We have suggested that altered maternal metabolism may affect the subsequent anthropometric and neuropsychological development of children who were in utero during disturbances in maternal fuel economy. This study reports the physical growth through 8 yr of age and the neuropsychological development through 4 yr of age in offspring of diabetic mothers (ODM). At birth, 50% of infants had weights greater than 90th percentile for gestational age. By 12 mo, length and weight were similar to the general population. Height remained normal until 7 yr of age, when it became slightly greater than average. After 5 yr of age, relative weight increased dramatically, and by 8 yr of age, half of the ODM had weights greater than 90th percentile. This childhood obesity in ODM is correlated with maternal prepregnant weight and independently with amniotic fluid insulin at 32-38 wk gestation. The Brazelton Neonatal Behavioral Assessment Scale (BNBAS) was administered to 185 newborn ODM. Significant correlations were found between poorer second- and third-trimester glycemic regulation and lower scores in three of four newborn BNBAS dimensions. The Stanford-Binet Intelligence Scale was measured in 102 ODM at 4 yr of age. We found an inverse correlation between childhood IQ and second- and third-trimester maternal lipid metabolism (serum free fatty acids and beta-hydroxybutyrate). This correlation is not explained by adverse perinatal events, socioeconomic status, maternal IQ, ethnicity, or diabetes type. These long-range associations between altered maternal metabolism and childhood growth and development continue to support Freinkel's hypothesis of fuel-mediated teratogenesis.

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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 A1 (FPG less than 105 mg/dl [N = 129]), class A2 (FPG 105-129 mg/dl [N = 47]), and class B1 (FPG greater than or equal to 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 less than A2 less than 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.(ABSTRACT TRUNCATED AT 250 WORDS)

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Insulin-like growth factors (IGFs) circulate in association with a family of specific binding proteins (BPs). Recently, we reported that circulating levels of IGFBP-1 and IGFBP-2 are increased in streptozotocin-diabetic adult rats and are differentially regulated in accordance with insulin and metabolic status. Since IGF BPs appear to be important modulators of IGF bioactivity in post-natal life, we asked whether serum levels of IGF BPs also might be altered in utero when the delivery of maternal nutrients is restricted and fetal growth is impaired. Bilateral uterine artery ligation or sham surgery was performed on maternal rats on d 19 of gestation (term 21.5 d). One day after ligation (d 20), fetuses were (SGA) compared to shams (3.1 +/- 1 vs 3.7 +/- 0.2 g, p less than .02) and serum levels of glucose (70 +/- 5 vs 96 +/- 6 mg/dL, p less than .01) and insulin (62 +/- 4 vs 138 +/- 14 microU/mL) also were reduced. In contrast, serum [125I]IGF-I binding activity was markedly increased in SGA litters compared to sham (65 +/- 5% maximum binding with 2.5 microL/mL SGA serum vs 14 +/- 3% for sham serum, p less than .001), and correlated with fetal weight (r = -0.539, p less than .05) and insulin (r = -0.622, p less than .05). Ligand blotting with [125I]IGF-I revealed that serum levels of IGFBP-1 (32 K) were greater in SGA than shams, while immunoblotting with specific antiserum demonstrated that levels of IGFBP-2 (34 K), the major fetal rat IGF BP, were similar in serum from SGA and shams litters. Affinity labeling and immunoprecipitation confirmed that IGF binding activity is increased in SGA, due largely to increased availability of IGFBP-1. In addition, Northern analysis of hepatic RNA revealed that the abundance of IGFBP-1 mRNA is increased in the SGA fetal rat, while hepatic mRNA for IGFBP-2 is similar in SGA and sham-operated litters. We conclude that circulating levels of IGFBP-1 and the abundance of hepatic mRNA are increased in the SGA fetal rat. IGFBP-1 may be an important modulator of IGF bioactivity and somatic growth in utero.

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