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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. Diabetes 58:318-328, 2009
Huntington's disease is an inherited neurodegenerative disorder typified by involuntary body movements and psychiatric and cognitive abnormalities. The incidence of Huntington's disease is ~5-10 cases per 100,000 worldwide, making it one of the most common inherited neurodegenerative disorders (1). The genetic defect underlying Huntington's disease involves expansion of CAG trinucleotide repeats in exon 1 of the Huntington's disease gene, resulting in polyglutamine expansions in the huntingtin (htt) protein (2). Polyglutamine expansion in htt leads to its abnormal processing and deleterious intracellular aggregation. The number of polyglutamine repeats in htt is inversely correlated with the age of onset, with 70-100 repeats leading to juvenile onset (1). The wild-type htt protein is thought to be a scaffolding protein involved in multiple...