Inst. of Veterinary Pathology, Center for Clinical Veterinary Medicine, Munich, Germany.
Am J Physiol Endocrinol Metab. 2010 Mar;298(3):E512-23. doi: 10.1152/ajpendo.00465.2009. Epub 2009 Dec 1.
Several mutant mouse models for human diseases such as diabetes mellitus have been generated in the large-scale Munich ENU (N-ethyl-N-nitrosourea) mouse mutagenesis project. The aim of this study was to identify the causal mutation of one of these strains and to characterize the resulting diabetic phenotype. Mutants exhibit a T to G transversion mutation at nt 629 in the glucokinase (Gck) gene, leading to an amino acid exchange from methionine to arginine at position 210. Adult Munich Gck(M210R) mutant mice demonstrated a significant reduction of hepatic glucokinase enzyme activity but equal glucokinase mRNA and protein abundances. While homozygous mutant mice exhibited growth retardation and died soon after birth in consequence of severe hyperglycemia, heterozygous mutant mice displayed only slightly elevated blood glucose levels, present from birth, with development of disturbed glucose tolerance and glucose-induced insulin secretion. Additionally, insulin sensitivity and fasting serum insulin levels were slightly reduced in male mutant mice from an age of 90 days onward. While beta-cell mass was unaltered in neonate heterozygous and homozygous mutant mice, the total islet and beta-cell volumes and the total volume of isolated beta-cells were significantly decreased in 210-day-old male, but not female heterozygous mutant mice despite undetectable apoptosis. These findings indicate that reduced total islet and beta-cell volumes of male mutants might emerge from disturbed postnatal islet neogenesis. Considering the lack of knowledge about the pathomorphology of maturity-onset diabetes of the young type 2 (MODY 2), this glucokinase mutant model of reduced total islet and total beta-cell volume provides the opportunity to elucidate the impact of a defective glucokinase on development and maintenance of beta-cell mass and its relevance in MODY 2 patients.
几种人类疾病的突变型小鼠模型，如糖尿病，已经在大规模的慕尼黑 ENU（N-乙基-N-亚硝基脲）小鼠诱变项目中产生。本研究的目的是确定其中一个品系的致病突变，并对由此产生的糖尿病表型进行特征描述。突变体在葡萄糖激酶（Gck）基因的 nt629 处发生 T 到 G 的颠换突变，导致第 210 位的蛋氨酸被精氨酸取代。成年慕尼黑 Gck（M210R）突变小鼠表现出肝葡萄糖激酶酶活性显著降低，但葡萄糖激酶 mRNA 和蛋白丰度相等。虽然纯合突变小鼠表现出生长迟缓，并因严重高血糖而在出生后不久死亡，但杂合突变小鼠仅表现出出生时就存在的轻度升高的血糖水平，伴有葡萄糖耐量受损和葡萄糖诱导的胰岛素分泌障碍。此外，90 天大的雄性突变小鼠的胰岛素敏感性和空腹血清胰岛素水平略有降低。虽然新生杂合和纯合突变小鼠的β细胞质量没有改变，但 210 天大的雄性突变小鼠的总胰岛和β细胞体积以及分离的β细胞的总体积显著减少，而雌性突变小鼠则没有。尽管未检测到细胞凋亡。这些发现表明，雄性突变体的总胰岛和β细胞体积减少可能源于出生后胰岛新生的紊乱。考虑到对 2 型年轻发病型糖尿病（MODY2）的病理形态学知之甚少，这种葡萄糖激酶突变型模型的总胰岛和总β细胞体积减少为阐明缺陷葡萄糖激酶对β细胞质量的发育和维持的影响提供了机会，并在 MODY2 患者中具有重要意义。
