METS-IR is a novel score to evaluate cardiometabolic risk in healthy and at-risk subjects and a promising tool for screening of insulin sensitivity.

Performing genetic studies in multiple human populations can identify disease risk alleles that are common in one population but rare in others1, with the potential to illuminate pathophysiology, health disparities, and the population genetic origins of disease alleles. We analyzed 9.2 million single nucleotide polymorphisms (SNPs) in each of 8,214 Mexicans and Latin Americans: 3,848 with type 2 diabetes (T2D) and 4,366 non-diabetic controls. In addition to replicating previous findings2–4, we identified a novel locus associated with T2D at genome-wide significance spanning the solute carriers SLC16A11 and SLC16A13 (P=3.9×10−13; odds ratio (OR)=1.29). The association was stronger in younger, leaner people with T2D, and replicated in independent samples (P=1.1×10−4; OR=1.20). The risk haplotype carries four amino acid substitutions, all in SLC16A11; it is present at ≈50% frequency in Native American samples and ≈10% in East Asian, but rare in European and African samples. Analysis of an archaic genome sequence indicated the risk haplotype introgressed into modern humans via admixture with Neandertals. The SLC16A11 mRNA is expressed in liver, and V5-tagged SLC16A11 protein localizes to the endoplasmic reticulum. Expression of SLC16A11 in heterologous cells alters lipid metabolism, most notably causing an increase in intracellular triacylglycerol levels. Despite T2D having been well studied by genome-wide association studies (GWAS) in other populations, analysis in Mexican and Latin American individuals identified SLC16A11 as a novel candidate gene for T2D with a possible role in triacylglycerol metabolism.

We hypothesized that a common SNP in the 3' untranslated region of the upstream transcription factor 1 (USF1), rs3737787, may affect lipid traits by influencing gene expression levels, and we investigated this possibility utilizing the Mexican population, which has a high predisposition to dyslipidemia. We first associated rs3737787 genotypes in Mexican Familial Combined Hyperlipidemia (FCHL) case/control fat biopsies, with global expression patterns. To identify sets of co-expressed genes co-regulated by similar factors such as transcription factors, genetic variants, or environmental effects, we utilized weighted gene co-expression network analysis (WGCNA). Through WGCNA in the Mexican FCHL fat biopsies we identified two significant Triglyceride (TG)-associated co-expression modules. One of these modules was also associated with FCHL, the other FCHL component traits, and rs3737787 genotypes. This USF1-regulated FCHL-associated (URFA) module was enriched for genes involved in lipid metabolic processes. Using systems genetics procedures we identified 18 causal candidate genes in the URFA module. The FCHL causal candidate gene fatty acid desaturase 3 (FADS3) was associated with TGs in a recent Caucasian genome-wide significant association study and we replicated this association in Mexican FCHL families. Based on a USF1-regulated FCHL-associated co-expression module and SNP rs3737787, we identify a set of causal candidate genes for FCHL-related traits. We then provide evidence from two independent datasets supporting FADS3 as a causal gene for FCHL and elevated TGs in Mexicans.

Background The Mexican population and others with Amerindian heritage exhibit a substantial predisposition to dyslipidemias and coronary heart disease. Yet, these populations remain underinvestigated by genomic studies, and to date, no genome-wide association (GWA) studies have been reported for lipids in these rapidly expanding populations. Methods and Findings We performed a two-stage GWA study for hypertriglyceridemia and low high-density lipoprotein cholesterol (HDL-C) in Mexicans (n=4,361) and identified a novel Mexican-specific genome-wide significant locus for serum triglycerides (TGs) near the Niemann-Pick type C1 protein (NPC1) gene (P=2.43×10−08). Furthermore, three European loci for TGs (APOA5, GCKR, and LPL) and four loci for HDL-C (ABCA1, CETP, LIPC and LOC55908) reached genome-wide significance in Mexicans. We utilized cross-ethnic mapping to narrow three European TG GWA loci, APOA5, MLXIPL, and CILP2 that were wide and contained multiple candidate variants in the European scan. At the APOA5 locus, this reduced the most likely susceptibility variants to one, rs964184. Importantly, our functional analysis demonstrated a direct link between rs964184 and postprandial serum apoAV protein levels, supporting rs964184 as the causative variant underlying the European and Mexican GWA signal. Overall, 52 of the 100 reported associations from European lipid GWA meta-analysis generalized to Mexicans. However, in 82 of the 100 European GWA loci, a different variant other than the European lead/best-proxy variant had the strongest regional evidence of association in Mexicans. Conclusions This first Mexican GWA study of lipids identified a novel GWA locus for high TG levels; utilized the inter-population heterogeneity to significantly restrict three previously known European GWA signals; and surveyed whether the European lipid GWA SNPs extend to the Mexican population.

Metabolomics is a promising approach for the identification of chemical compounds that serve for early detection, diagnosis, prediction of therapeutic response and prognosis of disease. Moreover, metabolomics has shown to increase the diagnostic threshold and prediction of type 2 diabetes. Evidence suggests that branched-chain amino acids, acylcarnitines and aromatic amino acids may play an early role on insulin resistance, exposing defects on amino acid metabolism, β-oxidation, and tricarboxylic acid cycle. This review aims to provide a panoramic view of the metabolic shifts that antecede or follow type 2 diabetes. Key messages BCAAs, AAAs and acylcarnitines are strongly associated with early insulin resistance. Diabetes risk prediction has been improved when adding metabolomic markers of dysglycemia to standard clinical and biochemical factors.

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Objective: Fibroblast growth factor 21 (FGF21) levels have been linked with beneficial effects on glucose and lipid metabolism in animals. It is elevated in humans with the metabolic syndrome. This study investigates independent factors associated with serum FGF21 levels. Design: Cross-sectional study done in healthy blue-collar workers. Methods: A medical history was taken, and FGF21 (measured using an ELISA commercial kit), glucose, uric acid, plasma lipids, total/high-molecular weight (HMW) adiponectin, and retinal-binding protein 4 (RBP4) were measured in 210 individuals with (nZ81) and without (nZ129) metabolic syndrome. Results: The median of serum FGF21 levels were higher in subjects with metabolic syndrome (339.5 vs 276.4 ng/l, PZ0.01). Serum FGF21 levels correlated positively with body mass index (BMI; rZ0.23, PZ0.001) and age (rZ0.17, PZ0.01). After adjusting for age and BMI, a significant positive correlation persisted for fasting glucose, uric acid, and physical activity in both males (rZ0.21, rZ0.11, and rZ0.19, all P!0.05) and females (rZ0.20, rZ0.19, and rZ0.14, all P!0.05). In addition, FGF21 also correlates negatively with RBP4 (rZK0.27, PZ0.02), total (rZK0.26, PZ0.03), and HMW adiponectin (rZK0.30, PZ0.01) in women. A multiple linear regression model analysis identified that BMI (standardized b (SB)Z0.247; PZ0.008), glucose (SBZ0.226; PZ0.003), uric acid (SBZ0.191; PZ0.04), and physical activity (SBZ0.223; PZ0.004) are independent factors influencing serum FGF21 levels (FZ10.05, r 2 Z0.19, P!0.001). In addition, fasting hyperglycemia R100 mg/dl, excess body weight with BMI R25 kg/m 2 , and uric acid R5.5 mg/dl predicted higher serum FGF21 levels. Conclusion: Serum FGF21 levels are influenced by BMI, fasting glycemia, uric acid, and physical activity.

Type 2 diabetes (T2D) affects more than 415 million people worldwide, and its costs to the health care system continue to rise. To identify common or rare genetic variation with potential therapeutic implications for T2D, we analyzed and replicated genome-wide protein coding variation in a total of 8,227 individuals with T2D and 12,966 individuals without T2D of Latino descent. We identified a novel genetic variant in the IGF2 gene associated with ∼20% reduced risk for T2D. This variant, which has an allele frequency of 17% in the Mexican population but is rare in Europe, prevents splicing between IGF2 exons 1 and 2. We show in vitro and in human liver and adipose tissue that the variant is associated with a specific, allele-dosage–dependent reduction in the expression of IGF2 isoform 2. In individuals who do not carry the protective allele, expression of IGF2 isoform 2 in adipose is positively correlated with both incidence of T2D and increased plasma glycated hemoglobin in individuals without T2D, providing support that the protective effects are mediated by reductions in IGF2 isoform 2. Broad phenotypic examination of carriers of the protective variant revealed no association with other disease states or impaired reproductive health. These findings suggest that reducing IGF2 isoform 2 expression in relevant tissues has potential as a new therapeutic strategy for T2D, even beyond the Latin American population, with no major adverse effects on health or reproduction.