Exendin-4 Improves Glycemic Control, Ameliorates Brain and Pancreatic Pathologies, and Extends Survival in a Mouse Model of Huntington's Disease

  1. Bronwen Martin1,
  2. Erin Golden1,
  3. Olga D. Carlson2,
  4. Paul Pistell3,
  5. Jie Zhou2,
  6. Wook Kim2,
  7. Brittany P. Frank4,
  8. Sam Thomas2,
  9. Wayne A. Chadwick1,
  10. Nigel H. Greig1,
  11. Gillian P. Bates5,
  12. Kirupa Sathasivam5,
  13. Michel Bernier2,
  14. Stuart Maudsley1,
  15. Mark P. Mattson1 and
  16. Josephine M. Egan2
  1. 1Laboratory of Neurosciences, National Institute on Aging Intramural Research Program, Baltimore, Maryland
  2. 2Laboratory of Clinical Investigation, National Institute on Aging Intramural Research Program, Baltimore, Maryland
  3. 3Laboratory of Experimental Gerontology, National Institute on Aging Intramural Research Program, Baltimore, Maryland
  4. 4Research Resources Branch, National Institute on Aging Intramural Research Program, Baltimore, Maryland
  5. 5King's College London, School of Medicine, Guy's Hospital, London, U.K
  1. Corresponding authors: Mark P. Mattson, mattsonm{at}grc.nia.nih.gov, and Josephine M. Egan, eganj{at}grc.nia.nih.gov

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.

Footnotes

  • Published ahead of print at http://diabetes.diabetesjournals.org on 4 November 2008.

    S.M., M.P.M., and J.M.E. contributed equally to this work.

    Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.org/licenses/by-nc-nd/3.0/ for details.

    The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

    • Accepted October 27, 2008.
    • Received June 17, 2008.
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  1. Diabetes vol. 58 no. 2 318-328
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