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ABSTRACT: Alpha-defensins are natural antibiotics made by neutrophils that have been reported to modulate cholesterol metabolism and vascular function; however, their role in vivo remains largely unknown. We hypothesized that alpha-defensins 1 to 3 (DEFA1-3) are associated with serum lipids and vascular reactivity in humans.
One hundred thirteen apparently-healthy White men, participants in a prospective study of cardiovascular risk factors, were assessed for a lipid profile, insulin sensitivity (S(I), frequently-sampled intravenous glucose tolerance test), and non-stressed circulating DEFA1-3 (ELISA). In a subset of 52 subjects, vascular reactivity (high-resolution ultrasound of the brachial artery) was also assessed. Subjects in the highest quartile for plasma DEFA1-3 were found to be leaner and more insulin sensitive, and to have significantly reduced total and LDL-cholesterol, compared with subjects in the lowest quartile for circulating DEFA1-3 (P<0.0001 to P=0.002 for linear trend ANOVA). The associations with serum lipids persisted after adjustment for age, body mass index, insulin sensitivity, and smoking (which was associated with reduced plasma DEFA1-3 concentrations). Finally, endothelium-independent vasodilation increased with increasing circulating DEFA1-3 (P=0.003) and this association was not explained by age, body mass index, serum cholesterol, insulin sensitivity, or smoking.
Circulating DEFA1-3 are associated with serum cholesterol and vascular reactivity in humans. Alpha-defensins may have clinical implications in patients with either hypercholesterolemia or vascular dysfunction.
Arteriosclerosis Thrombosis and Vascular Biology 06/2007; 27(5):1166-71. · 6.37 Impact Factor
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ABSTRACT: We investigated the pattern of cardiovascular disease and the factors that predict such disease in outpatients with type-2 diabetes and hypercholesterolemia.
This prospective open observational study included outpatients of both sexes (mean age 62 [8] years) with type-2 diabetes and hypercholesterolemia. Clinical manifestations of cardiovascular disease (e.g., angina, myocardial infarction, stroke and peripheral arterial disease), glucose and HbA1c levels, and cardiovascular risk factors were recorded every 4 months throughout the 2-year follow-up period. Overall, 838 patients completed follow-up.
During follow-up, 81 patients (9.6%) presented with a cardiovascular event, nine of which were fatal. Cardiovascular events were more frequent in patients with a history of an ischemic condition than in those without: 58 of 258 (22.5%) and 23 of 579 (4%), respectively (P<.01). Previous angina or myocardial infarction was the strongest predictor of cardiovascular risk (relative risk [RR]=4.08, 95% confidence interval [CI] 2.39-6.95), followed by previous stroke (RR=2.96, 95% CI 1.26-6.93), high low-density lipoprotein (LDL)-cholesterol level > or =135 mg/dL (RR=2.79, 95% CI 1.56-5.01), peripheral arterial disease (RR=2.44, 95% CI 1.27-4.68), a high HbA1c level (RR=2.08, 95% CI 1.22-3.57), and obesity (RR=1.69, 95% CI 1.0-2.86).
The incidence of cardiovascular disease in this southern European population of patients with type-2 diabetes and hypercholesterolemia was high. A history of an ischemic condition and a high LDL-cholesterol level during follow-up were the strongest predictors of cardiovascular disease.
Revista Espa de Cardiologia 03/2007; 60(3):251-8. · 2.53 Impact Factor
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ABSTRACT: The innate immune system can immediately respond to microorganism intrusion by helping to prevent further invasion. Bactericidal/permeability-increasing protein (BPI) is a major constituent of neutrophils that possesses anti-inflammatory properties. Inflammation is increasingly recognized as a component of the metabolic syndrome. We hypothesized that the production of BPI could be linked to insulin sensitivity and glucose tolerance. We studied circulating BPI across categories of glucose tolerance. We also studied whether these cross-sectional associations were of functional importance. For this reason, we investigated circulating bioactive lipopolysaccharide and the effects of changing insulin action-after treatment with an insulin sensitizer (metformin)-on circulating BPI in subjects with glucose intolerance. Finally, we tested whether a 3'-untranslated region (UTR) BPI polymorphism led to differences in BPI and insulin action among nondiabetic subjects. Age- and BMI-adjusted circulating BPI was significantly lower among patients with type 2 diabetes. Circulating BPI correlated negatively with fasting and postload glucose and insulin concentrations. In subjects with glucose intolerance, BPI was also linked to BMI, waist-to-hip ratio, and age- and BMI-adjusted insulin sensitivity. Bioactive lipopolysaccharide was negatively correlated with circulating BPI (r = -0.57, P < 0.0001) and positively with plasma lipopolysaccharide-binding protein (r = 0.54, P = 0.002). In parallel to improved insulin sensitivity, plasma BPI significantly increased in the metformin group but not in the placebo group. A 3'-UTR BPI polymorphism was simultaneously associated with plasma BPI concentration, waist-to-hip ratio, fasting and postload insulin concentration, fasting plasma triglycerides, and insulin sensitivity. These findings suggest that this component of the innate immune system is associated with metabolic pathways.
Diabetes 01/2006; 55(1):216-24. · 8.29 Impact Factor
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ABSTRACT: Interleukin (IL)-18 has been associated with obesity and insulin resistance, both risk factors for the development of liver disease, but the role of IL-18 in liver disease associated with insulin resistance is presently unknown. We hypothesized that circulating IL-18 would be related to serum concentrations of liver chemistry tests (LCTs) in apparently healthy subjects and wished to study whether this correlation was dependent on insulin sensitivity (S(I)).
One hundred six apparently healthy white men consecutively enrolled in a cross-sectional, population-based study dealing with S(I) in men were studied, and S(I) (minimal model analysis), LCTs (colorimetry), and IL-18 serum concentrations (immunoassay) were assessed.
Compared with subjects in the lowest quartile for serum IL-18, subjects in the highest quartile exhibited increased serum triglycerides and decreased S(I), in addition to higher serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) (all p < 0.05). The direct association between both ALT and AST and IL-18 was further confirmed by examining the distribution of serum IL-18 by quartiles of ALT and AST. Subjects in the highest quartile for serum ALT and AST had higher IL-18 concentrations compared with subjects in the lowest quartile for these LCTs (both p = 0.01). In multiple regression analysis, IL-18, but not S(I), was an independent predictor of serum concentrations of ALT and AST, explaining 7% and 4% of their variance, respectively.
In summary, IL-18 serum concentrations are associated in apparently healthy humans with plasma concentrations of various LCTs. IL-18 could contribute to the development of liver disease associated with insulin resistance.
Obesity research 12/2005; 13(11):1925-31. · 4.95 Impact Factor
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ABSTRACT: High cholesterol levels might contribute to the presence of albuminuria. The objective of our study was to evaluate the influence of lipid levels on the development of incipient diabetic nephropathy. Secondary objectives were to evaluate the effects of diabetes control, high blood pressure, age, sex, years of diabetes evolution, body mass index and smoking.
930 subjects were enrolled in an open observational prospective cohort study of subjects with type 2 diabetes mellitus and high cholesterol levels (ESODIAH study) for 2 years. In our nephropathy study we selected 590 patients who had albuminuria measurements done. In every 4-month interval visit we made a clinical evaluation and blood analysis including HbA1c, lipid profile and microalbuminuria. Statistical analysis included t-Student, chi2 test, and binary logistic regressions.
51.7% men, aged 62.08 years of age and with an evolution of their diabetes of 8.49 years were studied. 40.6% had microalbuminuria and 59.4% had normoalbuminuria. High HbA1c correlated with the presence of albuminuria (odds ratio [OR] = 1.3; 95% confidence interval [CI], 1.12-1.55; p = 0.001). The development of microalbuminuria was more frequent in younger (OR = 0.93; 95% CI, 0.89-0.98), smoker (OR = 3.19; 95% CI, 1.02-9.96), subjects with high systolic blood pressure (OR = 1.02; 95% CI, 1-1.05). Total cholesterol levels at the end of the study were higher in new microalbuminuric (group I) than normoalbuminuric patients (group II) (group I: 211.08 [34.75] mg/dl vs group II: 200.67 [30.50]; p = 0.042).
Tobacco, blood pressure and diabetes control influences the presence and development of microalbuminuria. More studies are required to study the influence of hypercholesterolemia.
Medicina Clínica 11/2005; 125(11):401-4. · 1.38 Impact Factor
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ABSTRACT: Tumor necrosis factor alpha has a key role in insulin resistance. We study the effects of metformin on glucose tolerance, insulin resistance, beta cell function, and soluble tumor necrosis factor receptor (sTNFR) levels.
We performed a double-blind, randomized metformin-placebo study. Twenty-three subjects with impaired glucose tolerance or impaired fasting glucose were studied. Oral glucose tolerance, homeostasis model assessment, and continuous infusion of glucose with model assessment tests were used to evaluate glucose tolerance, insulin sensitivity, and beta cell function, respectively. Soluble tumor necrosis factor receptor levels were measured before and after therapy. Repeated measures analysis of variance was used for statistical analysis.
After 12-week treatment, fasting glucose (110.1 +/- 9.9 to 98.9 +/- 15.7 mg/dl, P < .001), fasting insulin (11.6 +/- 5.4 to 8.8 +/- 3.5 mU/L, P = .05), fasting C-peptide (2.5 +/- 0.7 to 1.8 +/- 0.5 ng/mL, P < .05), and achieved C-peptide (5.2 +/- 1.2 to 4.2 +/- 1 ng/mL, P < .05) levels decreased in the metformin group. In addition, there was an improvement in insulin sensitivity (37.4% +/- 15.2% to 50.4% +/- 23.2%, P < .05) with unchanged sTNFR1 (2.0 +/- 0.8 to 2.3 +/- 1.2 microg/L, P = NS) and sTNFR2 (4.8 +/- 1.7 to 4.4 +/- 1.2 microg/L, P = NS) levels.
Metformin is able to reverse insulin resistance and hyperglycemia in high-risk subjects for type 2 diabetes mellitus independently of the effects on tumor necrosis factor alpha system activity.
Metabolism 03/2005; 54(2):235-9. · 2.66 Impact Factor
