Increased serum pigment epithelium-derived factor is associated with microvascular complications, vascular stiffness and inflammation in Type 1 diabetes.

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) microg/ml, vs. complication-free patients [5.3 (4.7-6.0) microg/ml, P < 0.001] and control subjects [5.3 (4.6-6.1) microg/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 log(e)C-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 log(e)CRP 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 (r(2) = 0.427). CONCLUSIONS: In Type 1 diabetes, serum PEDF levels are associated with microvascular complications, poor vascular health, hyperglycaemia, adiposity and inflammation.

Traditional risk factor assessment does not capture the extent of cardiovascular risk in systemic lupus erythematosus.

BACKGROUND: Systemic lupus erythematosus (SLE) is associated with accelerated atherosclerosis. However, the degree of endothelial dysfunction and its relationship to traditional and novel cardiovascular risk factors have not been examined in SLE. METHODS: In a case-control design, 35 patients with clinically stable SLE and 35 control subjects matched for age, sex, body mass index and smoking status were studied. Arterial elasticity, lipid profile, homocysteine, measures of inflammation and oxidative stress were determined. RESULTS: Among traditional vascular risk factors, there was a nonsignificant trend towards lower blood pressure in the control subjects, whereas low-density lipoprotein (LDL) cholesterol levels were significantly lower in the SLE group (2.5 vs 3.3 mmol/L, P < 0.001). Patients with SLE had significantly lower small artery elasticity (SAE; 4.9 vs 7.0 ml/mmHg x 100, P < 0.001) and higher plasma homocysteine (11.4 vs 8.3 mmol/L, P = 0.002) than control subjects. Levels of serum sVCAM-1 (614 vs 494 ng/mL, P = 0.002), oxidized LDL (144 vs 97, P < 0.001) and CD40 ligand (4385 vs 1373 pg/ml, P = 0.001) were significantly higher in SLE. Oxidized LDL levels, older age at SLE diagnosis and higher disease damage scores correlated inversely with SAE but not traditional risk factors. CONCLUSION: Impaired endothelial function as shown by decreased SAE, and an adverse profile of novel proatherogenic and prothrombotic vascular disease risk factors were prevalent in clinically quiescent SLE. These findings show the vulnerability of patients with SLE for atherosclerosis, and emphasize that assessments based on traditional risk factors alone may be inadequate.

Insulin resistance as a major determinant of increased coronary heart disease risk in postmenopausal women with Type 2 diabetes mellitus.

AIM: To investigate the risk factors associated with clinically defined coronary heart disease (CHD) in women with Type 2 diabetes mellitus (DM). METHODS: CHD status was assessed via standard history and resting electrocardiogram in 41 postmenopausal diabetic and 41 age- and body mass index-matched normoglycaemic women recruited from a community-based cohort. The following parameters were assessed: body composition by dual energy X-ray absorptiometry, blood pressure, metabolic and lipoprotein profile and haemostatic factors. RESULTS: Diabetic women with CHD (n = 14) had greater insulin resistance, calculated by homeostasis model assessment (10.2 (7.0-14.8) vs. 6.5 (5.5-7.7), P = 0.010), and higher plasminogen activator inhibitor-1 (PAI-1) levels (45 (29-69) vs. 24 (19-32) ng/ml, P = 0.013), than those without CHD. They also had higher triglycerides (2.9 (2.2-3.8) vs. 2.1 (1.8-2.4) mmol/l, P = 0.016) and a trend towards reduced low-density lipoprotein particle size (25.5 +/- 0.6 vs. 25.8 +/- 0.5 nm, P = 0.097). In a logistic regression model, insulin resistance was a significant independent predictor of CHD status (odds ratio = 1.33, 95% confidence interval = 1.06-1.68, P = 0.015). In contrast, in normoglycaemic women the major risk factors for CHD were elevated cholesterol, apolipoprotein(a), apolipoprotein B and systolic blood pressure (P = 0.018, P = 0.016, P = 0.006 and P = 0.049, respectively). CONCLUSIONS: Increased insulin resistance in association with elevated PAI-1 and dyslipidaemia appears to underpin the increased risk of CHD in women with Type 2 DM. Therapeutic approaches that increase insulin sensitivity may serve to reduce CHD risk in this vulnerable group. Diabet. Med. 18, 476-482 (2001)

A comparison of LDL size determination using gradient gel electrophoresis and light-scattering methods.

This study compared gradient gel electrophoresis (GGE) and light-scattering (LS) methods of determining low density lipoprotein (LDL) particle size. LDL was isolated from 27 fasting subjects. Peak particle size was determined by GGE on 3-13% gradient gels (Gradipore, Sydney, Australia) and by LS using a Zetasizer 3000 (Malvern Instruments, Malvern, UK). Repeated measurements on a single specimen indicated a coefficient of variation (CV) of 0.3%. A correlation was noted (P < 0.0001; r = 0.78) when comparing LDL particle size determined by LS methodology and GGE. Particle diameter results obtained by LS were smaller than those obtained by GGE (23.1 +/- 0.1 vs. 26.1 +/- 0.1 nm; P < 0.0001). LDL particle size determined by LS methodology correlated inversely with the log of triglyceride level (P < 0.0001; r = -0.77) and positively with high density lipoprotein (HDL) cholesterol level (P < 0.002; r = 0.57).

Factors influencing Lp[a]- particle size as determined by gradient gel electrophoresis.

This study examined factors influencing the particle diameter of Lp[a]-, the low density lipoprotein (LDL)-like moiety of Lp[a], in 26 subjects chosen to provide a range of Lp[a] and triglyceride levels. Lp[a] and LDL fractions were isolated by vertical density ultracentrifugation. Lp[a] was further purified using a lysine-Sepharose affinity column and Lp[a]- obtained by incubating Lp[a] with dithiothreitol. Lp[a], LDL, and Lp[a]- fractions were run on 3-13% gradient gels to determine particle diameter. Lp[a] size correlated positively with LDL size (r = 0.62; P < 0.001), but the association between Lp[a]- size and LDL size was stronger (r = 0.82; P < 0.0001). Log triglyceride level correlated inversely with Lp[a]- size (r = -0.72; P < 0.0001) and LDL size (r = 0.69; P < 0.0001). HDL cholesterol level correlated positively with Lp[a]- size (r = 0.67; P < 0.0005) and LDL size (r = 0.64; P < 0.0005). The strong correlation between LDL size and Lp[a]- size may be due to extracellular utilization of circulating LDL in the production of Lp[a] or may reflect the same metabolic processes influencing both these particles once Lp[a] has been formed.