Atypical diabetes associated with inclusion formation in the R6/2 mouse model of Huntington's disease is not improved by treatment with hypoglycaemic agents.
The R6/2 transgenic mouse model of Huntington's disease (HD) develops a progressive neurological phenotype that involves severe motor and cognitive dysfunctions. Although not a cardinal sign, diabetes has been described in R6/2 mice. It is not clear, however, whether the diabetes contributes to the HD-like phenotype of R6/2 mice. In our study we found that the severity of diabetes in R6/2 mice was associated with the progressive formation of ubiquinated inclusions in pancreatic beta cells. Diabetes is dissociated from early motor and cognitive dysfunctions and did not correlate with motor impairment and survival of R6/2 mice. However, chronic behavioural testing (at a level higher than that which is reported to improve several aspects of the R6/2 phenotype) exacerbated the onset of diabetes. Pharmacological treatment of the diabetes was attempted using two oral hypoglycaemic agents commonly used by diabetics. The mice responded acutely to glibenclamide (which induces exocytosis of insulin) but not to rosiglitazone (which induces sensitization to insulin). This supports the suggestion that the diabetes in R6/2 mice is caused by an impairment in insulin release rather than insulin insensitivity. However, chronic treatment with these hypoglycaemic agents had no effect on either the course of the diabetes or the disease in R6/2 mice.
Hunt
Mark J
MJ
Department of Pharmacology, University of Cambridge, Tennis Court Road, Cambridge, CB2 1PD, UK.
Morton
A Jennifer
AJ
D000284:Administration, Oral; D000818:Animals; D001522:Behavior, Animal; D003920:Diabetes Mellitus / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D004195:Disease Models, Animal; D005089:Exocytosis / Q000187:drug effects; D018149:Glucose Intolerance / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D005905:Glyburide / Q000494:pharmacology*; D006029:Glycosuria / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D006816:Huntington Disease / Q000150:complications* / Q000235:genetics; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007328:Insulin / Q000378:metabolism; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D008818:Mice, Neurologic Mutants; D008822:Mice, Transgenic; D000077154:Rosiglitazone; D045162:Thiazolidinediones / Q000494:pharmacology
D007004:Hypoglycemic Agents; D007328:Insulin; D045162:Thiazolidinediones; D000077154:Rosiglitazone; D005905:Glyburide