Large-for-Gestational-Age May Be Associated With Lower Fetal Insulin Sensitivity and β-Cell Function Linked to Leptin

Context: Fetal overgrowth is associated with increased risk for type 2 diabetes in adulthood. It is unclear whether there are alterations in insulin sensitivity and beta-cell function in early life. Objective: To determine whether large-for-gestational-age (LGA) (birth weight. 90th percentile), an indicator of fetal overgrowth, is associated with altered fetal insulin sensitivity and beta-cell function. Study Design, Population, and Outcomes: In the Design, Development, and Discover birth cohort in Canada, we studied 106 pairs of LGA and optimal-for-gestational-age (OGA; birth weight, 25th to 75th percentiles) infants matched by maternal ethnicity, smoking status, and gestational age. Cord plasma glucose-to-insulin ratio was used as an indicator of fetal insulin sensitivity, and proinsulin-to-insulin ratio was used as an indicator of beta-cell function. Cord plasma leptin and high-molecular weight (HMW) adiponectin concentrations were measured. Results: Comparisons of infants who were born LGA vs OGA, adjusted for maternal and newborn characteristics, showed that cord blood insulin, proinsulin, and leptin concentrations were significantly higher, whereas HWM adiponectin concentrations were similar. Glucose-to-insulin ratios were significantly lower (15.4 +/- 28.1 vs 22.0 +/- 24.9; P = 0.004), and proinsulin-to-insulin ratios significantly higher (0.73 +/- 0.82 vs 0.60 +/- 0.78; P = 0.005) in LGA vs OGA newborns, indicating lower insulin sensitivity and b-cell function in LGA newborns. These significant differences were almost unchanged after further adjustment for cord blood adiponectin levels but disappeared upon additional adjustment for cord blood leptin levels. Conclusions: This study demonstrates that LGA may be associated with decreases in both fetal insulin sensitivity and beta-cell function. The alterations appear to be linked to elevated leptin levels.