Maternal Glucose Tolerance in Pregnancy Affects Fetal Insulin Sensitivity

OBJECTIVE

Offspring of mothers with impaired glucose tolerance are far more likely to develop type 2 diabetes. We tested the hypothesis that maternal glucose tolerance in pregnancy affects fetal insulin sensitivity or β-cell function.

RESEARCH DESIGN AND METHODS

In a prospective singleton pregnancy cohort study, we analyzed glucose, insulin, and proinsulin concentrations in maternal blood at the 50-g oral glucose tolerance test (OGTT) at 24–28 weeks of gestation and in venous cord blood (n = 248). The cord blood glucose-to-insulin ratio and proinsulin concentration were used as indicators of fetal insulin sensitivity and the proinsulin-to-insulin ratio was used as an indicator of fetal β-cell function.

RESULTS

Higher OGTT blood glucose levels were associated with significantly lower cord plasma glucose-to-insulin ratios (r = −0.31, P < 0.001) and higher proinsulin concentrations (r = 0.31, P < 0.001) but not with proinsulin-to-insulin ratios. In a comparison of gestational diabetic (n = 26) versus euglycemic pregnancy, cord blood glucose-to-insulin ratios were substantially lower (geometric mean 10.1 vs. 20.0 mg/dl/μU/ml; P < 0.001), whereas proinsulin concentrations were much higher (24.4 vs. 13.8 pmol/l; P < 0.001), despite similar cord blood glucose concentrations indicating adequate management of diabetes. The differences remained significant after controlling for prepregnancy and fetal adiposity, family history of diabetes, gestational age, and other potential confounders. Significant changes in the glucose-to-insulin ratio and proinsulin concentration were also observed in obese (n = 31) mothers, but the differences became not statistically significant after adjustment for maternal glucose tolerance and fetal adiposity.

CONCLUSIONS

Maternal glucose intolerance may impair fetal insulin sensitivity (but not β-cell function) and consequently “program” the susceptibility to type 2 diabetes.The metabolic syndrome and type 2 diabetes have become a worldwide epidemic of concern (1,2). The rapid rise of the epidemic over recent decades points to the predominant role of preventable “environmental” influences. The question is, what factors at what time points are critically important targets for effective interventions? There is an increasing recognition that the fetal environment may “program” susceptibility to the metabolic syndrome and related disorders (3,4). This suggests an opportunity for early interventions to halt the increasing occurrence of the metabolic syndrome if we could know more about the targets and mechanisms of metabolic programming in early life.Maternal metabolic status affects the fetal environment and plausibly has the potential to program the metabolic function axis of the offspring during critical developmental stages through various mechanisms (e.g., epigenetic changes) (5). Indeed, independent of the type of diabetes (pregestational type 1 or type 2 or gestational), offspring of diabetic mothers are far more likely to develop metabolic syndrome and type 2 diabetes (6–10). Most cases (∼90%) of diabetes in pregnancy are gestational diabetes mellitus (11). Mild gestational glucose intolerance not meeting the criteria for the diagnosis of gestational diabetes mellitus has also been associated with adverse pregnancy outcomes and elevated cord blood C-peptide levels (12). Obesity is closely associated with impaired glucose tolerance (2,13), and, recently, increased insulin resistance was observed among neonates of obese mothers (14). Taken together, these observations suggest that impaired glucose tolerance in pregnancy may program the propensity to development of the metabolic syndrome. However, there is a dearth of prospective pregnancy cohort data to demonstrate what metabolic parameters are programmed in utero. We aimed to test the hypothesis that maternal glucose tolerance in pregnancy affects fetal insulin sensitivity or β-cell function. Such a relationship may underlie the long-term predisposition to the metabolic syndrome and related disorders in offspring of diabetic mothers.