Human Molecular Genetics Advance Access originally published online on January 13, 2005
Human Molecular Genetics 2005 14(5):565-574; doi:10.1093/hmg/ddi053
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Human Molecular Genetics, Vol. 14, No. 5 © Oxford University Press 2005; all rights reserved
The R6/2 transgenic mouse model of Huntington's disease develops diabetes due to deficient ß-cell mass and exocytosis
1Department of Cell and Molecular Biology, BMC C11, 221 84 Lund, Sweden, 2Department of Physiological Sciences, The Diabetes Programme at Lund University, BMC B11, SE-211 84 Lund, Sweden, 3Section for Neuroendocrine and Cell Biology BMC F10, 221 84 Lund, Sweden and 4Section for Neuronal Survival, BMC A10, 221 84 Lund, Sweden
* To whom correspondence should be addressed at: Department of Cell and Molecular Biology, Section for Molecular Signaling, Lund University, BMC C11, SE-221 84 Lund, Sweden. Email: mana.bjorkqvist{at}medkem.lu.se
Received September 15, 2004; Revised December 15, 2004; Accepted January 4, 2005
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 
-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.
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