Multiple metabolic defects during late pregnancy in women at high risk fortype 2 diabetes

Detailed metabolic studies were carried out to compare major regulatory ste ps in glucose metabolism in vivo between 25 normal pregnant Latino women wi thout and 150 pregnant Latino women with gestational diabetes mellitus (GDM ). The two groups were frequency-matched for age, BMI, and gestational age at testing in the third trimester. After an overnight fast, women with GDM had higher fasting plasma glucose. (P = 0.0001) and immunoreactive insulin (P = 0.0003) concentrations and higher glucose production rates (P = 0.01) but lower glucose clearance rates (P = 0.001) compared with normal pregnant women. During steady-state hyperinsulinemia (similar to 600 pmol/l) and eu glycemia (similar to 4.9 mmol/l), women with GDM had lower glucose clearanc e rates (P = 0.0001) but higher glucose production rates (P = 0.0001) and p lasma free fatty acid (FFA) concentrations (P = 0.0002) than the normal wom en. These intergroup differences persisted when a subgroup of 116 women wit h GDM who were not diabetic less than or equal to 6 months after pregnancy were used in the analysis. When all subjects were considered, there was a v ery close correlation between glucose production rates and plasma FFA conce ntrations throughout the glucose clamps in control (r = 0.996) and GDM (r = 0.995) groups. Slopes and intercepts of the relationships were nearly iden tical, suggesting that blunted suppression of FFA concentrations contribute d to blunted suppression of glucose production in the GDM group. In additio n to these defects in insulin action, women with GDM had a 67% impairment o f pancreatic beta-cell compensation for insulin resistance compared,vith no rmal pregnant women. These results demonstrate that women with GDM have mul tiple defects in insulin action together with impaired compensation for ins ulin resistance. Our findings suggest that defects in the regulation of glu cose clearance, glucose production, and plasma FFA concentrations, together with defects in pancreatic beta-cell function, precede the development of type 2 diabetes in these high-risk women.