Objective:To examine if clustering of cardiometabolic risk factors in pregnancy predicts type 2 diabetes and cardiovascular disease (CVD) risk at 10 years in women with gestational diabetes mellitus (GDM).Study design and subjects:A prospective case–control study in 150 GDM and 72 overweight women with normal glucose tolerance (NGT) measured cardiometabolic risk factors (body mass index (BMI), systolic blood pressure (SBP), fasting glucose, insulin, and triglycerides and high-density lipoprotein (HDL) cholesterol) at 28 weeks gestation and 6 months and 10 years after pregnancy. Cluster analysis of cardiometabolic risk factors in pregnancy was used to stratify GDM as ‘high' and ‘low risk' for diabetes and CVD risk at 10 years. The data in pregnancy were used to determine a simple method for assessing risk of future diabetes.Results:BMI in the 150 GDM at study entry was similar to NGT, but 35% of GDM fell into a ‘high-risk cluster' with elevated BMI, SBP, glucose, insulin and triglycerides and lower HDL levels. At 10 years, type 2 diabetes was sixfold higher in ‘high-risk' GDM (odds ratio (OR)=6.75, confidence interval (CI)=2.0, 22.7, P=0.002) compared with ‘low-risk' GDM and was not reported in NGT. The ‘high-risk' cluster predicted type 2 diabetes better than BMI>30 (OR=2.13, CI=0.71, 6.4, P=0.179) or fasting glucose >5.5 mmol l–1, (OR=4.56, CI=1.50, 13.85, P=0.007). We determined that GDM with any four of the cardiometabolic risk factors (BMI>30 kg m–2, fasting glucose>5.0 mmol l–1, insulin>7.8 mU l–1, triglycerides >2.4 mmol l–1, HDL<1.6 mmol l–1 or SBP>105 mm Hg) in pregnancy would be in a ‘high-risk' cluster.Conclusions:A metabolic syndrome-like cluster in pregnant GDM identifies risk for type 2 diabetes providing an opportunity to focus on rigorous lifestyle interventions after delivery to reduce the burden of disease attributed to this condition.
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Methods Mean arterial pressure (MAP) was measured via telemetry in 14 week old wild-type (WT) (n ϭ 9) and AT 2 R knockout (AT 2 R-KO) (n ϭ 7) mice prior to, during and after pregnancy. FACS analysis was used to determine immune cell infi ltration into kidneys collected from virgin and pregnant (gestational day (GA) 16) WT and AT 2 R-KO mice (n ϭ 3-5).Results Pre-conception MAP was similar between WT and AT 2 R-KO mice (92 Ϯ 1 vs 91 Ϯ 1 mmHg, respectively). During gestation MAP decreased during early and mid-gestation in the WT mice, reaching a nadir at GA10 (-6.7 Ϯ 1.5 mmHg compared to basal, P Ͻ 0.05) and returning to near pre-conception levels during late gestation. In the AT 2 R-KO mice the gestational decrease in MAP was completely abolished, with MAP signifi cantly increased from GA10 to GA21as compared to WT mice (P Ͻ 0.05). Immune cell infi ltration into the kidneys of WT mice was suppressed at GA16, but was unchanged in the AT 2 R-KO mice.Conclusion These data indicate that the AT 2 R plays an important role in arterial pressure regulation and may modulate renal immune cell infi ltration during pregnancy. A corollary of this is that defi cits in AT 2 R expression may contribute to pregnancy-induced hypertension and thus may represent a potential therapeutic target.Objective Preeclampsia (PreE) is a hypertensive disorder in pregnancy. PreE has multiple pathophysiologic triggers and the renin-angiotensin system (RAS) has been implicated in PreE pathogenesis, however, there is no data showing involvement of (pro)renin and its receptor. Study Design(1) (Pro)renin levels were assayed in plasma from 32 PreE and 57 NP patients.(2) An established rat model of PreE and normal pregnant (NP) rats were used to evaluate the role of (pro)renin and its receptor in the pathogenesis of PreE. ERK1/2 phosphorylation and plasma and placental levels of RAS components, (pro)renin and its receptor were assayed. (3) Cytotrophoblast (CTB) cells were transfected with human (pro)renin receptor. The binding of (pro)renin to its receptor and the interference of this binding by decoy peptide were assayed. Results(1) Plasma (pro)renin of PreE patients differs (p Ͻ 0.05) from NP. (2) Active renin, renin, and Ang II concentrations in the plasma were lower while placental levels were higher, plasma and placental (pro)renin levels were higher, placental (pro)renin receptor expression and ERK1/2 phosphorylation were higher in PreE compared to NP (p Ͻ 0.05). (3) (Pro)renin was activated (85%) by recombinant (pro) renin receptor and the decoy peptide was observed to attenuate this effect.Conclusions These data suggest that peripheral RAS is downregulated, while uteroplacental RAS is upregulated in PreE. However, both circulatory and uteroplacental (pro)renin and its receptor are upregulated in PreE rats. This study suggests a key role of (pro)renin and its receptor in PreE pathogenesis and involvement of (pro)renin receptor-mediated detrimental cellular signaling in PreE.
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