Journal
EXPERIMENTAL NEUROLOGY
Volume 231, Issue 2, Pages 314-319Publisher
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.expneurol.2011.06.016
Keywords
Body weight; Huntington's disease; Hyperglycemia; IGF-1; Insulin; R6/2 mice
Categories
Funding
- European Social Fund [SFRH/BPD/26872/2006]
- Fundacao Calouste Gulbenkian, Portugal
- European Foundation for the Study of Diabetes
- Swedish Research Council
- Nordic Center of Excellence on Neurodegeneration
- Strong Research Environment Neurofortis
- Fundação para a Ciência e a Tecnologia [SFRH/BPD/26872/2006] Funding Source: FCT
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Huntington's disease (HD) is the most prevalent polyglutamine expansion disorder. HD is caused by an expansion of CAG triplet in the huntingtin (HIT) gene, associated with striatal and cortical neuronal loss. Central and peripheral metabolic abnormalities and altered insulin-like growth factor-1 (IGF-1) levels have been described in HD. Thus, we hypothesized that restoration of IGF-1-mediated signaling pathways could rescue R6/2 mice from metabolic stress and behavioral changes induced by polyglutamine expansion. We analyzed the in vivo effect of continuous peripheral IGF-1 administration on diabetic parameters, body weight and motor behavior in the hemizygous R6/2 mouse model of HD. We used 9 week-old and age-matched wildtype mice, subjected to continuously infused recombinant IGF-I or vehicle, for 14 days. IGF-1 treatment prevented the age-related decrease in body weight in R6/2 mice. Although blood glucose levels were higher in R6/2 mice, they did not reach a diabetic state. Even though, IGF-1 ameliorated poor glycemic control in HD mice. This seemed to be associated with a decrease in blood insulin levels in R6/2 mice, which was increased following IGF-1 infusion. Similarly, blood IGF-1 levels decreased during aging in both wild-type and R6/2 mice, being significantly improved upon its continuous infusion. Although no significant differences were found in motor function in R6/2-treated mice, IGF-1 treatment highly improved paw clasping scores. In summary, these results suggest that IGF-1 has a protective role against HD-associated impaired glucose tolerance, by enhancing blood insulin levels. (C) 2011 Elsevier Inc. All rights reserved.
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