-0475
language
English
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yes
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01d3fb3a-e8f9-468a-ac46-d177be2f26e6 (old id 1462749)
alternative location
http://www.ncbi.nlm.nih.gov/pubmed/19213846?dopt=Abstract
date added to LUP
2009-08-31 11:01:57
date last changed
2017-09-24 03:46:53
@article{01d3fb3a-e8f9-468a-ac46-d177be2f26e6,
  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)},
  author       = {Olofsson, Charlotta S. and Hakansson, Joakim and Salehi, Albert and Bengtsson, Martin and Galvanovskis, Juris and Partridge, Chris and Sörhede Winzell, Maria and Xian, Xiaojie and Eliasson, Lena and Lundquist, Ingmar and Semb, Henrik and Rorsman, Patrik},
  issn         = {0013-7227},
  language     = {eng},
  number       = {7},
  pages        = {3067--3075},
  publisher    = {Endocrine Society},
  series       = {Endocrinology},
  title        = {Impaired Insulin Exocytosis in Neural Cell Adhesion Molecule(-/-) Mice Due to Defective Reorganization of the Submembrane F-Actin Network},
  url          = {http://dx.doi.org/10.1210/en.2008-0475},
  volume       = {150},
  year         = {2009},
}