Atypical diabetes associated with inclusion formation in the R6/2 mouse model of Huntington's disease is not improved by treatment with hypoglycaemic agents
Atypical diabetes associated with inclusion formation in the R6/2 mouse model of Huntington's disease is not improved by treatment with hypoglycaemic agents
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DOI：
10.1007/s00221-005-2357-z
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发表时间：
2005-10-01
影响因子：
2
通讯作者：
Morton, AJ
中科院分区：
文献类型：
--
作者：
Hunt, MJ;Morton, AJ
亨廷顿病 (HD) 的 R6/2 转基因小鼠模型会形成一种进行性神经表型，涉及严重的运动和认知功能障碍。尽管不是主要症状，但在 R6/2 小鼠中已经描述了糖尿病。然而，尚不清楚糖尿病是否会导致 R6/2 小鼠出现 HD 样表型。在我们的研究中，我们发现 R6/2 小鼠糖尿病的严重程度与胰腺 β 细胞中泛素化包涵体的逐渐形成有关。糖尿病与早期运动和认知功能障碍无关，并且与 R6/2 小鼠的运动损伤和生存无关。然而，长期行为测试（其水平高于据报道可改善 R6/2 表型的几个方面的水平）加剧了糖尿病的发病。尝试使用糖尿病患者常用的两种口服降血糖药对糖尿病进行药物治疗。小鼠对格列本脲（诱导胰岛素胞吐作用）反应强烈，但对罗格列酮（诱导胰岛素敏感性）反应不强烈。这支持了 R6/2 小鼠的糖尿病是由胰岛素释放受损而不是胰岛素不敏感引起的观点。然而，这些降血糖药物的长期治疗对 R6/2 小鼠的糖尿病病程或疾病没有影响。
The R6/2 transgenic mouse model of Huntington's disease (HD) develops a progressive neurological phenotype that involves severe motor and cognitive dysfunctions. Although not a cardinal sign, diabetes has been described in R6/2 mice. It is not clear, however, whether the diabetes contributes to the HD-like phenotype of R6/2 mice. In our study we found that the severity of diabetes in R6/2 mice was associated with the progressive formation of ubiquinated inclusions in pancreatic beta cells. Diabetes is dissociated from early motor and cognitive dysfunctions and did not correlate with motor impairment and survival of R6/2 mice. However, chronic behavioural testing (at a level higher than that which is reported to improve several aspects of the R6/2 phenotype) exacerbated the onset of diabetes. Pharmacological treatment of the diabetes was attempted using two oral hypoglycaemic agents commonly used by diabetics. The mice responded acutely to glibenclamide (which induces exocytosis of insulin) but not to rosiglitazone (which induces sensitization to insulin). This supports the suggestion that the diabetes in R6/2 mice is caused by an impairment in insulin release rather than insulin insensitivity. However, chronic treatment with these hypoglycaemic agents had no effect on either the course of the diabetes or the disease in R6/2 mice.