A Novel Locus, Mody4, Distal to D7Mit189 on Chromosome 7 Determines Early-Onset NIDDM in Nonobese C57BL/6 (Akita) Mutant Mice

Abstract

In this article, we report on a nonobese C57BL/6 (B6) mouse model of NIDDM named Akita mouse, characterized by early age onset and autosomal dominant mode of inheritance. At 7 weeks of age, the mean morning blood glucose levels (mmol/1) under ad libitum feeding conditions were significantly higher (P < 0.01, analysis of variance [ANOVA]) in diabetic mice than in unaffected mice: 27.3 ± 5.3 for diabetic males (n = 50) and 9.3 ± 1.2 for unaffected males (n = 50); 13.6 ± 3.8 for diabetic females (n = 50) and 8.7 ± 1.1 for unaffected females (n = 50), while corresponding immunoreactive insulin levels in plasma were significantly lower in diabetic mice than in unaffected mice. In vitro insulin secretion was also impaired, even at 4 weeks of age. The 50% survival time for male diabetic mice (305 days) was significantly shorter than that of unaffected counterpart mice but not for diabetic females. Obesity did not occur in diabetic mice. Histological examinations of the pancreas in diabetic mice, from 4 to 35 weeks of age, revealed decreases in the numbers of active β-cells without insulitis. Morphometry demonstrated specific decreases in immunologically detectable insulin density in islets in diabetic mice, even at 4 weeks of age, without changes of relative islet areas. By linkage analysis, a single locus was identified on the basis of 178 N2 mice [(B6 × C3H/He)F1 × B6 and (B6 × C3H/He)F1 × C3H/He]. This locus, which we named Mody4, was mapped to chromosome 7 in a region 2–8 cM distal to D7Mitl89 (logarithm of odds [LOD] score = 15.6 and 10.3).