Genetic regulation of impaired fasting glucose in congenic mice

Abstract

Previously, we identified a quantitative trait locus (QTL) linked to 4‐hour fasting plasma glucose levels on mouse chromosome 4, Tanidd4, using F2 progeny of normal C57BL/6 (B6) and type 2 diabetic TALLYHO/Jng (TH) mice. For this locus, the TH allele was associated with hyperglycemia. Subsequently, we have generated congenic mice that carry the tanidd4 QTL derived from TH mice on a B6 background. In this study, we characterized the glucose metabolism, body composition, and energy balance in the congenic mice. Overnight fasting plasma glucose levels were significantly increased in the congenic mice compared to B6 control mice [140±6 vs. 113±3, 13 weeks of age (wk); 165±9 vs. 114±11, 24 wk; means±SE; males]. However, there was no difference in glucose tolerance between the two strains (by IPGTT). Interestingly, the congenic mice were significantly heavier than B6 mice, and the body weight difference was accounted for by an increase in lean body mass rather than fat mass (by MRI). The congenic mice also showed increased energy expenditure (heat production; kcal/hour) and locomotor activity compared to B6 mice (by Comprehensive Laboratory Animal Monitoring System; 19–20 wk). There was no difference in fuel source preference, as respiratory exchange ratio. In summary, tanidd4 congenic mice offer a useful model for identifying genetic determinants of impaired fasting glucose, a characteristic of pre‐diabetes in humans.