Exendin-4 Improves Glycemic Control, Ameliorates Brain and Pancreatic Pathologies, and Extends Survival in a Mouse Model of Huntington's Disease
Open Access
- 1 February 2009
- journal article
- Published by American Diabetes Association in Diabetes
- Vol. 58 (2), 318-328
- https://doi.org/10.2337/db08-0799
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.Keywords
This publication has 58 references indexed in Scilit:
- Liraglutide, a once‐daily human GLP‐1 analogue, improves pancreatic B‐cell function and arginine‐stimulated insulin secretion during hyperglycaemia in patients with Type 2 diabetes mellitusDiabetic Medicine, 2008
- Unbiased Gene Expression Analysis Implicates the huntingtin Polyglutamine Tract in Extra-mitochondrial Energy MetabolismPLoS Genetics, 2007
- Selective defect of in vivo glycolysis in early Huntington's disease striatumProceedings of the National Academy of Sciences of the United States of America, 2007
- Hypothalamic Dysfunction and Neuroendocrine and Metabolic Alterations in Huntington Disease: Clinical Consequences and Therapeutic ImplicationsProgress in Neurobiology, 2007
- Mechanisms of action of glucagon-like peptide 1 in the pancreasPharmacology & Therapeutics, 2006
- Evidence of GLP-1-mediated neuroprotection in an animal model of pyridoxine-induced peripheral sensory neuropathyExperimental Neurology, 2006
- Hypothalamic–endocrine aspects in Huntington's diseaseEuropean Journal of Neuroscience, 2006
- Decreasing hypothalamic insulin receptors causes hyperphagia and insulin resistance in ratsNature Neuroscience, 2002
- Tissue distribution of rat glucagon receptor and GLP-1 receptor gene expressionMolecular and Cellular Endocrinology, 1998
- Diabetes mellitus in Huntington diseaseClinical Genetics, 1985