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Defective secretion of islet hormones in chromogranin-B deficient mice.

Obermüller, Stefanie LU ; Calegari, Federico; King, Angus; Lindqvist, Anders LU ; Lundquist, Ingmar LU ; Salehi, S Albert LU ; Francolini, Maura; Rosa, Patrizia; Rorsman, Patrik LU and Huttner, Wieland B, et al. (2010) In PLoS One 5(1).
Abstract
Granins are major constituents of dense-core secretory granules in neuroendocrine cells, but their function is still a matter of debate. Work in cell lines has suggested that the most abundant and ubiquitously expressed granins, chromogranin A and B (CgA and CgB), are involved in granulogenesis and protein sorting. Here we report the generation and characterization of mice lacking chromogranin B (CgB-ko), which were viable and fertile. Unlike neuroendocrine tissues, pancreatic islets of these animals lacked compensatory changes in other granins and were therefore analyzed in detail. Stimulated secretion of insulin, glucagon and somatostatin was reduced in CgB-ko islets, in parallel with somewhat impaired glucose clearance and reduced... (More)
Granins are major constituents of dense-core secretory granules in neuroendocrine cells, but their function is still a matter of debate. Work in cell lines has suggested that the most abundant and ubiquitously expressed granins, chromogranin A and B (CgA and CgB), are involved in granulogenesis and protein sorting. Here we report the generation and characterization of mice lacking chromogranin B (CgB-ko), which were viable and fertile. Unlike neuroendocrine tissues, pancreatic islets of these animals lacked compensatory changes in other granins and were therefore analyzed in detail. Stimulated secretion of insulin, glucagon and somatostatin was reduced in CgB-ko islets, in parallel with somewhat impaired glucose clearance and reduced insulin release, but normal insulin sensitivity in vivo. CgB-ko islets lacked specifically the rapid initial phase of stimulated secretion, had elevated basal insulin release, and stored and released twice as much proinsulin as wildtype (wt) islets. Stimulated release of glucagon and somatostatin was reduced as well. Surprisingly, biogenesis, morphology and function of insulin granules were normal, and no differences were found with regard to beta-cell stimulus-secretion coupling. We conclude that CgB is not required for normal insulin granule biogenesis or maintenance in vivo, but is essential for adequate secretion of islet hormones. Consequentially CgB-ko animals display some, but not all, hallmarks of human type-2 diabetes. However, the molecular mechanisms underlying this defect remain to be determined. (Less)
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PLoS One
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5
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Public Library of Science
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  • WOS:000274138000014
  • PMID:20126668
  • Scopus:77749251923
ISSN
1932-6203
DOI
10.1371/journal.pone.0008936
language
English
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yes
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a29449ec-1c94-46c6-9d9b-bb677e1d6cea (old id 1553005)
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http://www.ncbi.nlm.nih.gov/pubmed/20126668?dopt=Abstract
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2010-03-02 15:26:49
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@article{a29449ec-1c94-46c6-9d9b-bb677e1d6cea,
  abstract     = {Granins are major constituents of dense-core secretory granules in neuroendocrine cells, but their function is still a matter of debate. Work in cell lines has suggested that the most abundant and ubiquitously expressed granins, chromogranin A and B (CgA and CgB), are involved in granulogenesis and protein sorting. Here we report the generation and characterization of mice lacking chromogranin B (CgB-ko), which were viable and fertile. Unlike neuroendocrine tissues, pancreatic islets of these animals lacked compensatory changes in other granins and were therefore analyzed in detail. Stimulated secretion of insulin, glucagon and somatostatin was reduced in CgB-ko islets, in parallel with somewhat impaired glucose clearance and reduced insulin release, but normal insulin sensitivity in vivo. CgB-ko islets lacked specifically the rapid initial phase of stimulated secretion, had elevated basal insulin release, and stored and released twice as much proinsulin as wildtype (wt) islets. Stimulated release of glucagon and somatostatin was reduced as well. Surprisingly, biogenesis, morphology and function of insulin granules were normal, and no differences were found with regard to beta-cell stimulus-secretion coupling. We conclude that CgB is not required for normal insulin granule biogenesis or maintenance in vivo, but is essential for adequate secretion of islet hormones. Consequentially CgB-ko animals display some, but not all, hallmarks of human type-2 diabetes. However, the molecular mechanisms underlying this defect remain to be determined.},
  articleno    = {e8936},
  author       = {Obermüller, Stefanie and Calegari, Federico and King, Angus and Lindqvist, Anders and Lundquist, Ingmar and Salehi, S Albert and Francolini, Maura and Rosa, Patrizia and Rorsman, Patrik and Huttner, Wieland B and Barg, Sebastian},
  issn         = {1932-6203},
  language     = {eng},
  number       = {1},
  publisher    = {Public Library of Science},
  series       = {PLoS One},
  title        = {Defective secretion of islet hormones in chromogranin-B deficient mice.},
  url          = {http://dx.doi.org/10.1371/journal.pone.0008936},
  volume       = {5},
  year         = {2010},
}