Etiology and pathogenesis of gestational diabetes

Abstract

A significant amount of information regarding the pathogenesis of gestational diabetes mellitus (GDM) has been gathered since the Third Workshop-Conference on GDM. In spite of this, it is still not known why GDM develops in 2-3% of all pregnant women. Similar frequencies of HLA-DR2, DR3, and DR4 antigens in healthy pregnant women and women with GDM and low prevalences of markers for autoimmune destruction of the beta-cells in GDM pregnancy rule out the possibility that GDM is a disease of autoimmune origin. Insulin secretion during an oral glucose tolerance test (OGTT) or a meal is substantially increased in women with GDM compared with the same women postpartum. However, insulin secretion increases less in women with GDM than in pregnant women who retain normal glucose tolerance (NGT). Peak insulin concentrations during an OGTT occur later in women with GDM, and following intravenous glucose, a reduced first-phase insulin response is also seen in these women. Second-phase insulin responses are similar in pregnant women with NGT and GDM. Excessive secretion of proinsulin, which does not always return to normal postpartum, is often observed in women with GDM. It is conceivable that this might reflect a stress on the beta-cells and that the beta-cells are stressed because they try to counter the decreased insulin sensitivity that develops during pregnancy. Thus, insulin sensitivity decreases by 50-70% in both normal and GDM pregnancy, but whereas insulin sensitivity returns to normal postpartum in pregnant women with NGT, this is not always the case in GDM. Insulin receptor binding to target tissues is largely unaffected by normal and GDM pregnancy; the same is true for basal and insulin-stimulated insulin receptor-bound tyrosine kinase activity. There is indication that certain post-insulin-insulin receptor binding events are altered in tissues from women with GDM. However, data are still scarce, and more studies are needed before the intracellular events leading to a decreased insulin sensitivity have been resolved. Hormones that circulate in high concentrations in pregnancy (e.g., progesterone, cortisol, prolactin, human placental lactogen, and estrogen) have all been shown, in animal models, to be able to influence beta-cell function and/or the peripheral tissue sensitivity to insulin, but whether they play similar roles in human pregnancy remains to be investigated.