Institute of Veterinary Pathology, Center for Clinical Veterinary Medicine, LMU Munich, Munich, Germany.
Mol Cell Endocrinol. 2012 Oct 15;362(1-2):139-48. doi: 10.1016/j.mce.2012.06.001. Epub 2012 Jun 12.
In the large-scale Munich N-ethyl-N-nitrosourea (ENU) mouse mutagenesis project murine models recapitulating human diseases were generated. In one strain, a novel missense mutation (D217V) in the glucokinase (Gck) gene was identified, resulting in decreased glucokinase activity. Heterozygous mutants display mild hyperglycaemia, disturbed glucose tolerance, and decreased glucose-induced insulin secretion. In contrast, homozygous mutants exhibit severe but not survival affecting hyperglycaemia, mild growth retardation, diminished oxidative capacity, and increased abundance of CHOP protein in the islets. Furthermore, the total islet and β-cell volumes and the total volume of isolated β-cells are significantly decreased in adult homozygous mutants, whereas in neonatal mice, β-cell mass is not yet significantly decreased and islet neogenesis is unaltered. Therefore, reduced total islet and β-cell volumes of adult homozygous mutants might predominantly emerge from disturbed postnatal islet neogenesis. Thus, we identified a novel Gck mutation in mice, with relevance in humans, leading to glycaemic disease.
在大规模的慕尼黑 N-乙基-N-亚硝脲（ENU）小鼠诱变项目中，生成了模拟人类疾病的小鼠模型。在一个品系中，发现了葡萄糖激酶（Gck）基因中的一个新的错义突变（D217V），导致葡萄糖激酶活性降低。杂合突变体表现出轻度高血糖、葡萄糖耐量受损和葡萄糖诱导的胰岛素分泌减少。相比之下，纯合突变体表现出严重但不影响生存的高血糖、轻度生长迟缓、氧化能力降低以及胰岛中 CHOP 蛋白丰度增加。此外，成年纯合突变体的总胰岛和β细胞体积以及分离的β细胞的总体积显著减少，而在新生小鼠中，β细胞质量尚未显著减少，胰岛新生也未改变。因此，成年纯合突变体总胰岛和β细胞体积的减少主要可能源于出生后胰岛新生的紊乱。因此，我们在小鼠中发现了一个新的 Gck 突变，与人类相关，导致血糖疾病。
