Impaired glucose tolerance in the R6/1 transgenic mouse model of Huntington's disease.
Previous reports have highlighted a possible link between Huntington's disease (HD) and diabetes mellitus (DM), but the association has not been characterised in detail. A transgenic mouse model for HD, the R6/2 mouse, also develops diabetes. In the present study, we examined the R6/1 mouse, which carries a shorter CAG repeat than the R6/2 mouse, and found that, although not diabetic, the mice showed several signs of impaired glucose tolerance. First, following i.p. glucose injection, the blood glucose concentration was approximately 30% higher in young R6/1 mice (10 weeks) compared to wild-type mice (P = 0.004). In older mice (38 weeks), glucose tolerance was further impaired in both R6/1 and wild-type animals. Second, during glucose challenge, the R6/1 mice reached higher plasma insulin levels than wild-type mice, but the peripheral insulin sensitivity was normal as measured by injection of human or mouse insulin or when evaluated by the quantitative insulin sensitivity check index (QUICKI). Third, the beta cell volume was 17% and 39% smaller at 10 and 38 weeks of age, respectively, compared to age-matched wild-type littermates and the reduction was not caused by apoptosis at either age. Finally, we demonstrated the presence of the HD gene product, huntingtin (htt), in both alpha- and beta-cells in R6/1 islets of Langerhans. Since pancreatic beta cells and neurons share several common traits, clarification of the mechanism associating neurodegenerative diseases with diabetes might improve our understanding of the pathogenic events leading to both groups of diseases.
Josefsen
K
K
Bartholin Instituttet, Rigshospitalet, Copenhagen, Denmark. knud@eln.dk
Nielsen
M D
MD
Jørgensen
K H
KH
Bock
T
T
Nørremølle
A
A
Sørensen
S A
SA
Naver
B
B
Hasholt
L
L
D000818:Animals; D001921:Brain / Q000473:pathology; D002452:Cell Count; D004195:Disease Models, Animal; D005260:Female; D018149:Glucose Intolerance / Q000175:diagnosis / Q000235:genetics / Q000473:pathology; D005951:Glucose Tolerance Test; D006801:Humans; D006816:Huntington Disease / Q000235:genetics / Q000473:pathology / Q000503:physiopathology*; D007004:Hypoglycemic Agents / Q000097:blood; D007328:Insulin / Q000097:blood; D050417:Insulin-Secreting Cells / Q000473:pathology; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D008822:Mice, Transgenic; D013045:Species Specificity; D018911:Trinucleotide Repeats
D007004:Hypoglycemic Agents; D007328:Insulin