Insulin Gene Variable Number of Tandem Repeat Genotype and the Low Birth Weight, Precocious Pubarche, and Hyperinsulinism Sequence

Low birth weight associations with hyperinsulinemia and other adulthood disease risk factors have been described in several cohorts, including girls who present with precocious pubarche (pubic hair <8 yr). We hypothesized that these associations might be influenced by the insulin gene (INS) variable number of tandem repeat (VNTR), a common polymorphism related to INS transcription levels. In 141 Caucasian girls, who presented with precocious pubarche, hyperinsulinemia was assessed from mean insulin levels during an oral glucose load (MSI), and insulin sensitivity was determined from fasting glucose and insulin levels. Fasting blood lipid profiles were also measured. DNA was genotyped for INS VNTR allele class (I or III) in precocious pubarche girls and in 140 age- and body mass index-matched control girls. INS VNTR genotype distribution was similar in precocious pubarche and control girls. However among precocious pubarche girls, INS VNTR genotype was related to the severity of phenotype; I/I and I/III genotypes had lower birth weights (P < 0.01), higher MSI (P < 0.005), and lower insulin sensitivity (P < 0.005) than III/III girls. In precocious pubarche girls, birth weight was also inversely related to MSI (r = -0.29; P < 0.0005), total cholesterol (r = -0.38; P < 0.0005), and low density lipoprotein cholesterol (r = -0.44; P < 0.0005). Using logistic regression, additive adverse effects of I/* genotype and low birth weight were seen on MSI (P = 0.03 and P = 0.004, respectively) and total cholesterol levels (P = 0.01 and P < 0.0001). In summary, in girls who presented with precocious pubarche, hyperinsulinemia and dyslipidemia were related to both low birth weight and INS VNTR class I alleles. A similar interaction between genotype and intrauterine growth restraint may underlie other reported links between low birth weight and adulthood disease risks.