Identification of two chromosomal loci determining glucose intolerance in a C57BL/6 mouse strain

Background and Purpose: Our objective was to map the genes responsible for poor glucose tolerance in a C57BL/6 (B6) mouse model, which provides a huma n model of non-insulin-dependent diabetes mellitus, Insulin secretion was f ound to be significantly lower in B6 than in C3H/He (C3H) mice (analysis of variance, P < 0.05) at 10, 20, and 30 minutes during the intraperitoneal g lucose tolerance test (IPGTT: 1.5 g glucose/kg of body weight). Methods: Mean 30-minute blood glucose values during IPGTT at 8, 9, and 10 w eeks of age were used as a surrogate for glucose tolerance. The primers of 87 genetic microsatellite markers (14.9 +/- 6.2 cM apart) genome-wide quant itative trait linkage (QTL) analysis in F2 and F3 mice with the highest and lowest (n = 15 for each extreme) 30-minute blood glucose values were used. Results: Genome-wide QTL analysis confirmed the locus (D2Mit48) on chromoso me 2, with a LOD score of 8.3, and the locus (D13Mit48) on chromosome 13, w ith a LOD score of 4.2 in F3. Direct sequencing of candidate genes, proprot ein convertase-2 (PC2) on chromosome 2 and proprotein convertase-1/3 (PC1/P C3) on chromosome 13, failed to reveal a mutation or polymorphism specific to B6 mice. Conclusions: Use of QTL mapping revealed two loci associated with poor gluc ose tolerance of B6.