OBJECTIVE -The ability of the Adult Treatment Panel III (ATP III) criteria of metabolic syndrome to identify insulin-resistant subjects at increased cardiovascular risk is suboptimal, especially in the absence of obesity and diabetes. Nonalcoholic fatty liver disease (NAFLD) is associated with insulin resistance and is emerging as an independent cardiovascular risk factor. We compared the strength of the associations of ATP III criteria and of NAFLD to insulin resistance, oxidative stress, and endothelial dysfunction in nonobese nondiabetic subjects. RESEARCH DESIGN AND METHODS-Homeostasis model assessment of insulin resistance (HOMA-IR) Ͼ2, oxidative stress (nitrotyrosine), soluble adhesion molecules (intracellular adhesion molecule-1, vascular cell adhesion molecule-1, and E-selectin), and circulating adipokines (tumor necrosis factor-␣, leptin, adiponectin, and resistin) were cross-sectionally correlated to ATP III criteria and to NAFLD in 197 unselected nonobese nondiabetic subjects.RESULTS -NAFLD more accurately predicted insulin resistance than ATP III criteria: sensitivity 73 vs. 38% (P ϭ 0.0001); positive predictive value: 81 vs. 62% (P ϭ 0.035); negative predictive value 87 vs. 74% (P ϭ 0.012); positive likelihood ratio 4.39 vs. 1.64 (P ϭ 0.0001); and negative likelihood ratio 0.14 vs. 0.35 (P ϭ 0.0001). Adding NAFLD to ATP III criteria significantly improved their diagnostic accuracy for insulin resistance. Furthermore, NAFLD independently predicted HOMA-IR, nitrotyrosine, and soluble adhesion molecules on logistic regression analysis; the presence of NAFLD entailed more severe oxidative stress and endothelial dysfunction, independent of adiposity or any feature of the metabolic syndrome in insulinresistant subjects.CONCLUSIONS -NAFLD is more tightly associated with insulin resistance and with markers of oxidative stress and endothelial dysfunction than with ATP III criteria in nonobese nondiabetic subjects and may help identify individuals with increased cardiometabolic risk in this population. Diabetes Care 31:562-568, 2008M etabolic syndrome is a cluster of metabolic and cardiovascular risk factors that sharing the hallmark of insulin resistance; its prevalence according to Adult Treatment Panel III (ATP III) criteria is 20% among Western adults (1). Insulin resistance is an independent predictor of cardiovascular disease and type 2 diabetes and should be identified and treated early (2-5).Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in Western countries (1). NAFLD predicts incident diabetes independent of classic risk factors and C-reactive protein in large prospective cohort studies and may therefore be an early marker of mechanisms predisposing to future metabolic events (1,6). In a parallel way, NAFLD is emerging as a marker of early atherosclerosis: liver enzymes predicted incident cardiovascular disease independent of traditional risk factors, C-reactive protein and metabolic syndrome, and liver histology correlated with early carotid atherosclerosis in NAF...

Little is known about the association between prior gestational hyperglycemia of different severity and the subsequent risk for the metabolic syndrome. Eighty-one women with prior gestational diabetes mellitus (GDM), 25 with one abnormal value at the oral glucose tolerance test (OGTT), and 65 with normal OGTT were studied after a mean of 8.5 yr from the index pregnancy. Patients with prior gestational hyperglycemia (both one abnormal value at the OGTT and GDM) showed a worse metabolic pattern than subjects with gestational normoglycemia [respectively higher values of body mass index (BMI), waist, blood pressure, serum glucose, insulin, C-peptide, homeostatic model assessment (HOMA), fibrinogen and lower levels of HDL-cholesterol]. Prevalence of the metabolic syndrome and its components was 2-4-fold higher in women with prior gestational hyperglycemia (and 10-fold higher if pre-pregnancy obesity coexisted) when compared to normoglycemic controls; in a Cox proportional hazard model, after adjustments for age and pre-pregnancy BMI, gestational hyperglycemia and pre-pregnancy BMI predicted subsequent metabolic syndrome [respectively: hazard ratio (HR)=4.26 and HR=1.21] and most of its components. In the same model, the highest quartile of fasting serum glucose at the OGTT of the index pregnancy was significantly associated to the metabolic syndrome and its components. Gestational hyperglycemia and fasting glucose values were also associated to subsequent fibrinogen values, but not to albumin excretion rates. In young adult women, prior gestational hyperglycemia (particularly abnormal fasting glucose values), above all in combination with pre-pregnancy obesity, anticipates a subsequent syndrome at high cardiovascular risk and, possibly, a mild chronic inflammatory response.

Objective-Circulating angiogenic cells (CACs) expansion is a multistage process requiring sequential activation of transcriptional factors, including STAT5. STAT5, in concert with peroxisome proliferator-activated receptors (PPARs), seems to induce discrete biological responses in different tissues. In the present study we investigated the role of STAT5 and PPAR␥ in regulating CAC expansion in normal and diabetic settings. Methods and Results-Normal

Integrin/cytokine receptor interaction provides permissive signals leading to neoangiogenesis, and integrins are crucial for differentiation of endothelial progenitor cells (EPCs). It is known that the inflammatory interleukin-3 (IL-3), released in the tumoral microenvironment, contributes to both angiogenesis and vasculogenic processes. Herein, we generated IL-3 receptor beta common (IL-3Rbc) extracellular domain-derived fusion proteins (Fc) to elucidate the molecular mechanisms regulating these processes. Three different Fc were generated, containing the entire extracellular domain of IL-3Rbc (Fc1.4), a fragment corresponding to domains 1-3 (Fc1.3) and a fragment corresponding to domain 4 (Fc4), respectively. The ability of the fusion proteins to interfere with IL-3Rbc/b1 integrin interaction was assessed on endothelial cells (ECs), EPCs and murine-derived ECs. Pull-down experiments showed that Fc1.4 and Fc4 fusion proteins specifically interacted with b1 integrin. Fc4 and Fc1.4 fragments prevented IL-3-mediated EPC expansion, arterial morphogenesis and tumour-derived EC migration, without affecting cell adhesion. Fc4 in vivo inhibited the IL-3-mediated vasculogenic process, as well as inflammatory and tumour vascular growth. In conclusion, these data identify the b1 integrininteracting domain in the juxta-membrane IL-3Rbc extracellular domain, and provide the rational for targeting this interaction to impair vascular growth.

We aimed to determine if increased non-enzymatic glycosylation of the LDL was sufficient to increase the susceptibility to in vivo oxidation of the LDL particles. Twenty-two type 2 diabetic patients (11 males and 11 females) were included in this study. They were enrolled on the basis of good [glycated hemoglobin (HbA 1c ) < 7%] and poor glycemic control [(HbA 1c ) > 8%]. LDL were isolated by sequential ultracentrifugation and analyzed by capillary electrophoresis (CE) for diene conjugate content and for electronegativity. The glyc-LDL levels were increased in all diabetic type 2 patients, peaking in the diabetic subjects in poor diabetic control (17.3 ± 8.07%). The LDL content of diene conjugates was similar between the two groups (6.65 ± 0.77% for the patients with good glycemic control versus 6.88 ± 0.74% for those with poor glycemic control; P = 0.49) as was the electrophoretic mobility ((−1.14544 ± 0.089) × 10 −4 cm 2 /(V s) for the patients with good glycemic control and (−1.13666 ± 0.073) × 10 −4 cm 2 /(V s) for those with poor glycemic control; P = 0.80).The susceptibility to in vivo oxidation of LDL from type 2 diabetic patients in poor glycemic control did not differ from that of well-controlled diabetic patients. LDL glycosylation was not able to increase the oxidizability of LDL in the diabetic patients with poor glycemic control.