Low birth weight is a risk factor for
obesity and
type 2 diabetes. The fetal
insulin hypothesis proposes that low birth weight might be mediated partly by genetic factors that impair insulin secretion/sensitivity during the fetal stage, as shown for
glucokinase, the
ATP-sensitive K+ channel subunit Kir6.2, and the small heterodimer partner genes.
Glutamic acid decarboxylase 2 gene (GAD2) overexpression impairs insulin secretion in animals. Recently, polymorphisms in the GAD2 gene were associated with adult
morbid obesity. In the present study, we investigated potential effects of the functional -243 A-->G polymorphism in the 5' promoter region of the GAD2 gene on fetal growth, insulin secretion, food intake, and risk of
obesity in 635 French Caucasian severely obese children from three different medical centers. The case/control study confirmed the association between the GAD2 single-nucleotide polymorphism (SNP) -243 A-->G and
obesity (odds ratio, 1.25; P = 0.04). In addition, SNP -243 GG children carriers showed a 270 g lower
birth weight and a 1.5 cm lower birth height compared with AA carriers (P = 0.009 and P = 0.013, respectively). The relation between
birth weight and Z score of BMI was linear in AA carrier children (P = 0.00001) and quadratic (U-shaped curve) in AG/GG carrier children (P = 0.0009). G allele children carriers presented a trend toward lower insulinogenic index with 25% reduction of insulin secretion in response to
glucose load compared with A carriers (P = 0.09). Eighteen percent of GG obese carriers vs. 5.7% of AA carriers reported
binge eating phenotype (P = 0.04). These results confirm the association between GAD2-243 promoter SNP and the risk for
obesity and suggest that GAD2 may be a polygenic component of the complex mechanisms linking
birth weight to further risk for
metabolic diseases, possibly involving the pleiotropic effect of
insulin on fetal growth and later on feeding behavior.