Exendin-4 improves glycemic control, ameliorates brain and pancreatic pathologies, and extends survival in a mouse model of huntington's disease

Bronwen Martin, Erin Golden, Olga D. Carlson, Paul Pistell, Jie Zhou, Wook Kim, Brittany P. Frank, Sam Thomas, Wayne A. Chadwick, Nigel H. Greig, Gillian P. Bates, Kirupa Sathasivam, Michel Bernier, Stuart Maudsley, Mark P. Mattson, Josephine M. Egan

Research output: Contribution to journalArticle

Abstract

OBJECTIVE-The aim of this study was to find an effective treatment for the genetic form of diabetes that is present in some Huntington's disease patients and in Huntington's disease mouse models. Huntington's disease is a neurodegenerative disorder caused by a polyglutamine expansion within the huntingtin protein. Huntington's disease patients exhibit neuronal dysfunction/degeneration, chorea, and progressive weight loss. Additionally, they suffer from abnormalities in energy metabolism affecting both the brain and periphery. Similarly to Huntington's disease patients, mice expressing the mutated human huntingtin protein also exhibit neurodegenerative changes, motor dysfunction, perturbed energy metabolism, and elevated blood glucose levels. RESEARCH DESIGN AND METHODS-Huntington's disease mice were treated with an FDA-approved antidiabetic glucagon-like peptide 1 receptor agonist, exendin-4 (Ex-4), to test whether euglycemia could be achieved, whether pancreatic dysfunction could be alleviated, and whether the mice showed any neurological benefit. Blood glucose and insulin levels and various appetite hormone concentrations were measured during the study. Additionally, motor performance and life span were quantified and mutant huntingtin (mhtt) aggregates were measured in both the pancreas and brain. RESULTS-Ex-4 treatment ameliorated abnormalities in peripheral glucose regulation and suppressed cellular pathology in both brain and pancreas in a mouse model of Huntington's disease. The treatment also improved motor function and extended the survival time of the Huntington's disease mice. These clinical improvements were correlated with reduced accumulation of mhtt protein aggregates in both islet and brain cells. CONCLUSIONS-Targeting both peripheral and neuronal deficits, Ex-4 is an attractive agent for therapeutic intervention in Huntington's disease patients suffering from diabetes.

Original languageEnglish (US)
Pages (from-to)318-328
Number of pages11
JournalDiabetes
Volume58
Issue number2
DOIs
StatePublished - Feb 2009
Externally publishedYes

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

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    Martin, B., Golden, E., Carlson, O. D., Pistell, P., Zhou, J., Kim, W., Frank, B. P., Thomas, S., Chadwick, W. A., Greig, N. H., Bates, G. P., Sathasivam, K., Bernier, M., Maudsley, S., Mattson, M. P., & Egan, J. M. (2009). Exendin-4 improves glycemic control, ameliorates brain and pancreatic pathologies, and extends survival in a mouse model of huntington's disease. Diabetes, 58(2), 318-328. https://doi.org/10.2337/db08-0799