GH levels and insulin sensitivity are differently associated with biomarkers of cardiovascular disease in active acromegaly

Context: Acromegaly is characterized by GH excess and insulin resistance. It is not known which of these disorders is responsible for the increased atherogenic risk in these patients. Objective: To analyse the associations of GH and homoeostasis model assessment (HOMA) with biomarkers of cardiovascular disease and to compare the above-mentioned variables between patients with active acromegaly and controls. Design and setting: This open cross-sectional study was conducted at a University Hospital. Patients: Twenty-two outpatients were compared with sex- and age-matched control subjects. Main outcomes: Included clinical features, hormonal status, markers of insulin resistance, lipoprotein profile and biomarkers of cardiovascular disease. Results: Patients presented higher triglyceride (median [IQR]) (1·2[1·1-1·6] vs 0·9[0·6-1·1] mm, P < 0·05), low-density lipoprotein-cholesterol (LDL-C) (mean ± SD) (3·5 ± 0·9 vs 3·0 ± 0·7mm, P < 0·05), apoB (0·98 ± 0·23 vs 0·77 ± 0·22 g/l, P < 0·05), free fatty acid (0·69 ± 0·2 vs 0·54 ± 0·2 mM, P < 0·05), oxidized-LDL (120 ± 22 vs 85 ± 19 U/l, P < 0·05) and endothelin-1 (0·90 ± 0·23 vs 0·72 ± 0·17 ng/l, P < 0·05) levels, increased cholesteryl ester transfer protein (CETP) activity (179 ± 27 vs 138 ± 30%/ml/h, P < 0·01) and lower C reactive protein (CRP) (0·25[0·1-0·9] vs 0·85[0·4-1·4] mg/l; P < 0·05) levels than control subjects. Vascular cell adhesion molecule (VCAM-1) concentration was not different. By multiple linear regression analyses, HOMA explained the variability of triglycerides (25%), high-density lipoprotein-cholesterol (HDL-C) (30%) and CETP activity (28%), while GH independently predicted LDL-C (18%), oxidized-LDL (40%) and endothelin-1 levels (19%). Conclusions: In patients with active acromegaly, GH excess contributes to the development of insulin resistance, and the interaction between both disturbances would be responsible for the appearance of atherogenic pro-oxidative and pro-inflammatory factors. Insulin resistance would be preferably associated with an atherogenic lipoprotein profile and to high CETP activity, while high GH levels would independently predict the increase in LDL-C, ox-LDL and endothelin-1

High risk of cardiovascular disease in iron overload patients

Introduction: Iron overload (IO) is defined as an increase in storage iron, regardless of the presence or absence of tissue damage. Whether increased iron stores are involved in the pathogenesis of cardiovascular disease remains controversial.Objectives: To study insulin resistance markers, lipoprotein profile, activities of anti and prooxidant enzymes and cholesteryl ester transfer protein (CETP) in patients with IO.Methods: Twenty patients with IO were compared with 20 sex and age-matched controls. General biochemical parameters, lipoprotein profile, and activities of paraoxonase 1, employing two substrates, paraoxon (PON) and phenylacetate (ARE), lipoprotein-associated phospholipase A2 (Lp-PLA2) and CETP were determined.Results: IO patients showed higher levels of HOMA-IR and triglycerides (median [Q1-Q3]) (128[93-193] vs. 79[51-91]mg/dl,p<0.0005) while lower HDL-cholesterol (mean±SD) (41±9 vs. 52±10mg/dl,p<0.0005) in comparison with controls. Moreover, the triglycerides/HDL-cholesterol (3.2[2.0-5.1] vs. 1.5[1.0-1.9],p<0.0005) ratio and oxidized LDL levels (94[64-103] vs. 68[59-70]IU/l,p<0.05) were increased in the patient group. Though no difference was observed in ARE activity, PON activity was decreased in IO patients (246[127-410] vs. 428[263-516]nmol.ml-1.min-1,p<0.05). In addition, CETP and Lp-PLA2 activities were also increased in the patients (189±31 vs. 155±36%.ml-1.h-1,p<0.005; and 10.1±2.9 vs. 8.2±2.4µmol.ml-1.h-1,p<0.05, respectively). Associations between ferritin concentration and the alterations in lipid metabolism were also found. Multiple regression analyses identified HOMA-IR as independent predictor of CETP activity (B=65.9,p<0.0001,r2=0.35), as well as ferritin concentration of Lp-PLA2 activity (B=3.7,p<0.0001,r2=0.40) after adjusting for confounding variables.Conclusions: IO patients presented not only insulin resistance, but also metabolic alterations which were related to elevated iron stores and are associated to high risk of cardiovascular disease.Fil: Meroño, Tomás. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Fisiopatología y Bioquímica Clínica; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay; ArgentinaFil: Gomez Rosso, Leonardo Adrián. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Fisiopatología y Bioquímica Clínica; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay; ArgentinaFil: Sorroche, Patricia. Hospital Italiano; ArgentinaFil: Boero, Laura. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Fisiopatología y Bioquímica Clínica; ArgentinaFil: Arbelbide, Jorge. Hospital Italiano; ArgentinaFil: Brites, Fernando Daniel. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Fisiopatología y Bioquímica Clínica; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay; Argentin

Association of common variants in JAK2 gene with reduced risk of metabolic syndrome and related disorders

<p>Abstract</p> <p>Background</p> <p>Disturbances in leptin and insulin signaling pathways are related to obesity and metabolic syndrome (MS) with increased risk of diabetes and cardiovascular disease. Janus kinase 2 (JAK2) is a tyrosine kinase involved in the activation of mechanisms that mediate leptin and insulin actions. We conducted a population cross-sectional study to explore the association between two common variants in JAK2 gene and MS related traits in 724 Argentinean healthy male subjects.</p> <p>Methods</p> <p>A total of 724 unrelated men aged 37.11 ± 10.91 yr were included in a cross-sectional study. Physical examination, anthropometric measurements and biochemical analysis were determined by a standardized protocol. rs7849191 and rs3780378 were genotyped. Analyses were done separately for each SNP and followed up by haplotype analysis.</p> <p>Results</p> <p>rs7849191 and rs3780378 were both associated with reduced risk of MS [p = 0.005; OR (95%CI) = 0.52 (0.33-0.80) and p = 0.006; OR (95% CI) = 0.59 (0.40-0.86) respectively, assuming a dominant model]. rs3780378 T allele was associated with triglyceridemia values under 150 mg/dl [p = 0.007; OR (95%CI) = 0.610 (0.429-0.868)] and TT carriers showed lower triglycerides (p = 0.017), triglycerides/HDL-C ratio (p = 0.022) and lipid accumulation product (p = 0.007) compared to allele C carriers. The two-SNPs-haplotype analysis was consistent with single locus analysis.</p> <p>Conclusions</p> <p>It was found for the first time, significant associations of JAK2 common variants and related haplotypes with reduced risk of MS. These findings could be explained by the role of JAK2 in insulin and/or leptin signaling.</p

Vascular reactivity and biomarkers of endothelial function in healthy subjects exposed to acute hypobaric hypoxia

Aims: The aim of this study was to evaluate the effects of acute hypobaric hypoxia (HH) on vascular reactivity and biochemical markers associated with endothelial function (EF). Main methods: Ten healthy subjects were exposed to a simulated altitude of 4,000. meters above sea level for 4. hours in a hypobaric chamber. Vascular reactivity was measured by the flow-mediated vasodilatation (FMVD) test. Endothelin-1, high sensitive-C reactive protein (hsCRP), vascular cell adhesion molecule 1, interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), paraoxonase and adiponectin levels, and FMVD were evaluated before and after the exposure. Key findings: Subjects were young (age: 32±6years), lean [body mass index: 23.9±2.0kg/m2, waist circumference: 77(IQR: 72-80) cm], and presented normal clinical and biochemical parameters. No significant changes were evidenced in FMVD in response to HH (pre: 0.45 (0.20-0.70) vs. during: 0.50 (0.20-1.22) mm; p=0.594). On the other hand, endothelin-1 (+54%, p<0.05), hsCRP (+37%, p<0.001), IL-6 (+75%, p<0.05), TNF-α (+75%, p<0.05), and adiponectin (-39%, p<0.01) levels were significantly altered post-HH. FMVD was increased in 7 subjects, and it was decreased in 3 individuals during HH exposure. Interestingly, when EF biomarkers were compared between these two subgroups of subjects, only post exposure-adiponectin levels were significantly different (49±5 vs. 38±6μg/ml, respectively, p<0.05). Significance: HH exposure had an effect on endothelin-1, adiponectin, hsCRP, IL-6, and TNF-α concentration. However, adiponectin was the only biomarker associated with an altered vascular reactivity.Fil: Iglesias, Diego. Sociedad Argentina de Medicina de Montaña; Argentina. Hospital Italiano; Argentina. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica; ArgentinaFil: Gomez Rosso, Leonardo Adrián. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Vainstein, Nora. Hospital Italiano; ArgentinaFil: Meroño, Tomás. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Lezón, Christian Esteban. Sociedad Argentina de Medicina de Montaña; ArgentinaFil: Brites, Fernando Daniel. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentin

Adiponectin: an adipocytokine with multiple protective functions

Actualmente, se considera que el tejido adiposo es un órgano dinámico involucrado en muchos procesos fisiológicos y metabólicos. Expresa y secreta una gran variedad de péptidos activos conocidos como adipocitoquinas que actúan en forma local y sistémica. Además, expresa numerosos receptores que le permiten responder a señales aferentes de diferentes órganos endocrinos y del sistema nervioso central. La adiponectina es una hormona de 30 kDa producida exclusivamente por el tejido adiposo. A diferencia de las demás adipocitoquinas conocidas, sus niveles se encuentran disminuídos en estados asociados con resistencia insulínica, tal como obesidad, diabetes tipo 2 y síndrome metabólico. A esta proteína se le ha atribuído un rol antidiabético, antiinflamatorio y antiaterogénico. El objetivo de este trabajo es realizar una revisión acerca de la estructura, las funciones biológicas, el o los posibles mecanismos de acción, las implicancias fisiopatológicas y las posibles aplicaciones de la evaluación de los niveles de esta adipocitoquina a nivel clínico.The adipose tissue is considered a dynamic organ, which is involved in a wide range of physiological and metabolic processes. This tissue expresses and secretes a variety of bioactive peptides, known as adipocytokines, which act both at the local and at the systemic levels. The adipose tissue also expresses several receptors that allow it to respond to afferent signals from different endocrine organs, as well as form the central nervous system. Adiponectin is a 30 kDa hormone exclusively secreted by adipocytes. Unlike the other known adipocytokines, its concentration is reduced in conditions associated to insulin resistance, like obesity, type2 diabetes and metabolic syndrome. Several studies suggest that adiponectin has antidiabetic, antiinflammatory and antiatherogenic actions. The aim of this work is to review the new advances in structure, biological functions, mechanisms of action and potential clinical applications of adiponectin evaluation.Fil: Elissondo, Natalia. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica; ArgentinaFil: Gomez Rosso, Leonardo Adrián. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay; ArgentinaFil: Maidana, Patricia. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica; ArgentinaFil: Brites, Fernando Daniel. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay; Argentin

Alterations in biomarkers of cardiovascular disease (CVD) in active acromegaly

Objectives: In acromegalic patients, cardiovascular and metabolic comorbidities contribute to enhance mortality. Available data on the lipoprotein profile of these patients are controversial. Our aim was to characterize the lipoprotein profile and emergent biomarkers of cardiovascular disease in active acromegalic patients in comparison with sex- and age-matched healthy controls. Patients: Eighteen patients with active acromegaly and 18 controls were studied. Measurements: Glucose levels, hormonal status, lipoprotein profile and C reactive protein (CRP) were evaluated by standardized methods. Cholesteryl ester transfer protein (CETP) and lipoprotein-associated phospholipase A2 (Lp-PLA2) were measured by radiometric techniques, endothelin-1 and vascular cell adhesion molecule (VCAM)-1 by enzyme-linked immunosorbent assay, and leucocytes CD18, CD49d and CD54 by flow cytometry. Results: After adjusting for body mass index (BMI), acromegalic patients presented a more atherogenic lipoprotein profile, consisting of higher levels of triglycerides and apolipoprotein B and alterations in the ratios which estimate insulin resistance and atherogenic risk. CETP activity was significantly increased in acromegalic patients as compared to controls (168 ± 17 vs. 141 ± 30% per ml h, respectively; P < 0.05). Endothelin-1 levels evidenced an increase in the patients' group (0.9 ± 0.2 vs. 0.7 ± 0.2 ng/l, respectively; P < 0.01) and showed positive and significant correlations with GH, IGF-1 and IGFBP-3 (r = 0.45, 0.42 and 0.44, respectively; P < 0.01 for all of them; with BMI as a fixed variable). Lymphocytes from acromegalic patients showed increased CD49d content (282 ± 59 vs. 246 ± 48 arbitrary units, respectively; P < 0.05). Conclusions: Taken together, the alterations described seem to contribute to constituting a state of higher propensity for the development of atherosclerotic cardiovascular disease, which adds to the presence of specific cardiomyopathy.Fil: Boero, Laura Estela. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay; ArgentinaFil: Manavela, M.. Universidad de Buenos Aires. Facultad de Medicina. Hospital de Clínicas General San Martín; ArgentinaFil: Gomez Rosso, Leonardo Adrián. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay; ArgentinaFil: Insua, C.. Gobierno de la Ciudad de Buenos Aires. Hospital General de Niños Pedro Elizalde (ex Casa Cuna); ArgentinaFil: Berardi, V.. No especifíca;Fil: Fornari, M.C.. No especifíca;Fil: Brites, Fernando Daniel. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay; Argentin

Low plasma triiodothyronine levels in heart failure are associated with a reduced anabolic state and membrane damage

BACKGROUND: Low plasma triiodothyronine (T(3)) levels are considered a prognostic predictor of death in heart failure (HF) patients. AIM: To study an association between plasma T(3) levels and several cardiac, neurohormonal, and metabolic markers of HF. METHODS: A total of 133 ambulatory HF patients (114 males; mean age 63.2 years) with left ventricular ejection fraction <40% were enrolled. TSH, total tetraiodothyronine (T(4)) and T(3), N-terminal pro-brain natriuretic peptide (NT-proBNP), and other cardiac and metabolic parameters were measured. The lowest tertile of T(3) (group 1) was compared against the two upper ones (group 2). RESULTS: In simple logistic regression, the lowest T(3) tertile was associated with more advanced HF disease status: older (age: odds ratio (OR)=1.05; confidence interval (CI) 95% 1.01-1.09, P=0.004), lower functional capacity (walking test: OR=0.996; CI 95% 0.993-0.999, P=0.008), higher NT-proBNP (OR=1.64; CI 95% 1.19-2.27, P=0.003) and adiponectin levels (OR=1.07; CI 95% 1.02-1.11, P=0.004), lower DHEAS log-transformed (OR=0.50; CI 95% 0.31-0.80, P=0.004), and the presence of lower phase angle values as measured by body bioelectrical impedance analysis (OR=3.18; CI 95% 1.50-6.71, P=0.04) and worse renal function (OR=0.96; CI 95% 0.94-0.98, P=0.003). T(3) levels in the lowest tertile were independently associated with low phase angle values (OR=2.95, CI 95% 1.16-7.50, P=0.02) and the log transformation of DHEAS (OR=0.56; CI 95% 0.32-0.97, P=0.04). CONCLUSION: We have demonstrated an association between plasma T(3) levels in the lower range and other deranged hormonal and metabolic parameters in HF patients.Fil: Brenta, Gabriela. Gobierno de la Ciudad de Buenos Aires. Hospital César Milstein; ArgentinaFil: Thierer, Jorge. Instituto Cardiovascular de Buenos Aires; ArgentinaFil: Sutton, Marcela. Instituto Cardiovascular de Buenos Aires; ArgentinaFil: Acosta, Adriana. Instituto Cardiovascular de Buenos Aires; ArgentinaFil: Vainstein, Nora. Instituto Cardiovascular de Buenos Aires; ArgentinaFil: Brites, Fernando Daniel. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Boero, Laura. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica; ArgentinaFil: Gomez Rosso, Leonardo Adrián. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Anker, Stefan. Istituto di Ricovero e Cura a Carattere Scientifico; Italia. Charité Universitätsmedizin Berlin; Alemani

HOMA-IR and non-HDL-C as predictors of high cholesteryl ester transfer protein activity in patients at risk for type 2 diabetes

Background and aims: Metabolic syndrome (MS) and type 2 diabetes are highly associated with an abnormal lipoprotein profile, which may be generated and accentuated by high cholesteryl ester transfer protein (CETP) activity. Given the difficulty in measuring CETP activity, the aim was to identify simple biochemical predictors of high CETP activity. Design and methods: Eighty five subjects at risk for type 2 diabetes were classified according to the presence of MS. Lipoprotein profile, HOMA-IR and endogenous CETP activity were evaluated. Results: As expected, MS patients presented higher concentration of glucose, insulin, triglycerides and non-HDL-C and lower HDL-C levels. Moreover, MS patients exhibited increased HOMA-IR and CETP activity. Employing a ROC curve for MS, high CETP activity was defined as >250%ml⁻¹ h⁻¹. The predictive variables of high CETP were non-HDL-C≥160mg/dl (OR=11.1;95%IC=3.3-38.2;p2.1 (OR=4.4;95%IC=1.3-14.8;p<0.05). Conclusions: High non-HDL-C and insulin resistance were predictors for increased CETP activity which measurement is not accessible for clinical laboratories

Aumento del riesgo de enfermedad cardiovascular en pacientes con enfermedad celíaca

En pacientes con enfermedad celíaca (EC), se ha observado mayor incidencia de eventos cardiovasculares que en controles, sin la presencia de factores de riesgo aterogénico clásicos. El objetivo de este estudio fue evaluar los factores de riesgo nóveles y biomarcadores de inflamación y enfermedad cardiovascular en pacientes con EC, con presentación típica y atípica. Fueron seleccionados 14 pacientes con EC sin tratamiento y controles pareados por sexo y edad. Se determinaron parámetros hematológicos, indicadores del metabolismo de los hidratos de carbono, proteína C reactiva ultrasensible (PCRus), per- fil lipoproteico y actividades de proteína transportadora de colesterol esterificado (CETP) y fosfolipasa A2 asociada a lipoproteínas (Lp-PLA2). Los pacientes con EC presentaron niveles plasmáticos mayores de insulina (7,2 mU/l vs. 4,4 mU/l; p<0,05) y mayor índice HOMA-IR (1,45 vs. 0,98; p<0,05) que los controles. Por otro lado, se observó menor concentración de colesterol-HDL (50 vs. 62 mg/dl; p<0,05), mayor cociente triglicéridos/colesterol-HDL y niveles de PCRus más altos (4,56 vs. 1,17 mg/l; p<0,05) en los pacientes que en los controles. Al comparar a los pacientes con presentación típica (n=8) y atí- pica (n=6), aquellos con presentación típica mostraron menores niveles de apo A-I (128 vs. 178 mg/dl; p<0,01) y aumento del cociente apo B/apo A-I (0,72 vs. 0,43; p<0,05), así como mayor actividad de LpPLA2 (7,9 umol/ml.h vs. 6,15 umol/ml.h; p<0,05). La interacción de las alteraciones descriptas durante períodos de tiempo prolongados en una condición patológica crónica como la EC constituirían un mayor riesgo de desarrollo de enfermedad cardiovascular aterosclerótica.In patients with celiac disease (CD), it has been reported higher incidence of cardiovascular events than in controls, without the presence of classical atherogenic risk factors. The aim of this study was to evaluate the novel risk factors and biomarkers of inflammation and cardiovascular disease in patients with CD, with typical and atypical presentation. We selected 14 patients with CD without treatment and 14 healthy sex and age-matched controls. Haematological parameters, indicators of carbohydrates metabolism, high sensitive C reactive protein (hsCRP), lipoprotein profile and the activities of cholesteryl ester transfer protein (CETP) and lipoprotein-associated phospholipase A2 (Lp-PLA2) were determined. CD patients presented higher insulin plasma levels (7.2 mU/l vs. 4.4 mU/l, p <0.05) and increased HOMA-IR index (1.45 vs. 0.98, p <0.05) than controls. On the other hand, lower HDLcholesterol concentration (50 vs. 62 mg/dl, p<0.05), higher TG/HDL-cholesterol ratio and increased hsCRP levels (4.56 vs. 1.17 mg / l, P <0.05) were observed in comparison with control subjects. When comparing patients with typical (n=8) and atypical (n=6) presentation, the former showed lower apo A-I levels (128 vs. 178 mg/dl, p<0.01), and higher apo B/apo A-I ratio (0.72 vs. 0.43, p<0.05) and LpPLA2 activity (7.9 umol/ml.h vs. 6.15 umol/ml.h, p<0.05). The interaction among the alterations above described during long periods of time in a chronic pathological condition such as CD could constitute higher risk of development of atherosclerotic cardiovascular disease.Fil: Menafra, Martín. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Bioquímica Clínica; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Meroño, Tomás. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Bioquímica Clínica; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Matoso, María Dolores. Hospital Italiano; ArgentinaFil: Boero, Laura Estela. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Bioquímica Clínica; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Gomez Rosso, Leonardo Adrián. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Bioquímica Clínica; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Saez, María Soledad. Hospital Italiano; ArgentinaFil: Sorroche, Patricia Beatriz. Hospital Italiano; ArgentinaFil: de Paula, P.. Hospital Italiano; ArgentinaFil: Brites, Fernando Daniel. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Bioquímica Clínica; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentin

Poor glycemic control in type 2 diabetes enhances functional and compositional alterations of small, dense HDL3c

High-density lipoprotein (HDL) possesses multiple biological activities; small, dense HDL3c particles displaying distinct lipidomic composition exert potent antiatherogenic activities which can be compromised in dyslipidemic, hyperglycemic insulin-resistant states. However, it remains indeterminate (i) whether such functional HDL deficiency is related to altered HDL composition, and (ii) whether it originates from atherogenic dyslipidemia, dysglycemia, or both. In the present work we analyzed compositional characteristics of HDL subpopulations and functional activity of small, dense HDL3c particles in treatment-naïve patients with well-controlled (n=10) and poorly-controlled (n=8) type 2 diabetes (T2D) and in normolipidemic age- and sex-matched controls (n=11). Our data reveal that patients with both well- and poorly-controlled T2D displayed dyslipidemia and low-grade inflammation associated with altered HDL composition. Such compositional alterations in small, dense HDL subfractions were specifically correlated with plasma HbA1c levels. Further analysis using a lipidomic approach revealed that small, dense HDL3c particles from T2D patients with poor glycemic control displayed additional modifications of their chemical composition. In parallel, antioxidative activity of HDL3c towards oxidation of low-density lipoprotein was diminished. These findings indicate that defective functionality of small, dense HDL particles in patients with T2D is not only affected by the presence of atherogenic dyslipidemia, but also by the level of glycemic control, reflecting compositional alterations of HDL. Keywords: Antioxidative activity; Functionality; HDL; Lipidomics; Type 2 diabetes