Mapping of susceptibility genes to diabetes by high fat diet following QTL analysis of diabetic db mice

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To identify the susceptibility genes to type 2 diabetes (T2D), we previously identified 2 quantitative trait loci (QTL), which affect body weight, fat pad weight, and fasting blood glucose concentrations in a leptin receptor deficient obese F2 intercross derived from BKS and DBA2 (D2) mice. We also generated congenic mice by repeatingly backcrossing donor (db) mice to recipient D2 mice carrying a given QTL-containing genomic region to test the effect of each QTL on diabetic phenotypes. Introgression of two QTL regions of D2 into BKS background replicated the increase in body weight and fat pad weight. The effect of QTL was dependent on obesity associated with the db/db-induced diabetes. To identify the factors promoting obesity-induced T2D, we conducted genetic studies on two lines of wild type congenic mice (without db loci) with high fat diet. Our findings are as follows ; 1) We found the suitable high fat diet to promote obesity-induced T2D in males and females. 2) We generated congenic mice without db loci by repeatingly backcrossing donor (db) mice to recipient D2 mice. Effects of genomic region were tested by comparing congenic mice having one region from D2 with having BKS alleles. Differences in phenotypes were replicated in body weight and fat pad weight in one line of congenic mice. 3) In another a line, we could not map the locus correlating obesity-induced T2D. 4) In the first line, analyses of six sub-lines identified the target region of eight Mb, which affects body weight induced by high fat diet. Our identification provides insight of obesity-induced type 2 diabetes mellitus.