We have examined gravida with gestational diabetes mellitus (GDM), as defined by the National Diabetes Data Group (Diabetes 1979; 28:1039), for phenotypic and genotypic heterogeneity. Fasting plasma glucose (FPG) at diagnosis was used for further stratification of GDM according to putative metabolic severity into class A, (FPG < 105 mg/dl [N = 129]), class A2 (FPG 105–129 mg/dl [N = 47]), and class B1 (FPG ≥ 130 mg/dl [N = 23]). All GDM classes tended to be older and heavier than consecutive gravida with documented normal glucose tolerance (controls, N = 148). Subdivision into “lean” and “obese” indicated that plasma immunoreactive insulin (IRI) was greater after overnight fast in the obese of all groups except B1. However, absolute increases in IRI above fasting levels in response to glucose during OGTT were significantly enhanced by obesity only in class A2 gravida. Adjustment for the effects of age and weight by covariate analysis indicated that the IRI response to glycemic stimulation is usually attenuated in all forms of GDM. Mean values for increases in IRI above fasting values during the first 15 min and IRI increments relative to the increases in plasma glucose throughout the 180-min OGTT were below control values in all GDM groups and progressively so, i.e.,A1 < A2 < B1. The absolute insulinopenia was not invariable; a small number of gravida from all GDM groups displayed well-preserved IRI responses to oral glucose. Genotypic evaluation of the GDM population disclosed an increased occurrence of “markers” known to be associated with type I diabetes mellitus. HLA antigens DR3 and DR4 were more frequent in all GDM groups, and the incidence of cytoplasmic islet cell antibodies was enhanced significantly in class A2, and even more so in class B1. Thus, GDM appears to be a heterogeneous entity with substantial phenotypic and genotypic diversity in the mothers.

Offspring from some class A1 and diet-treated class A2 gravida were examined to assess whether minimal abnormalities in maternal metabolism suffice to impact on intrauterine development independent of maternal diversity. Amniotic fluid insulin at 36 ± 0.1 wk of gestation and cord plasma C-peptide at birth were increased in offspring of mothers with class A1 GDM, thus indicating that even the mildest forms of GDM can cause accelerated maturation of fetal islet function. Birth weight and symmetry index in the newborn from class A1 arid diet-treated class A2 gravida were significantly increased above control values, even after adjustment for maternal age and weight, thus documenting for the first time that GDM per se can influence the anthropometric characteristics of the neonate. The findings underscore that GDM constitutes an independent risk factor with particular implications for islet and somatic development during fetal life. These unequivocal effects of maternal metabolism on cell development in the fetus may provide the most compelling reason for aggressive approaches to GDM, especially if prospective as well as retrospective studies continue to support their postulated association with increased obesity and diabetes in later life (i.e., “fuel-mediated teratogenesis”; Diabetes 1980; 29:1023).

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