Genetic analysis of non-insulin-dependent diabetes mellitus in KK and KK-Ay mice

The KK mouse is considered suitable as a polygenic model for human non-insulin-dependent diabetes mellitus. To identify the quantitative trait loci (QTLs) responsible for hyperglycemia and impaired glucose tolerance in KK mice, linkage analysis using 97 microsatellite markers was carried out in a 192 F2 progeny, comprising 93 mice with the a/a genotype at the agouti locus (chromosome 2) and 99 mice with the A y /a genotype, produced by a cross between a C57BL/6J female and a KK-A y (A y congenic) male. In F2 a/a progenies, we identified a QTL for fasting glucose levels on chromosome 6 (LOD score 6.0) and three loci with suggestive linkage on chromosomes 3, 5 and 14, but could not identify loci accounting for glucose tolerance and plasma insulin levels. In F2 A y /a progenies, there were no loci with statistically significant linkage, but three suggestive loci were identified: a locus for fasting glucose on chromosome 9, and two loci for glucose tolerance on chromosomes 1 and 8. It would thus appear that, although the fasting glucose level is controlled by QTLs in KK mice, these QTLs may be masked by the strong hyperglycemic influence of the A y allele. Suggestive loci accounting for glucose tolerance may interact with the A y allele, since these loci were identified only in F2 A y /a progeny. This is consistent with the finding that the impaired glucose tolerance in KK mice is moderate and becomes overt when associated with the A y allele.