Abstract
BackgroundThe prevalence of Type 2 Diabetes (T2D) mellitus in the past decades, has reached epidemic proportions. Several lines of evidence support the role of genetic variation in the pathogenesis of T2D and insulin resistance. Elucidating these factors could contribute to developing new medical treatments and tools to identify those most at risk. The aim of this study was to characterize the phenotypic response of the Collaborative Cross (CC) mouse genetic resource population to high-fat diet (HFD) induced T2D-like disease to evluate its suitability for this purpose.ResultsWe studied 683 mice of 21 different lines of the CC population. Of these, 265 mice (149 males and 116 females) were challenged by HFD (42 % fat); and 384 mice (239 males and145 females) of 17 of the 21 lines were reared as control group on standard Chow diet (18 % fat). Briefly, 8 week old mice were maintained on HFD until 20 weeks of age, and subsequently assessed by intraperitoneal glucose tolerance test (IPGTT). Biweekly body weight (BW), body length (BL), waist circumstance (WC), and body mass index (BMI) were measured. On statistical analysis, trait measurements taken at 20 weeks of age showed significant sex by diet interaction across the different lines and traits. Consequently, males and females were analyzed, separately. Differences among lines were analyzed by ANOVA and shown to be significant (P <0.05), for BW, WC, BMI, fasting blood glucose, and IPGTT-AUC. We use these data to infer broad sense heritability adjusted for number of mice tested in each line; coefficient of genetic variation; genetic correlations between the same trait in the two sexes, and phenotypic correlations between different traits in the same sex.ConclusionsThese results are consistent with the hypothesis that host susceptibility to HFD-induced T2D is a complex trait and controlled by multiple genetic factors and sex, and that the CC population can be a powerful tool for genetic dissection of this trait.Electronic supplementary materialThe online version of this article (doi:10.1186/s12863-015-0321-x) contains supplementary material, which is available to authorized users.
Highlights
The prevalence of Type 2 Diabetes (T2D) mellitus in the past decades, has reached epidemic proportions
Glycemic stage in our study was measured via fasting blood glucose (6 h fasting) and via calculation of Area under curve across 180 min of a Glucose tolerance test (IPGTT), In the present study, we show that the high-fat diet (HFD) induces increased body weight, waist circumference, body mass index (BMI) and fasting glucose levels, and impairs Glucose tolerance
We propose that for females, development of obesity for most Collaborative Cross (CC) lines under our experimental conditions is below the threshold, exposing the positive correlation between obesity and insulin resistance; while for males, development of obesity for most lines is above the threshold
Summary
The prevalence of Type 2 Diabetes (T2D) mellitus in the past decades, has reached epidemic proportions. Several lines of evidence support the role of genetic variation in the pathogenesis of T2D and insulin resistance. Elucidating these factors could contribute to developing new medical treatments and tools to identify those most at risk. With a lag of about a decade, we are seeing the beginning of a far worse obesity/MTS/T2D epidemic in Asia and South America similar to that observed as Native American peoples adopted Westernized lifestyles [3]. Several lines of evidence provide support for the role of genetic variation in the pathogenesis of T2D and insulin resistance [4,5,6,7]. Identification of the underlying genes may help clarify the relationship of T2D and MTS [10, 11]
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