Boesgaard T W, Nielsen T T, Josefsen K, Hansen T, Jørgensen T, Pedersen O, Nørremølle A, Nielsen J E, Hasholt L
Steno Diabetes Center, Gentofte, Denmark.
J Neuroendocrinol. 2009 Sep;21(9):770-6. doi: 10.1111/j.1365-2826.2009.01898.x. Epub 2009 Jul 7.
Huntington's disease (HD) is an autosomal, dominantly inherited, neurodegenerative disorder characterised by neurological, cognitive and psychiatric symptoms. HD has been associated with diabetes mellitus, which is, to some extent, supported by studies in transgenic HD mice. In transgenic mice, the severity of the diabetic phenotype appears to correlate with the length of a polyglutamine expansion in the protein huntingtin. In the present study, we investigated the association between diabetes mellitus and HD by performing an oral glucose-tolerance test (OGTT) to evaluate the glucose-tolerance status and OGTT-related insulin release in 14 HD patients. Furthermore, we expressed N-terminal huntingtin fragments with different polyglutamine lengths in an insulinoma-cell line (INS-1E) to investigate how mutant huntingtin influences glucose-stimulated insulin release in vitro. We found no difference between a group of early- and middle-stage HD patients and a large group of control individuals in any of the assessed variables. However, the glucose-stimulated induction of insulin release was significantly reduced in the insulinoma-cell line expressing highly expanded huntingtin compared to cells expressing huntingtin with modestly elongated polyglutamine stretches. These data indicate that insulin release from beta-cells expressing mutant huntingtin appears to be polyglutamine length-dependent, and that polyglutamine lengths within the range normally found in adult onset HD do not influence insulin release. This challenges the assumption of an increased risk of diabetes among HD patients, although our results do not exclude a changed glucose tolerance in end-stage HD patients or in patients with juvenile onset HD. It also raises the question of which extent transgenic mice models reflect the pathology of human HD in this regard.
亨廷顿舞蹈症（HD）是一种常染色体显性遗传的神经退行性疾病，其特征为神经、认知和精神症状。HD与糖尿病有关，这在一定程度上得到了转基因HD小鼠研究的支持。在转基因小鼠中，糖尿病表型的严重程度似乎与亨廷顿蛋白中多聚谷氨酰胺扩展的长度相关。在本研究中，我们通过对14名HD患者进行口服葡萄糖耐量试验（OGTT）以评估其葡萄糖耐量状态及OGTT相关的胰岛素释放，来研究糖尿病与HD之间的关联。此外，我们在胰岛素瘤细胞系（INS-1E）中表达了具有不同多聚谷氨酰胺长度的N端亨廷顿片段，以研究突变型亨廷顿蛋白如何在体外影响葡萄糖刺激下胰岛素的释放。我们发现，在任何评估变量中，早期和中期HD患者组与一大组对照个体之间均无差异。然而，与表达多聚谷氨酰胺适度延长的亨廷顿蛋白的细胞相比，在表达高度扩展的亨廷顿蛋白的胰岛素瘤细胞系中，葡萄糖刺激诱导的胰岛素释放显著降低。这些数据表明，表达突变型亨廷顿蛋白的β细胞释放胰岛素似乎依赖于多聚谷氨酰胺长度，且在成年发病HD中通常发现的多聚谷氨酰胺长度范围内不会影响胰岛素释放。这对HD患者患糖尿病风险增加这一假设提出了挑战，尽管我们的结果不排除终末期HD患者或青少年发病HD患者存在葡萄糖耐量改变的情况。这也引发了一个问题，即在这方面转基因小鼠模型在多大程度上反映了人类HD的病理情况。
