Genome-Wide Association Study of the Modified Stumvoll Insulin Sensitivity Index Identifies BCL2 and FAM19A2 as Novel Insulin Sensitivity Loci

Genome-wide association studies (GWAS) have found few common variants that influence fasting measures of insulin sensitivity. We hypothesized that a GWAS of an integrated assessment of fasting and dynamic measures of insulin sensitivity would detect novel common variants. We performed a GWAS of the modified Stumvoll Insulin Sensitivity Index (ISI) within the Meta-Analyses of Glucose and Insulin-Related Traits Consortium. Discovery for genetic association was performed in 16,753 individuals, and replication was attempted for the 23 most significant novel loci in 13,354 independent individuals. Association with ISI was tested in models adjusted for age, sex, and BMI and in a model analyzing the combined influence of the genotype effect adjusted for BMI and the interaction effect between the genotype and BMI on ISI (model 3). In model 3, three variants reached genome-wide significance: Rs13422522 (NYAP2; P = 8.87 × 10-11), rs12454712 (BCL2; P = 2.7 × 10-8), and rs10506418 (FAM19A2; P = 1.9 × 10-8). The association at NYAP2 was eliminated by conditioning on the known IRS1 insulin sensitivity locus; the BCL2 and FAM19A2 associations were independent of known cardiometabolic loci. In conclusion, we identified two novel loci and replicated known variants associated with insulin sensitivity. Further studies are needed to clarify the causal variant and function at the BCL2 and FAM19A2 loci

Gut microbiota composition in male rat models under different nutritional status and physical activity and its association with serum leptin and ghrelin levels.

BACKGROUND: Several evidences indicate that gut microbiota is involved in the control of host energy metabolism. OBJECTIVE: To evaluate the differences in the composition of gut microbiota in rat models under different nutritional status and physical activity and to identify their associations with serum leptin and ghrelin levels. METHODS: In a case control study, forty male rats were randomly assigned to one of these four experimental groups: ABA group with food restriction and free access to exercise; control ABA group with food restriction and no access to exercise; exercise group with free access to exercise and feed ad libitum and ad libitum group without access to exercise and feed ad libitum. The fecal bacteria composition was investigated by PCR-denaturing gradient gel electrophoresis and real-time qPCR. RESULTS: In restricted eaters, we have found a significant increase in the number of Proteobacteria, Bacteroides, Clostridium, Enterococcus, Prevotella and M. smithii and a significant decrease in the quantities of Actinobacteria, Firmicutes, Bacteroidetes, B. coccoides-E. rectale group, Lactobacillus and Bifidobacterium with respect to unrestricted eaters. Moreover, a significant increase in the number of Lactobacillus, Bifidobacterium and B. coccoides-E. rectale group was observed in exercise group with respect to the rest of groups. We also found a significant positive correlation between the quantity of Bifidobacterium and Lactobacillus and serum leptin levels, and a significant and negative correlation among the number of Clostridium, Bacteroides and Prevotella and serum leptin levels in all experimental groups. Furthermore, serum ghrelin levels were negatively correlated with the quantity of Bifidobacterium, Lactobacillus and B. coccoides-Eubacterium rectale group and positively correlated with the number of Bacteroides and Prevotella. CONCLUSIONS: Nutritional status and physical activity alter gut microbiota composition affecting the diversity and similarity. This study highlights the associations between gut microbiota and appetite-regulating hormones that may be important in terms of satiety and host metabolism

Serum leptin (A) and grhelin (B) levels (C) at day 6 of study in all rat groups (N = 10 rats per group).

<p>The Mann-Whitney U test was used to compare a rat group to each other. Different superscript letters are significantly different <i>P</i><0.05 (Bonferroni <i>Post-hoc</i> test).</p

Representation of the relative daily body weight variation (A) and daily food intake (B) in the all study groups (N = 10 rats per group).

<p>The figure (C) shows a 23 h registered activity in ABA and exercise groups.</p

Dendrograms of electrophoretic band patterns obtained in the denaturing gel gradient electrophoresis experiment with universal primers in the fecal samples collected from ABA, control ABA (cABA), exercise and ad libitum rats.

<p>A: Cluster analysis; B: DGGE profiles of fecal samples.</p

Bacterial identification after the sequencing of the bands cloned from the DGGE analysis of fecal samples from the all rat groups.

a<p>Refers to the frequency (and percent) of each unique bacteria genus in the ABA or Control ABA or exercise or ad libitum group.</p><p>"n" number of bands cloned, sequenced and identified in each rat group.</p><p>N = 10 rats per group. Barnard's exact unconditional test was used to compare the proportions of one group of rats to each other.</p><p>Values in a row with different superscript letters are significantly different <i>P</i><0.05.</p