The R6/2 transgenic mouse model of Huntington's disease develops diabetes due to deficient beta-cell mass and exocytosis.
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 beta-cells. beta-cell mass failed to increase normally with age in R6/2 mice. Hence, at week 12, beta-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 beta-cells. However, exocytosis was virtually abolished in beta- 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 beta-cell mass and disrupted exocytosis.
Björkqvist
Maria
M
Department of Cell and Molecular Biology, Lund, Sweden. maria.bjorkqvist@medkem.lu.se
Fex
Malin
M
Renström
Erik
E
Wierup
Nils
N
Petersén
Asa
A
Gil
Joana
J
Bacos
Karl
K
Popovic
Natalija
N
Li
Jia-Yi
JY
Sundler
Frank
F
Brundin
Patrik
P
Mulder
Hindrik
H
D000367:Age Factors; D000818:Animals; D016923:Cell Death / Q000502:physiology; D002467:Cell Nucleus / Q000378:metabolism; D003920:Diabetes Mellitus / Q000235:genetics* / Q000378:metabolism; D005089:Exocytosis / Q000235:genetics / Q000502:physiology*; D005934:Glucagon / Q000378:metabolism; D005951:Glucose Tolerance Test; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000235:genetics* / Q000378:metabolism; D007150:Immunohistochemistry; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000378:metabolism* / Q000648:ultrastructure; D051379:Mice; D008822:Mice, Transgenic; D008854:Microscopy, Electron; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D012038:Regeneration / Q000502:physiology
C506812:Htt protein, mouse; D000071058:Huntingtin Protein; D007328:Insulin; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D005934:Glucagon