There are significant alterations in glucose metabolism during pregnancy. In women with normal glucose tolerance, there is a significant (30%) increase in basal hepatic glucose production, a progressive (60%) decrease in insulin sensitivity, and an associated 3.0-3.5-fold increase in insulin response by 34-36 weeks' gestation. In contrast, women with normal glucose tolerance before conception who develop gestational diabetes have significant decreased insulin sensitivity relative to women in a control group. This decrease in insulin sensitivity is most apparent before conception and becomes less significant with advancing gestation. Decreased first-phase insulin response and impaired suppression of hepatic glucose production with insulin infusion develop only in late pregnancy, resulting in clinically abnormal glucose tolerance. These results are consistent with the findings of DeFronzo and Bogardus, who showed that decreased insulin sensitivity preceded the development of decreased insulin response in subjects with impaired glucose tolerance and noninsulin-dependent diabetes. Because of the relatively small number of subjects in our study population and the fact that they were not obese, our results must be interpreted with care. Additional longitudinal studies in obese subjects using comparable methods should improve our understanding of the alterations in carbohydrate metabolism in gestation in women with normal and abnormal glucose tolerance.