Phenotypic and Pathomorphological Characteristics of a 1 Novel Mutant Mouse Model for Maturity - Onset Diabetes of 2 the Young Type 2 ( MODY 2 )

27 Several mutant mouse models for human diseases such as diabetes mellitus have been 28 generated in the large-scale Munich ENU (N-ethyl-N-nitrosourea) mouse mutagenesis project. 29 The aim of this study was to identify the causal mutation of one of these strains and to 30 characterize the resulting diabetic phenotype. Mutants exhibit a T to G transversion mutation 31 at nt 629 in the glucokinase (Gck) gene, leading to an amino acid exchange from methionine 32 to arginine at position 210. Adult Munich Gck mutants demonstrated a significant 33 reduction of hepatic glucokinase enzyme activity, but equal glucokinase mRNA and protein 34 abundances. While homozygous mutants exhibited growth retardation and died soon after 35 birth in consequence of severe hyperglycemia, heterozygous mutants displayed only slightly 36 elevated blood glucose levels, present from birth, with development of disturbed glucose 37 tolerance and glucose-induced insulin secretion. Additionally, insulin sensitivity and fasting 38 serum insulin levels were slightly reduced in male mutants from an age of 90 days onwards. 39 While β-cell mass was unaltered in neonate heterozygous and homozygous mutants, the total 40 islet and β-cell volumes and the total volume of isolated β-cells was significantly decreased in 41 210-day-old male, but not in female heterozygous mutants despite undetectable apoptosis. 42 These findings indicate that reduced total islet and β-cell volumes of male mutants might 43 emerge from disturbed postnatal islet neogenesis. Considering the lack of knowledge about 44 the pathomorphology of MODY 2, this glucokinase mutant model of reduced total islet and 45 total β-cell volume provides the opportunity to elucidate the impact of a defective glucokinase 46 on development and maintenance of β-cell mass, and its relevance in MODY 2 patients. 47