Background and objective: The maternal glucose-insulin axis is central for metabolic adaptations required for a healthy pregnancy. Metabolic changes in obese mothers in early pregnancy have been scantly described. Here we characterized the glucose-insulin axis in the first trimester of human pregnancy and assessed the effect of maternal obesity and fat mass. Methods: In this cross-sectional study, maternal blood samples ( N = 323) were collected during voluntary pregnancy termination (gestational age 4 +0 –11 +6 weeks) after overnight fasting. Smokers ( N = 198) were identified by self-report and serum cotinine levels (ELISA). Maternal BMI (kg/m 2 ) and serum leptin (ELISA) were used as proxy measures of obesity and maternal fat mass, respectively. BMI was categorized into under-/normal weight (BMI < 25.0 kg/m 2 ), overweight (BMI 25.0–29.9 kg/m 2 ) and obese (BMI ≥ 30.0 kg/m 2 ), and leptin in tertiles (1st tertile: leptin < 6.80 ng/ml, 2nd tertile: leptin 6.80–12.89 ng/ml, 3rd tertile: leptin > 12.89 ng/ml). IS HOMA insulin sensitivity index was calculated from glucose and C-peptide (ELISA) serum concentrations. Analyses of covariance including multiple confounders were performed to test for differences in glucose, C-peptide and IS HOMA between gestational age periods, BMI and leptin groups. C-peptide and IS HOMA were log-transformed before analyses. Results: At weeks 7–9, fasting glucose and C-peptide levels were lower ( P < 0.01 and P < 0.001, respectively) and insulin sensitivity higher ( P < 0.001) than at weeks 4–6. Glucose levels were not significantly different between BMI or leptin categories. In contrast, C-peptide increased by 19% ( P < 0.01) between the normal weight and the overweight group and by 39% ( P < 0.001) between the overweight and obese group. In the leptin groups, C-peptide increased by 25% ( P < 0.001) between the 1st and 2nd leptin tertile and by 15% ( P < 0.05) between the 2nd and 3rd leptin tertile. IS HOMA decreased with higher BMI and fat mass. IS HOMA decreased by 18% ( P < 0.01) between the normal weight and the overweight group and by 30% ( P < 0.01) between the overweight and the obese group. In the leptin groups, IS HOMA decreased by 22% ( P < 0.001) between the 1st and 2nd leptin tertile and by 14% ( P < 0.05) between the 2nd and 3rd leptin tertile. Conclusions: At the group level, fasting glucose, C-peptide and insulin sen...
Diabetes in pregnancy is associated with adverse pregnancy outcomes including preterm birth. Although the mechanisms leading to these pregnancy complications are still poorly understood, aberrant angiogenesis and endothelial dysfunction play a key role. FKBPL and SIRT-1 are critical regulators of angiogenesis, however, their roles in pregnancies affected by diabetes have not been examined before in detail. Hence, this study aimed to investigate the role of FKBPL and SIRT-1 in pre-gestational (type 1 diabetes mellitus, T1D) and gestational diabetes mellitus (GDM). Placental protein expression of important angiogenesis proteins, FKBPL, SIRT-1, PlGF and VEGF-R1, was determined from pregnant women with GDM or T1D, and in the first trimester trophoblast cells exposed to high glucose (25 mM) and varying oxygen concentrations [21%, 6.5%, 2.5% (ACH-3Ps)]. Endothelial cell function was assessed in high glucose conditions (30 mM) and following FKBPL overexpression. Placental FKBPL protein expression was downregulated in T1D (FKBPL; p<0.05) whereas PlGF/VEGF-R1 were upregulated (p<0.05); correlations adjusted for gestational age were also significant. In the presence of GDM, only SIRT-1 was significantly downregulated (p<0.05) even when adjusted for gestational age (r=-0.92, p=0.001). Both FKBPL and SIRT-1 protein expression was reduced in ACH-3P cells in high glucose conditions associated with 6.5%/2.5% oxygen concentrations compared to experimental normoxia (21%; p<0.05). FKBPL overexpression in endothelial cells (HUVECs) exacerbated reduction in tubule formation compared to empty vector control, in high glucose conditions (junctions; p<0.01, branches; p<0.05). In conclusion, FKBPL and/or SIRT-1 downregulation in response to diabetic pregnancies may have a key role in the development of vascular dysfunction and associated complications affected by impaired placental angiogenesis.
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