Glucose tolerance deteriorates in human pregnancy, but ∼97–98% of all pregnant women retain a normal glucose tolerance, and only 2–3% develop gestational diabetes mellitus (GDM). Both nondiabetic pregnant women and women with GDM exhibit much higher insulin responses to oral or intravenous administration of glucose or amino acids than found in the nonpregnant state, and the insulin responses to a protein-rich meal are also significantly enhanced in pregnancy. Both quantitative and qualitative differences in insulin secretion exist between pregnant women with normal glucose tolerance (NGT) and women with GDM. Insulin responses to oral glucose and protein-rich meals are thus lower in pregnant women with GDM than in women with NGT, despite significantly higher mean plasma glucose concentrations in the women with GDM. Furthermore, peak plasma insulin concentrations occur later in women with GDM than in pregnant control subjects. Finally, a reduced first-phase insulin response to intravenous glucose can be observed in some women with GDM. Impairment of glucose tolerance in pregnancy is not related to a disproportional secretion of proinsulin nor is increased insulin degradation involved. These observations point to pregnancy as a state of peripheral insulin resistance. Because insulin-receptor binding is only slightly changed in pregnancy and not significantly different in pregnant women with NGT and women with GDM, it follows that the insulin resistance is located at the postreceptor level. Insulin-clamp and “minimal model” studies have shown that the whole-body insulin sensitivity is similarly reduced by about two-thirds of nonpregnant values in pregnant women with NGT and women with GDM. The insulin sensitivity is restored postpartum in the pregnant women with NGT and most of the women with GDM, but about one-third of the women with GDM retain a reduced insulin sensitivity. The insulin resistance in pregnancy is predominantly located in the muscle tissue, where a reduced activity of certain key enzymes in glucose and lipid metabolism has been demonstrated. The insulin resistance is compensated by a considerable increase in insulin secretion, and hence most pregnant women are able to retain NGT. However, some women do not have the capacity to increase their insulin secretion to such an extent that the increased peripheral resistance can be overcome; these are the women who develop GDM.

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