Experiment
The recombinant inbred (RI) strain SMXA5 is derived from SM/J and A/J and exhibits impaired glucose tolerance, hyperinsulinemia, and mild obesity. SMXA5 is a mouse model for type 2 diabetes mellitus as the phenotype is exacerbated by a high fat diet. 255animals from a (SMXA5 x SM/J)F2 intercross were fed a high fat diet between 6-12 weeks of age and genotyped at 73 polymorphic loci. Body mass index (BMI) and all diabetic phenotypes are higher in SMXA5 compared to SM/J.
Significant linkage mapped to 50cMon mouse Chromosome 2 near D2Mit15 (LOD=12.6) and is designated T2dm2sa (type 2 diabetes mellitus 2 in SMXA RI mice). F2 animals homozygous for A/J-derived alleles at T2dm2sa exhibit increased blood glucose concentration at all time points during the intraperitoneal glucose tolerance test (IPGTT) compared to F2 animals homozygous for SM/J-derived alleles. This locus explains 9%-20% of the phenotypic variance in blood glucose concentration at all time points.
T2dm2sa was confirmed in the SM.A-T2dm2sa congenic line constructed by introgressing A/J-derived DNA between D2Mit295 (17 cM) and D2Mit281 (82 cM)onto an SM/J genetic background. SM.A-T2dm2sa congenic animals exhibit significantly increased body weight, BMI, fasting and free-fed blood glucose concentration, free-fed blood insulin concentration, and subcutaneous and mesenteric fat weight percentage compared to background strain SM/J.
Previously identified QTL mapping near T2dm2sa include Nidd5 (34.5 cM), Mob6 (49.6 cM), Mob7 (37 cM), T2dm3 (64 cM), and Mobe1 (44 cM, formerly Moo1). Nr1h3 (40.4 cM) is a potential candidate gene mapping near T2dm2sa.
Significant linkage to BMI and free-fed insulin concentration mapped to mouse Chromosome 12 at D12Mit58 (6 cM, LOD=4.8 and LOD=3.5, respectively).
Several suggestive loci were also identified in this experiement. Mouse Chromosome 5 is linked to free-fed blood glucose concentration at D5Mit239 (58 cM, LOD=2.7), chromosome 8 is linked to fasting blood glucose at D8Mit50 (41 cM, LOD=1.9), chromosome 11 is linked to BMI and glucose tolerance at D11Mit15 (40 cM, LOD=2.9 and LOD=2.3, respectively), chromosome 14 is linked to glucose tolerance atD14Mit131 (58 cM, LOD=2.7), chromosome 15 is linked to fasting serum insulin at D15Mit63 (29.2 cM, LOD=2.8), chromosome 17 is linked to BMI at D17Mit29 (15.1 cM, LOD=2.4) and glucose tolerance at D17Mit68 (24.5 cM, LOD=2.6), and chromosome 19 is linked to glucose tolerance at D19Mit30 (20 cM, LOD=1.9). Each locus contributes 3%-6% of the phenotypic variance.
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