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The R6/2 transgenic mouse model of Huntington's disease develops diabetes due to deficient {beta}-cell mass and exocytosis.

Björkqvist, Maria LU ; Fex, Malin LU ; Renström, Erik LU ; Wierup, Nils LU ; Petersén, Åsa LU ; Gil, Joana LU ; Bacos, Karl LU ; Popovic, Natalija LU ; Li, Jia-Yi LU and Sundler, Frank LU , et al. (2005) In Human Molecular Genetics 14(5). p.565-574
Abstract
Diabetes frequently develops in Huntington's disease (HD) patients and in transgenic mouse models of HD such as the R6/2 mouse. The underlying mechanisms have not been clarified. Elucidating the pathogenesis of diabetes in HD would improve our understanding of the molecular mechanisms involved in HD neuropathology. With this aim, we examined our colony of R6/2 mice with respect to glucose homeostasis and islet function. At week 12, corresponding to end-stage HD, R6/2 mice were hyperglycemic and hypoinsulinemic and failed to release insulin in an intravenous glucose tolerance test. In vitro, basal and glucose-stimulated insulin secretion was markedly reduced. Islet nuclear huntingtin inclusions increased dramatically over time,... (More)
Diabetes frequently develops in Huntington's disease (HD) patients and in transgenic mouse models of HD such as the R6/2 mouse. The underlying mechanisms have not been clarified. Elucidating the pathogenesis of diabetes in HD would improve our understanding of the molecular mechanisms involved in HD neuropathology. With this aim, we examined our colony of R6/2 mice with respect to glucose homeostasis and islet function. At week 12, corresponding to end-stage HD, R6/2 mice were hyperglycemic and hypoinsulinemic and failed to release insulin in an intravenous glucose tolerance test. In vitro, basal and glucose-stimulated insulin secretion was markedly reduced. Islet nuclear huntingtin inclusions increased dramatically over time, predominantly in ß-cells. ß-cell mass failed to increase normally with age in R6/2 mice. Hence, at week 12, ß-cell mass and pancreatic insulin content in R6/2 mice were 35±5 and 16±3% of that in wild-type mice, respectively. The normally occurring replicating cells were largely absent in R6/2 islets, while no abnormal cell death could be detected. Single cell patch-clamp experiments revealed unaltered electrical activity in R6/2 ß-cells. However, exocytosis was virtually abolished in ß- but not in {alpha}-cells. The blunting of exocytosis could be attributed to a 96% reduction in the number of insulin-containing secretory vesicles. Thus, diabetes in R6/2 mice is caused by a combination of deficient ß-cell mass and disrupted exocytosis. (Less)
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published
subject
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Human Molecular Genetics
volume
14
issue
5
pages
565 - 574
publisher
Oxford University Press
external identifiers
  • wos:000227128900001
  • pmid:15649949
  • scopus:20044392282
ISSN
0964-6906
DOI
10.1093/hmg/ddi053
language
English
LU publication?
yes
id
252265f9-f15b-4ac8-9b38-6454a8733b01 (old id 133152)
date added to LUP
2007-07-10 14:26:41
date last changed
2017-11-12 03:19:33
@article{252265f9-f15b-4ac8-9b38-6454a8733b01,
  abstract     = {Diabetes frequently develops in Huntington's disease (HD) patients and in transgenic mouse models of HD such as the R6/2 mouse. The underlying mechanisms have not been clarified. Elucidating the pathogenesis of diabetes in HD would improve our understanding of the molecular mechanisms involved in HD neuropathology. With this aim, we examined our colony of R6/2 mice with respect to glucose homeostasis and islet function. At week 12, corresponding to end-stage HD, R6/2 mice were hyperglycemic and hypoinsulinemic and failed to release insulin in an intravenous glucose tolerance test. In vitro, basal and glucose-stimulated insulin secretion was markedly reduced. Islet nuclear huntingtin inclusions increased dramatically over time, predominantly in ß-cells. ß-cell mass failed to increase normally with age in R6/2 mice. Hence, at week 12, ß-cell mass and pancreatic insulin content in R6/2 mice were 35±5 and 16±3% of that in wild-type mice, respectively. The normally occurring replicating cells were largely absent in R6/2 islets, while no abnormal cell death could be detected. Single cell patch-clamp experiments revealed unaltered electrical activity in R6/2 ß-cells. However, exocytosis was virtually abolished in ß- but not in {alpha}-cells. The blunting of exocytosis could be attributed to a 96% reduction in the number of insulin-containing secretory vesicles. Thus, diabetes in R6/2 mice is caused by a combination of deficient ß-cell mass and disrupted exocytosis.},
  author       = {Björkqvist, Maria and Fex, Malin and Renström, Erik and Wierup, Nils and Petersén, Åsa and Gil, Joana and Bacos, Karl and Popovic, Natalija and Li, Jia-Yi and Sundler, Frank and Brundin, Patrik and Mulder, Hindrik},
  issn         = {0964-6906},
  language     = {eng},
  number       = {5},
  pages        = {565--574},
  publisher    = {Oxford University Press},
  series       = {Human Molecular Genetics},
  title        = {The R6/2 transgenic mouse model of Huntington's disease develops diabetes due to deficient {beta}-cell mass and exocytosis.},
  url          = {http://dx.doi.org/10.1093/hmg/ddi053},
  volume       = {14},
  year         = {2005},
}