The promoter region of the adiponectin gene is a determinant in modulating insulin sensitivity in childhood obesity.

We investigated the association of the -11,391G>A, -11,377G>C, +45T>G, and +276G>T adiponectin single-nucleotide polymorphisms (SNPs) and expected haplotypes with the insulin resistance (IR) state in overweight/obese children; by using the haplotype background analysis, we also assessed the effect of each SNP independently. GG genotype at the -11,391 locus was associated with higher fasting insulin levels and homeostasis model assessment-IR index and lower adiponectin levels compared with GA + AA genotypes (p = 0.01, 0.002, and 0.03, respectively). Those heterozygous and homozygous for G allele at the -11,377 locus showed higher fasting glucose (p = 0.001 for both), fasting insulin (p = 0.001 for both), homeostasis model assessment-IR index (p < 0.001 for both), and triglyceride levels (p = 0.02 and 0.03, respectively) and lower adiponectin levels (p = 0.002 and 0.02, respectively) compared with C homozygotes. The +45G carriers showed higher fasting and 2-hour glucose levels (p = 0.01 for both) and lower adiponectin levels (p = 0.02) compared with non-carriers. Haplotype analysis suggested that, considering the same haplotypic background, each of the three polymorphisms exerted an independent effect on investigated parameters. The -11,391G>A, -11,377C>G, and +45T>G SNPs are associated with IR syndrome in overweight/obese children; they independently influence the investigated variables. The effect of +45T>G SNP seems to be marginal compared with the promoter SNPs. The GGT haplotype is associated with the highest degree of IR.

PPAR-gamma2 Pro12Ala variant is associated with greater insulin sensitivity in childhood obesity.

Several genetic variants of peroxisome proliferator-activated receptor-gamma2 (PPAR-gamma2), a molecule known to be involved in transcription of target genes, have been identified. Pro12Ala, a missense mutation in exon 2 of the gene, is highly prevalent in Caucasian populations. Conflicting conclusions about the association between this mutation and complex traits such as obesity, insulin sensitivity, and T2DM have been reported. We have investigated the association of PPAR-gamma2 Pro12Ala polymorphism with measures of insulin sensitivity in a population of Italian obese children (n = 200; mean age, 10.38 +/- 2.8 y) in whom clinical and biochemical analyses were performed. To estimate the insulin sensitivity status, the homeostasis model assessment of insulin resistance (HOMA-IR) was calculated in all subjects. The effect of the Pro12Ala polymorphism on quantitative variables was tested using multiple linear regression analysis. The frequency of Ala carriers was 17%, similar to that reported in other adult Caucasian populations. The X12Ala (either Pro12Ala or Ala12Ala) genotype was associated with significantly lower fasting insulin levels compared with Pro/Pro (p = 0.008). Consistent with this finding, significantly lower HOMA-IR was observed in X12Ala carriers (p = 0.023). In conclusion, our observations demonstrate that the X12Ala variant is significantly associated with greater insulin sensitivity in childhood obesity. Because obesity is one of the most important risk factors for cardiovascular diseases and type 2 diabetes, obese children, who are presumably at a higher risk, may be protected from these diseases by the phenotypic effect of the Ala 12 allele on insulin resistance.