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Abstract: Aims: To perform meta‐analyses of studies evaluating the risk of pre‐eclampsia in high‐risk insulin‐resistant women taking metformin prior to, or during pregnancy. Methods: A search was conducted of the Medline, EMBASE, Web of Science and Scopus databases. Both randomized controlled trials and prospective observational cohort studies of metformin treatment vs. placebo/control or insulin either prior to or during pregnancy were selected. The main outcome measure was the incidence of pre‐eclampsia in each treatment group. Results: Overall, in five randomized controlled trials comparing metformin treatment (n = 611) with placebo/control (n = 609), no difference in the risk of pre‐eclampsia was found [combined/pooled risk ratio (RR), 0.86 (95% CI 0.33–2.26); P = 0.76; I2 = 66%]. Meta‐analysis of four cohort studies again showed no significant effect [RR, 1.21 (95% CI 0.56–2.61); P = 0.62; I2 = 30%]. A meta‐analysis of eight randomized controlled trials comparing metformin (n = 838) with insulin (n = 836), however, showed a reduced risk of pre‐eclampsia with metformin [RR, 0.68 (95% CI 0.48–0.95); P = 0.02; I2 = 0%]. No heterogeneity was present in the metformin vs. insulin analysis of randomized controlled trials, whereas high levels of heterogeneity were present in studies comparing metformin with placebo/control. Pre‐eclampsia was a secondary outcome in most of the studies. The mean weight gain from time of enrolment to delivery was lower in the metformin group (P = 0.05, metformin vs. placebo; P = 0.004, metformin vs. insulin). Conclusions: In studies randomizing pregnant women to glucose‐lowering therapy, metformin was associated with lower gestational weight gain and a lower risk of pre‐eclampsia compared with insulin. [ABSTRACT FROM AUTHOR]

Aims To determine in Type 1 diabetes patients if levels of pigment epithelium-derived factor (PEDF), an anti-angiogenic, anti-inflammatory and antioxidant factor, are increased in individuals with complications and positively related to vascular and renal dysfunction, body mass index, glycated haemoglobin, lipids, inflammation and oxidative stress. Methods Serum PEDF levels were measured by ELISA in a cross-sectional study of 123 Type 1 diabetic patients (71 without and 52 with microvascular complications) and 31 non-diabetic control subjects. PEDF associations with complication status, pulse-wave analysis and biochemical results were explored. Results PEDF levels [geometric mean (95% CI)] were increased in patients with complications 8.2 (7.0–9.6) µg/ml, vs. complication-free patients [5.3 (4.7–6.0) µg/ml, P < 0.001] and control subjects [5.3 (4.6–6.1) µg/ml, P < 0.001;anova between three groups, P < 0.001], but did not differ significantly between control subjects and complication-free patients ( P > 0.05). In diabetes, PEDF levels correlated (all P < 0.001) with systolic blood pressure ( r = 0.317), pulse pressure ( r = 0.337), small artery elasticity ( r = –0.269), glycated haemoglobin ( r = 0.245), body mass index ( r = 0.362), renal dysfunction [including serum creatinine ( r = 0.491), cystatin C ( r = 0.500)], triglycerides ( r = 0.367), and inflammation [including logeC-reactive protein (CRP; r = 0.329), and soluble vascular cell adhesion molecule-1 ( r = 0.363)]. Age, blood urea nitrogen, systolic blood pressure, pulse pressure and logeCRP correlated with PEDF levels in control subjects (all P < 0.04). PEDF levels were not significantly correlated with measures of oxidative stress: isoprostanes, oxidized low-density lipoprotein or paraoxonase-1 activity. On stepwise linear regression analysis (all subjects), independent determinants of PEDF levels were renal function, triglycerides, inflammation, small artery elasticity and age ( r2 = 0.427). Conclusions In Type 1 diabetes, serum PEDF levels are associated with microvascular complications, poor vascular health, hyperglycaemia, adiposity and inflammation. [ABSTRACT FROM AUTHOR]

Aims To relate nuclear magnetic resonance lipoprotein subclass profiles (NMR-LSP) and other lipoprotein-related factors with carotid intima-media thickness (IMT) in Type 1 diabetes. Methods Lipoprotein-related factors were determined in sera (obtained in 1997-1999) from 428 female [age 39 ± 7 years (mean ± SD )] and 540 male (age 40 ± 7 years) Diabetes Control and Complications Trial (DCCT)/Epidemiology of Diabetes Interventions and Complications (EDIC) participants. NMR quantifies chylomicrons, three very low-density lipoprotein (VLDL) subclasses, intermediate density lipoprotein (IDL), three low-density lipoprotein (LDL) subclasses, two high-density lipoprotein (HDL) subclasses, mean VLDL, LDL and HDL size, and LDL particle concentration. Conventional lipids, ApoA1, ApoB and Lp(a) and in vitro LDL oxidizibility were also measured. IMT was determined (in 1994-1995) using high-resolution B-mode ultrasound. Relationships between IMT and lipoproteins were analysed by multiple linear regression, controlling for age, diabetes-related factors, and cardiovascular disease (CVD) risk factors. Results IMT associations with lipoproteins were stronger for the internal than the common carotid artery, predominantly involving LDL. Internal carotid IMT was positively ( P < 0.05) associated with NMR-based LDL subclasses and particle concentration, and with conventional LDL-cholesterol and ApoB in both genders. Common carotid IMT was associated, in men only, with large VLDL, IDL, conventional LDL cholesterol and ApoB. Conclusions NMR-LSP reveals significant associations with carotid IMT in Type 1 diabetic patients, even 4 years after IMT measurement. NMR-LSP may aid early identification of high-risk diabetic patients and facilitate monitoring of interventions. Longer DCCT/EDIC cohort follow-up will yield CVD events and IMT progression, permitting more accurate assessment of pre-morbid lipoprotein profiles as determinants of cardiovascular risk in Type 1 diabetes. [ABSTRACT FROM AUTHOR]

Objective: Increased advanced glycation end-products (AGEs) and their soluble receptors (sRAGE) have been implicated in the pathogenesis of pre-eclampsia (PE). However, this association has not been elucidated in pregnancies complicated by diabetes. We aimed to investigate the serum levels of these factors in pregnant women with Type 1 diabetes mellitus (T1DM), a condition associated with a four-fold increase in PE., Design: Prospective study in women with T1DM at 12.2 ± 1.9, 21.6 ± 1.5 and 31.5 ± 1.7 weeks of gestation [mean ± standard deviation (SD); no overlap] before PE onset., Setting: Antenatal clinics., Population: Pregnant women with T1DM (n = 118; 26 developed PE) and healthy nondiabetic pregnant controls (n = 21)., Methods: Maternal serum levels of sRAGE (total circulating pool), N(ε)-(carboxymethyl)lysine (CML), hydroimidazolone (methylglyoxal-modified proteins) and total AGEs were measured by immunoassays., Main Outcome Measures: Serum sRAGE and AGEs in pregnant women with T1DM who subsequently developed PE (DM PE+) versus those who remained normotensive (DM PE-)., Results: In DM PE+ versus DM PE-, sRAGE was significantly lower in the first and second trimesters, prior to the clinical manifestation of PE (P < 0.05). Further, reflecting the net sRAGE scavenger capacity, sRAGE:hydroimidazolone was significantly lower in the second trimester (P < 0.05) and sRAGE:AGE and sRAGE:CML tended to be lower in the first trimester (P < 0.1) in women with T1DM who subsequently developed PE versus those who did not. These conclusions persisted after adjusting for prandial status, glycated haemoglobin (HbA1c), duration of diabetes, parity and mean arterial pressure as covariates., Conclusions: In the early stages of pregnancy, lower circulating sRAGE levels, and the ratio of sRAGE to AGEs, may be associated with the subsequent development of PE in women with T1DM., (© 2012 The Authors BJOG An International Journal of Obstetrics and Gynaecology © 2012 RCOG.)