Type 2 diabetes (T2D) is the result of interaction between environmental factors and a strong hereditary component. We review the heritability of T2D as well as the history of genetic and genomic research in this area. Very few T2D risk genes were identified using candidate gene and linkage-based studies, but the advent of genome-wide association studies has led to the identification of multiple genes, including several that were not previously known to play any role in T2D. Highly replicated genes, for example TCF7L2, KCNQ1 and KCNJ11, are discussed in greater detail. Taken together, the genetic loci discovered to date explain only a small proportion of the observed heritability. We discuss possible explanations for this "missing heritability", including the role of rare variants, gene-environment interactions and epigenetics. The clinical utility of current findings and avenues of future research are also discussed.© 2013 Baishideng. All rights reserved.Key words: Type 2 diabetes; Genetics; TCF7L2; Genome-wide association studies; Heritability Core tip: We review the history and the current state of knowledge regarding the genetic component of type 2 diabetes risk. Genes like TCF7L2 that have been replicated in multiple studies are discussed in detail. The significance of these findings is discussed and gaps in our knowledge are identified, as are avenues for future research.

Objective Assess genetic and phenotypic correlations of obesity-related cardiometabolic risk factors in a family-based cohort. Methods Anthropometric, body composition and biochemical measurements were collected on 999 members of 111 extended Midwestern US families of Northern European origin. Forward stepwise regression was used to identify which of Tanner stage, sex, Tanner stage by sex, BFMI, body fat percent (BF%) (DXA), VF/SubQF (CT scan for adults or MRI for children), VF, SubQF, BMI% and waist to height ratio (WHtR) most influence HOMA, HDL-c, TG, and LDL-c. Results In children and adolescents, subcutaneous adiposity was the most significant covariate for HOMA (p<0.001) and TG (p=0.001) and BMI percentile for HDL-c (p=0.002) and LDL-c (p<0.001). In adults, waist-height ratio (p<0.001), visceral/subcutaneous fat ratio (p=0.001) and BMI (p=0.02) were most significant for HOMA; visceral fat (p<0.001) and BMI (p=0.02) for TG and visceral fat for LDL-c (p=0.001). Conclusion Subcutaneous adiposity at the waist is a more significant predictor of MetS traits in children and adolescents than it is in adults.

Epigenetic mechanisms, including DNA methylation, mediate the interaction between gene and environment and may play an important role in the obesity epidemic. We assessed the relationship between DNA methylation and obesity in peripheral blood mononuclear cells (PBMCs) at 485,000 CpG sites across the genome in family members (8-90 y of age) using a discovery cohort (192 individuals) and a validation cohort (1,052 individuals) of Northern European ancestry. After Bonferroni-correction (Pα=0.05 = 1.31 × 10−7) for genome-wide significance, we identified 3 loci, cg18181703 (SOCS3), cg04502490 (ZNF771), and cg02988947 (LIMD2), where methylation status was associated with body mass index percentile (BMI%), a clinical index for obesity in children, adolescents, and adults. These sites were also associated with multiple metabolic syndrome (MetS) traits, including central obesity, fat depots, insulin responsiveness, and plasma lipids. The SOCS3 methylation locus was also associated with the clinical definition of MetS. In the validation cohort, SOCS3 methylation status was found to be inversely associated with BMI% (P = 1.75 × 10−6), waist to height ratio (P = 4.18 × 10−7), triglycerides (P = 4.01 × 10−4), and MetS (P = 4.01 × 10−7), and positively correlated with HDL-c (P = 4.57 × 10−8). Functional analysis in a sub cohort (333 individuals) demonstrated SOCS3 methylation and gene expression in PBMCs were inversely correlated (P = 2.93 × 10−4) and expression of SOCS3 was positively correlated with status of MetS (P = 0.012). We conclude that epigenetic modulation of SOCS3, a gene involved in leptin and insulin signaling, may play an important role in obesity and MetS.

Background An inverse correlation between serum 25-hydroxyvitamin D concentration and atopic dermatitis (AD) severity has been suggested. Objective To determine if a statistically significant relationship exists between serum 25-hydroxyvitamin D concentration and AD severity. Methods A cross-sectional study was conducted of patients with AD aged 1–18 years. An objective Severity Scoring of Atopic Dermatitis (SCORAD) and a serum 25-hydroxyvitamin D concentration were measured for each subject. Statistical analysis was performed using appropriate univariate tests and multivariable models. Results Ninety-four of 97 enrolled subjects were included in the analysis. Vitamin D deficiency (25-hydroxyvitamin D <20ng/ml) was present in 37 (39%), insufficiency (25-hydroxyvitamin D 21–29 ng/mL) in 33 (35%), and sufficiency (25-hydroxyvitamin D ≥30 ng/ml) in 24 (26%). The correlation between 25-hydroxyvitamin D concentration and SCORAD was not significant (r=−0.001, p=0.99). A multivariate model showed that a lower serum 25-hydroxyvitamin D concentration was significantly associated with age ≥3-years (p<0.0001), black race (p<0.0001), and winter season (p=0.0084). Limitations Limitations of this study include the inability to control for natural sunlight exposure, vitamin D intake and AD treatment, and that only a single time point was captured. Conclusions Serum 25-hydroxyvitamin D concentration is not significantly correlated with AD severity in our pediatric population.

Insulin-like growth factor binding protein (IGFBP)-3 binds to IGF and modulates their actions and also possesses intrinsic activities. We investigated its effects on insulin action and found that when IGFBP-3 was added to fully differentiated 3T3-L1 adipocytes in culture, insulin-stimulated glucose transport was significantly inhibited to 60% of control in a time-and dose-dependent manner. Tumor necrosis factor (TNF)-␣ treatment also inhibited glucose transport to the same degree as IGFBP-3 and, in addition, increased IGFBP-3 levels 3-fold. Co-treatment with TNF-␣ and IGFBP-3 antisense partially prevented the inhibitory effect of TNF-␣ on glucose transport, indicating a role for IGFBP-3 in cytokine-induced insulin resistance. Insulin-stimulated phosphorylation of the insulin receptor was markedly decreased by IGFBP-3 treatment. IGFBP-3 treatment suppressed adiponectin expression in 3T3-L1 adipocytes. Infusion of IGFBP-3 to Sprague-Dawley rats for 3 h decreased peripheral glucose uptake by 15% compared with controls as well as inhibiting glycogen synthesis. Systemic administration of IGFBP-3 to rats for 7 d resulted in a dramatic 40% decrease in peripheral glucose utilization and glycogen synthesis. These in vitro and in vivo findings demonstrate that IGFBP-3 has potent insulin-antagonizing capability and suggest a role for IGFBP-3 in cytokine-induced insulin resistance and other mechanisms involved in the development of type-2 diabetes. (Pediatr Res 61: 159-164, 2007)