Exendin-4 improves glycemic control, ameliorates brain and pancreatic pathologies, and extends survival in a mouse model of Huntington's disease.
Exendin-4 improves glycemic control, ameliorates brain and pancreatic pathologies, and extends survival in a mouse model of Huntington's disease.
复制标题
作者：
Martin B;Golden E;Carlson OD;Pistell P;Zhou J;Kim W;Frank BP;Thomas S;Chadwick WA;Greig NH;Bates GP;Sathasivam K;Bernier M;Maudsley S;Mattson MP;Egan JM
亨廷顿-这项研究的目的是找到一种有效的治疗糖尿病的遗传形式，这是目前在一些亨廷顿氏病患者和亨廷顿氏病小鼠模型。亨廷顿氏病是由亨廷顿蛋白内的多聚谷氨酰胺扩增引起的神经退行性疾病。亨廷顿病患者表现出神经元功能障碍/变性、舞蹈病和进行性体重减轻。此外，他们患有影响大脑和外周的能量代谢异常。与亨廷顿病患者类似，表达突变的人亨廷顿蛋白的小鼠也表现出神经退行性变化、运动功能障碍、能量代谢紊乱和血糖水平升高。研究设计和方法-亨廷顿氏病小鼠用FDA批准的抗糖尿病胰高血糖素样肽1受体激动剂exendin-4（Ex-4）治疗，以测试是否可以达到正常血糖，胰腺功能障碍是否可以减轻，以及小鼠是否表现出任何神经学益处。在研究期间测量血糖和胰岛素水平以及各种食欲激素浓度。此外，运动性能和寿命进行了量化和突变亨廷顿蛋白（mhtt）聚集体测量在胰腺和大脑。在亨廷顿氏病小鼠模型中，BUTTS-Ex-4治疗改善了外周葡萄糖调节的异常并抑制了脑和胰腺中的细胞病理学。这种治疗还改善了运动功能，延长了患亨廷顿病小鼠的生存时间。这些临床改善与胰岛和脑细胞中mhtt蛋白聚集体的积累减少相关。结论-针对外周和神经元缺陷，Ex-4是一种有吸引力的药物，可用于患有糖尿病的亨廷顿病患者的治疗干预。
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.
登录
查看更多内容
影响因子：
30.8
作者：
ANDREW, SE;GOLDBERG, YP;HAYDEN, MR
通讯作者：
HAYDEN, MR
影响因子：
2
作者：
Altinova, Alev E.;Toruner, Fusun;Arslan, Metin
通讯作者：
Arslan, Metin
影响因子：
5.3
作者：
Adage, T;Scheurink, AJW;van Dijk, G
通讯作者：
van Dijk, G
影响因子：
6.1
作者：
Andreassen, OA;Dedeoglu, A;Beal, MF
通讯作者：
Beal, MF
影响因子：
2
作者：
Hunt, MJ;Morton, AJ
通讯作者：
Morton, AJ