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
  2. 2Laboratory of Clinical Investigation
  3. 3Laboratory of Experimental Gerontology
  4. 4Research Resources Branch, National Institute on Aging Intramural Research Program, 5600 Nathan Shock Drive, Baltimore MD 21224
  5. 5King's College London, School of Medicine, Guy's Hospital, London SE1 9RT, UK

    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 (HD) patients and in HD mouse models. HD is a neurodegenerative disorder caused by a polyglutamine expansion within the huntingtin protein. HD 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 HD 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: HD mice were treated with an FDA-approved anti-diabetic glucagon-like peptide 1 receptor agonist, exendin-4, to test if euglycemia could be achieved, if pancreatic dysfunction could be alleviated and if 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 aggregates were measured in both the pancreas and brain.

    Results: Exendin-4 treatment ameliorated abnormalities in peripheral glucose regulation and suppressed cellular pathology in both brain and pancreas in a mouse model of HD. The treatment also improved motor function and extended the survival time of the HD mice. These clinical improvements were correlated with reduced accumulation of mutant huntingtin protein aggregates in both islet and brain cells.

    Conclusions: Targeting both peripheral and neuronal deficits, exendin-4 is an attractive agent for therapeutic intervention in HD patients suffering from diabetes.

    Footnotes

      • Received June 17, 2008.
      • Accepted October 27, 2008.

    This Article

    1. Diabetes
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