RESUMEN
BACKGROUND/OBJECTIVES: This study aimed to determine the association between a Mediterranean diet and glycemic control and other cardiovascular risk factors among youth with type I diabetes (TID). SUBJECTS/METHODS: Incident TID cases aged <20 years at diagnosis between 2002 and 2005 were included. Participants were seen at baseline (N=793), 1-year (N=512) and 5-year follow-up visits (N=501). Mediterranean diet score was assessed using a modified KIDMED index (mKIDMED). Multivariate linear regression and longitudinal mixed model were applied to determine the association between mKIDMED score and log-HbA1c, lipids, blood pressure (BP) and obesity. RESULTS: In cross-sectional analyses using baseline data, for individuals with the hemoglobin A1c (HbA1c) of 7.5%, a two-point higher mKIDMED score (1 s.d.) was associated with 0.15% lower HbA1c (P=0.02). A two-point higher mKIDMED score was associated with 4.0 mg/dl lower total cholesterol (TC) (P=0.006), 3.4 mg/dl lower low-density lipoprotein cholesterol (LDL-C) (P=0.004), 3.9 mg/dl lower non-high-density lipoprotein cholesterol (non-HDL-C) (P=0.004) and 0.07 lower LDL-C/HDL-C ratio (P=0.02). Using longitudinal data, a two-point increase in mKIDMED score was associated with 0.01% lower log-HbA1c (P=0.07), 1.8 mg/dl lower TC (P=0.05), 1.6 mg/dl lower LDL-C (P=0.03) and 1.8 mg/dl lower non-HDL-C (P=0.03) than would otherwise have been expected. HbA1c mediated â¼20% of the association for lipids in both cross-sectional and longitudinal models. An unexpected positive association between mKIDMED score and systolic BP was found among non-Hispanic white youth in cross-sectional analyses (P=0.009). Mediterranean diet was not associated with obesity. CONCLUSIONS: Mediterranean diet may improve glycemic control and cardiovascular health in TID youth.
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Glucemia/metabolismo , Enfermedades Cardiovasculares/sangre , Diabetes Mellitus Tipo 1/dietoterapia , Dieta Mediterránea , Conducta Alimentaria , Hemoglobina Glucada/metabolismo , Lípidos/sangre , Adolescente , Adulto , Presión Sanguínea , Enfermedades Cardiovasculares/etiología , Niño , Preescolar , Estudios Transversales , Diabetes Mellitus Tipo 1/sangre , Diabetes Mellitus Tipo 1/complicaciones , Diabetes Mellitus Tipo 1/tratamiento farmacológico , Femenino , Estudios de Seguimiento , Humanos , Insulina/uso terapéutico , Lipoproteínas/sangre , Masculino , Obesidad , Cooperación del Paciente , Factores de Riesgo , Población Blanca , Adulto JovenRESUMEN
AIM: To examine concentrations of biomarkers (adiponectin, C-reactive protein, fibrinogen and tissue plasminogen-activator antigen) associated with glucose homeostasis and diabetes risk by history of gestational diabetes (GDM). METHODS: We conducted a secondary analysis of the Diabetes Prevention Program, a randomized trial of lifestyle intervention or metformin for diabetes prevention. At baseline, participants were overweight and had impaired glucose tolerance. Biomarkers at baseline and 1 year after enrolment were compared between parous women with (n = 350) and without histories of GDM (n = 1466). Cox proportional hazard models evaluated whether history of GDM was associated with diabetes risk, after adjustment for baseline biomarker levels as well as for change in biomarker levels, demographic factors and anthropometrics. RESULTS: At baseline, women with histories of GDM had lower adiponectin (7.5 µg/ml vs. 8.7 µg/ml; p < 0.0001) and greater log C-reactive protein (-0.90 mg/l vs. -0.78 mg/l, p = 0.04) levels than women without histories of GDM, but these associations did not persist after adjustment for demographic factors. Fibrinogen and tissue plasminogen-activator antigen were similar between women with and without histories of GDM. Women with and without histories of GDM had a similar pattern of changes in biomarkers within randomization arm. Adjustment for age, race/ethnicity, baseline weight, change in weight, baseline biomarker level and change in biomarker level did not significantly alter the association between history of GDM, and diabetes risk. CONCLUSIONS: Among women with impaired glucose tolerance, biomarkers in women with and without histories of GDM are similar and respond similarly to lifestyle changes and metformin. Adjustment for biomarker levels did not explain the higher risk of diabetes observed in women with histories of GDM.
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Adiponectina/sangre , Proteína C-Reactiva/análisis , Diabetes Mellitus Tipo 2/etiología , Diabetes Gestacional/fisiopatología , Intolerancia a la Glucosa/sangre , Sobrepeso/terapia , Activador de Tejido Plasminógeno/sangre , Adulto , Biomarcadores/sangre , Índice de Masa Corporal , Estudios de Cohortes , Terapia Combinada , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/epidemiología , Diabetes Mellitus Tipo 2/prevención & control , Dieta Reductora , Femenino , Fibrinógeno/análisis , Intolerancia a la Glucosa/complicaciones , Intolerancia a la Glucosa/etiología , Intolerancia a la Glucosa/terapia , Humanos , Hipoglucemiantes/uso terapéutico , Estilo de Vida , Persona de Mediana Edad , Actividad Motora , Sobrepeso/complicaciones , Embarazo , Riesgo , Estados Unidos/epidemiología , Pérdida de PesoRESUMEN
AIMS AND HYPOTHESIS: In patients with Type 2 diabetes, intensive glycaemic control is associated with hypoglycaemia and possibly increased mortality. However, no blood biomarkers exist to predict these outcomes. Using participants from the Action to Control Cardiovascular Risk in Diabetes (ACCORD) study, we hypothesized that insulin deficiency and islet autoantibodies in patients with clinically diagnosed Type 2 diabetes would be associated with severe hypoglycaemia and death. METHODS: A nested case-control study design was used. A case (n = 86) was a participant who died with at least one episode of severe hypoglycaemia, defined as hypoglycaemia requiring assistance, at any point during ACCORD follow-up. A control (n = 344) was a participant who did not die and did not have severe hypoglycaemia during follow-up. Each case was matched to four controls (glycaemic intervention arm, race, age and BMI). Baseline insulin deficiency (fasting C-peptide ≤ 0.15 nmol/l) and islet autoantibodies [glutamic acid decarboxylase (GAD), tyrosine phosphatase-related islet antigen 2 (IA2), insulin (IAA) and zinc transporter (ZnT8)] were measured. Conditional logistic regression with and without adjustment for age, BMI and diabetes duration was used. RESULTS: Death during ACCORD in those who experienced at least one episode of severe hypoglycaemia was associated with insulin deficiency [OR 4.8 (2.1, 11.1): P < 0.0001], GAD antibodies [OR 2.3 (1.1, 5.1): P = 0.04], the presence of IAA or baseline insulin use [OR 6.1 (3.5,10.7): P < 0.0001], which remained significant after adjusting for age, BMI, and diabetes duration. There was no significant association with IA2 or ZnT8 antibodies. CONCLUSIONS: In patients with Type 2 diabetes, C-peptide or GAD antibodies may serve as blood biomarkers predicting higher odds of subsequent severe hypoglycaemia and death. (Clinical Trial Registry No: NCT00000620, www.clinicaltrials.gov for original ACCORD study).
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Autoanticuerpos/sangre , Péptido C/sangre , Diabetes Mellitus Tipo 2/sangre , Hipoglucemia/sangre , Hipoglucemiantes/efectos adversos , Insulina/sangre , Mortalidad , Anciano , Autoanticuerpos/inmunología , Biomarcadores , Estudios de Casos y Controles , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/epidemiología , Femenino , Glutamato Descarboxilasa/inmunología , Humanos , Hipoglucemia/inducido químicamente , Hipoglucemia/epidemiología , Insulina/inmunología , Modelos Logísticos , Masculino , Persona de Mediana Edad , Proteínas Tirosina Fosfatasas Clase 8 Similares a Receptores/inmunología , Índice de Severidad de la Enfermedad , Transportador 8 de Zinc/inmunologíaRESUMEN
AIMS: To determine the association of metabolic syndrome (MetS) and its components with diabetes risk in participants with impaired glucose tolerance (IGT), and whether intervention-related changes in MetS lead to differences in diabetes incidence. METHODS: We used the National Cholesterol Education Program/Adult Treatment Panel III (NCEP/ATP III) revised MetS definition at baseline and intervention-related changes of its components to predict incident diabetes using Cox models in 3234 Diabetes Prevention Program (DPP) participants with IGT over an average follow-up of 3.2 years. RESULTS: In an intention-to-treat analysis, the demographic-adjusted hazard ratios (95% confidence interval) for diabetes in those with MetS (vs. no MetS) at baseline were 1.7 (1.3-2.3), 1.7 (1.2-2.3) and 2.0 (1.3-3.0) for placebo, metformin and lifestyle groups, respectively. Higher levels of fasting plasma glucose and triglycerides at baseline were independently associated with increased risk of diabetes. Greater waist circumference (WC) was associated with higher risk in placebo and lifestyle groups, but not in the metformin group. In a multivariate model, favourable changes in WC (placebo and lifestyle) and high-density lipoprotein cholesterol (placebo and metformin) contributed to reduced diabetes risk. CONCLUSIONS: MetS and some of its components are associated with increased diabetes incidence in persons with IGT in a manner that differed according to DPP intervention. After hyperglycaemia, the most predictive factors for diabetes were baseline hypertriglyceridaemia and both baseline and lifestyle-associated changes in WC. Targeting these cardiometabolic risk factors may help to assess the benefits of interventions that reduce diabetes incidence.
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Glucemia/metabolismo , Enfermedades Cardiovasculares/prevención & control , Diabetes Mellitus Tipo 2/prevención & control , Angiopatías Diabéticas/prevención & control , Intolerancia a la Glucosa/complicaciones , Intolerancia a la Glucosa/terapia , Hipoglucemiantes/uso terapéutico , Síndrome Metabólico/prevención & control , Metformina/uso terapéutico , Conducta de Reducción del Riesgo , Triglicéridos/sangre , Factores de Edad , Enfermedades Cardiovasculares/sangre , Enfermedades Cardiovasculares/epidemiología , Enfermedades Cardiovasculares/etiología , Diabetes Mellitus Tipo 2/sangre , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/epidemiología , Diabetes Mellitus Tipo 2/etiología , Angiopatías Diabéticas/sangre , Angiopatías Diabéticas/epidemiología , Dieta Reductora , Ejercicio Físico , Ayuno , Femenino , Intolerancia a la Glucosa/tratamiento farmacológico , Humanos , Incidencia , Masculino , Síndrome Metabólico/sangre , Síndrome Metabólico/epidemiología , Síndrome Metabólico/etiología , Persona de Mediana Edad , Modelos de Riesgos Proporcionales , Inducción de Remisión , Factores de Riesgo , Circunferencia de la CinturaRESUMEN
AIMS: To determine the prevalence of plasma vitamin D (25-dihydroxyvitamin D) insufficiency in individuals with Type 1 diabetes and to determine the cross-sectional and longitudinal associations of plasma vitamin D with insulin resistance. METHODS: Participants from the SEARCH for Diabetes in Youth Study [n = 1426; mean age 11.2 years (sd 3.9)] had physician-diagnosed Type 1 diabetes [diabetes duration mean 10.2 months (sd 6.5)] with data available at baseline and follow-up (approximately 12 and 24 months after baseline). Insulin resistance was estimated using a validated equation. Cross-sectional and longitudinal multivariate logistic regression models were used to determine the association of plasma vitamin D with insulin resistance, adjusting for potential confounders. RESULTS: Forty-nine per cent of individuals had plasma vitamin D < 50 nmol/l and 26% were insulin resistant. In cross-sectional multivariate analyses, participants who had higher plasma vitamin D (65 nmol/l) had lower odds of prevalent insulin resistance than participants with lower plasma vitamin D (25 nmol/l) (odds ratio 0.70, 95% CI 0.57-0.85). This association was attenuated after additional adjustment for BMI z-score, which could be a confounder or a mediator (odds ratio 0.81, 95% CI 0.64-1.03). In longitudinal multivariate analyses, individuals with higher plasma vitamin D at baseline had lower odds of incident insulin resistance, but this was not significant (odds ratio 0.85, 95% CI 0.63-1.14). CONCLUSIONS: Vitamin D insufficiency is common in individuals with Type 1 diabetes and may increase risk for insulin resistance. Additional prospective studies are needed to determine the association between plasma vitamin D and insulin resistance, and to further examine the role of adiposity on this association.
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Diabetes Mellitus Tipo 1/etiología , Deficiencia de Vitamina D/complicaciones , Vitamina D/análogos & derivados , Adolescente , Niño , Métodos Epidemiológicos , Femenino , Humanos , Resistencia a la Insulina/fisiología , Masculino , Vitamina D/sangre , Adulto JovenRESUMEN
AIMS: Whether long-term cardiovascular risk is reduced by the Diabetes Prevention Program interventions is unknown. The aim of this study was to determine the long-term differences in cardiovascular disease risk factors and the use of lipid and blood pressure medications by the original Diabetes Prevention Program intervention group. METHODS: This long-term follow-up (median 10 years, interquartile range 9.0-10.5) of the three-arm Diabetes Prevention Program randomized controlled clinical trial (metformin, intensive lifestyle and placebo), performed on 2766 (88%) of the Diabetes Prevention Program participants (who originally had impaired glucose tolerance), comprised a mean of 3.2 years of randomized treatment, approximately 1-year transition (during which all participants were offered intensive lifestyle intervention) and 5 years follow-up (Diabetes Prevention Program Outcomes Study). During the study, participants were followed in their original groups with their clinical care being provided by practitioners outside the research setting. The study determined lipoprotein profiles and blood pressure and medication use annually. RESULTS: After 10 years' follow-up from Diabetes Prevention Program baseline, major reductions were seen for systolic (-2 to -3) and diastolic (-6 to -6.5 mmHg) blood pressure, and for LDL cholesterol (-0.51 to -0.6 mmol/l) and triglycerides (-0.23 to -0.25 mmol/l) in all groups, with no between-group differences. HDL cholesterol also rose significantly (0.14 to 0.15 mmol/l) in all groups. Lipid (P = 0.01) and blood pressure (P = 0.09) medication use, however, were lower for the lifestyle group during the Diabetes Prevention Program Outcomes Study. CONCLUSION: Overall, intensive lifestyle intervention achieved, with less medication, a comparable long-term effect on cardiovascular disease risk factors, to that seen in the metformin and placebo groups.
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Diabetes Mellitus/prevención & control , Angiopatías Diabéticas/etiología , Análisis de Varianza , Antihipertensivos/uso terapéutico , Femenino , Estudios de Seguimiento , Humanos , Hipoglucemiantes/uso terapéutico , Hipolipemiantes/uso terapéutico , Masculino , Metformina/uso terapéutico , Persona de Mediana Edad , Factores de Riesgo , Conducta de Reducción del RiesgoRESUMEN
OBJECTIVE: To assess whether treatment of advanced periodontal disease affects plasma levels of serum amyloid A (SAA) and phospholipid transfer protein (PLTP) activity. DESIGN: We measured the levels of SAA and PLTP activity in plasma of 66 patients with advanced periodontal disease before and after treatment by full-mouth tooth extraction (FME). RESULTS: At baseline, median SAA levels in our study population were within the normal range (2.7 microg ml(-1)) but SAA was elevated (>5 microg ml(-1)) in 18% of periodontitis patients. Three months after FME, SAA levels were significantly reduced (P = 0.04). SAA did not correlate with any of the periodontal disease parameters. PLTP activity was elevated in patients with periodontitis, compared to the PLTP activity reference group (age-matched systemically healthy adults, n = 29; 18 micromol ml(-1) h(-1)vs 13 micromol ml(-1) h(-1), respectively, P = 0.002). PLTP activity inversely correlated with average periodontal pocket depth (PPD) per tooth (r(s) = -0.372; P = 0.002). Three months after FME, median PLTP activity did not change significantly. CONCLUSIONS: Full-mouth tooth extraction significantly reduces SAA, a marker of inflammation, while it does not affect plasma PLTP activity. However, the inverse correlation between PLTP activity and average PPD suggests that increased PLTP activity may limit periodontal tissue damage.
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Enfermedades Periodontales/terapia , Proteínas de Transferencia de Fosfolípidos/sangre , Proteína Amiloide A Sérica/análisis , Extracción Dental , Adulto , Proteína C-Reactiva/análisis , Estudios de Casos y Controles , Estudios de Cohortes , Enfermedad Coronaria/genética , Complicaciones de la Diabetes , Femenino , Estudios de Seguimiento , Recesión Gingival/terapia , Humanos , Hiperlipidemias/complicaciones , Hipertensión/complicaciones , Recuento de Leucocitos , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Neutrófilos/patología , Pérdida de la Inserción Periodontal/terapia , Enfermedades Periodontales/sangre , Bolsa Periodontal/sangre , Bolsa Periodontal/terapia , Periodontitis/sangre , Periodontitis/terapia , Enfermedades Vasculares Periféricas/complicaciones , Factores de Riesgo , FumarRESUMEN
Numerous studies have suggested a role of the kidney in lipoprotein(a) (Lp(a)) catabolism, but direct evidence is still lacking. Frischmann et al. demonstrate that the marked elevation of Lp(a) observed in hemodialysis patients results from a decrease in Lp(a) clearance rather than an increase in Lp(a) production, consistent with the notion that the kidney degrades Lp(a). More studies are needed to prove the biological relevance.
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Riñón/metabolismo , Lipoproteína(a)/metabolismo , Humanos , Metabolismo/fisiología , Diálisis RenalRESUMEN
This report from the first International Course on Integrated Biomarkers, Biochemical and Bioimaging Endpoints in Cardiovascular Diagnosis, Prevention, Therapy and Drug Development provides the basis for optimizing diagnostic, prognostic and therapeutic information in four areas of cardiovascular medicine: primary prevention of cardiovascular diseases, acute coronary syndromes, heart failure and stroke. Risk stratification and treatment strategies can be refined and enhanced through integration of bioimaging and biochemical markers to characterize sub-clinical and clinical atherosclerosis. For the integrative approach to be useful, each of the biomarkers must be validated and cost-effective. Clinical decision is the primary level of integration and is based on clinical evaluation and the use of a combination of bioimaging and biochemical markers. The decision to initiate preventive or therapeutic intervention must take into account the factors affecting the levels of expression of the biomarker and the potential input the biomarker has on metabolic processes or modulation of other biomarkers. The optimal approach to intervention must take into consideration the risk-benefit and cost-effectiveness ratios.
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Biomarcadores/sangre , Enfermedades Cardiovasculares/diagnóstico , Diagnóstico por Imagen/métodos , Enfermedades Cardiovasculares/complicaciones , Humanos , Medición de Riesgo , Accidente Cerebrovascular/complicaciones , Accidente Cerebrovascular/diagnósticoRESUMEN
BACKGROUND: The extent which universally common or population-specific alleles can explain between-population variations in phenotypes is unknown. The heritable coronary heart disease risk factor lipoprotein(a) (Lp(a)) level provides a useful case study of between-population variation, as the aetiology of twofold higher Lp(a) levels in African populations compared with non-African populations is unknown. OBJECTIVE: To evaluate the association between LPA sequence variations and Lp(a) in European Americans and African Americans and to determine the extent to which LPA sequence variations can account for between-population variations in Lp(a). METHODS: Serum Lp(a) and isoform measurements were examined in 534 European Americans and 249 African Americans from the Choices for Healthy Outcomes in Caring for End-Stage Renal Disease Study. In addition, 12 LPA variants were genotyped, including 8 previously reported LPA variants with a frequency of >2% in European Americans or African Americans, and four new variants. RESULTS: Isoform-adjusted Lp(a) level was 2.23-fold higher among African Americans. Three single-nucleotide polymorphisms (SNPs) were independently associated with Lp(a) level (p<0.02 in both populations). The Lp(a)-increasing SNP (G-21A, which increases promoter activity) was more common in African Americans, whereas the Lp(a)-lowering SNPs (T3888P and G+1/inKIV-8A, which inhibit Lp(a) assembly) were more common in European Americans, but all had a frequency of <20% in one or both populations. Together, they reduced the isoform-adjusted African American Lp(a) increase from 2.23 to 1.37-fold(a 60% reduction) and the between-population Lp(a) variance from 5.5% to 0.5%. CONCLUSIONS: Multiple low-prevalence alleles in LPA can account for the large between-population difference in serum Lp(a) levels between European Americans and African Americans.
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Negro o Afroamericano/genética , Lipoproteína(a)/genética , Polimorfismo de Nucleótido Simple/genética , Población Blanca/genética , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Alelos , Estudios de Cohortes , Frecuencia de los Genes , Humanos , Fallo Renal Crónico/sangre , Fallo Renal Crónico/genética , Fallo Renal Crónico/terapia , Desequilibrio de Ligamiento , Lipoproteína(a)/sangre , Persona de Mediana EdadRESUMEN
AIMS/HYPOTHESIS: Conformation-dependent autoantibodies directed against GAD65 are markers of Type 1 diabetes. In this study we aimed to determine whether the substitution of GAD65 with GAD67 amino acids would affect the binding of conformation-dependent GAD65 autoantibodies. METHODS: We used PCR-based site-directed mutagenesis to generate a series of mutated GAD65 cDNA constructs in which specific GAD65 coding sequences for regions of the protein critical for autoantibody binding were replaced with GAD67 coding sequences. RESULTS: The introduction of a point mutation at position 517, substituting glutamic acid with proline, markedly reduced the binding of disease-associated GAD65 antibodies. The binding of GAD65 antibodies to the E517P mutant was reduced in the sera of all newly diagnosed Type 1 diabetes patients ( n=85) by a mean of 72% ( p<0.0001) compared with binding to wild-type GAD65. Patients with latent autoimmune diabetes in adults ( n=24) showed a similar reduction in binding (79% reduction, p<0.0001). First-degree relatives who subsequently progressed to Type 1 diabetes ( n=12) showed a reduction in binding of 80% compared with a reduction of only 65% among relatives who had not progressed to disease ( n=38; p=0.025). In healthy GAD65Ab-positive individuals who did not progress to diabetes during a 9-year follow-up period ( n=51), binding to GAD65-E517P was reduced by only 28% compared with binding to wild-type GAD65. CONCLUSIONS/INTERPRETATION: Differences in autoantibody binding to wild-type GAD65 versus GAD65-E517P may provide predictive information about Type 1 diabetes risk beyond that provided by the presence or absence of GAD65 autoantibodies. Lack of binding to mutant GAD65-E517P defines GAD65-positive individuals who are at higher risk of developing diabetes.
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Autoanticuerpos/química , Diabetes Mellitus Tipo 1/inmunología , Glutamato Descarboxilasa/inmunología , Isoenzimas/inmunología , Secuencia de Aminoácidos , Animales , Anticuerpos Monoclonales , Autoanticuerpos/sangre , Secuencia de Bases , Sitios de Unión , Diabetes Mellitus Tipo 1/sangre , Progresión de la Enfermedad , Familia , Glutamato Descarboxilasa/genética , Humanos , Isoenzimas/genética , Datos de Secuencia Molecular , Mutación , Fragmentos de Péptidos/química , Reacción en Cadena de la Polimerasa , Conformación Proteica , Conejos , Valores de ReferenciaRESUMEN
BACKGROUND AND AIMS: Serum leptin levels are elevated in patients with kidney failure. Data on the associations of serum leptin and on the relationship of leptin with both kidney function and inflammation, are limited in patients with reduced glomerular filtration rate (GFR). We evaluated the independent associations of serum leptin in patients with reduced GFR. MATERIAL AND METHODS: Serum leptin and C-reactive protein (CRP) were measured in samples from 798 participants of the Modification of Diet in Renal Disease Study. Multivariable analysis was used to evaluate the independent effects of kidney function and CRP on leptin levels. RESULTS: Median (interquartile range) of serum leptin was 9.1 ng/ml (14.0). Female gender, higher percent body fat, higher insulin levels, older age, lower GFR and higher CRP were associated with higher serum leptin levels and explained 51% of the variability in the logarithm of serum leptin levels. After adjusting for the other variables, a 10 ml/min/1.73 m2 lower GFR was associated with 6% higher mean serum leptin levels. Percent body fat and gender, explained 45% of the variability in serum leptin levels. CONCLUSIONS: Level of kidney function and CRP are associated with serum leptin in patients with reduced GFR. However, there is a stronger association between serum leptin and indices of body fat and gender in patients in the earlier stages of chronic kidney disease. 50% of the variability remains unexplained in patients with reduced GFR.
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Fallo Renal Crónico/sangre , Leptina/sangre , Índice de Masa Corporal , Proteína C-Reactiva/análisis , Femenino , Tasa de Filtración Glomerular , Humanos , Insulina/sangre , Fallo Renal Crónico/fisiopatología , Masculino , Persona de Mediana Edad , Análisis Multivariante , Factores SexualesRESUMEN
The risk of cardiovascular disease is increased approximately two- to four-fold in patients with diabetes mellitus compared with non-diabetic controls. The nature of this increased risk cannot be completely explained by the contribution of traditional risk factors. As such, there has been a great deal of interest in assessing the role of lipoprotein(a) (Lp(a)), an LDL-like lipoprotein, in the vascular complications of diabetes. Although numerous studies in the non-diabetic population have demonstrated an association between elevated plasma Lp(a) concentration and risk for atherosclerotic disorders, the contribution of Lp(a) to the enhanced risk of vascular disease in the diabetic population is not clearly defined. Herein we review the structure and potential functions of Lp(a), the determination of Lp(a) levels, and the epidemiological evidence supporting its role in coronary heart disease and address the following controversial questions regarding the role of Lp(a) in diabetes mellitus: (1) are plasma Lp(a) levels and phenotype distributions altered in type 1 (insulin-dependent) diabetes mellitus and type 2 (non-insulin-dependent) diabetes mellitus and does the degree of metabolic control influence Lp(a) levels in these patients; (2) what is the relationship between Lp(a) and renal disease in patients with diabetes mellitus; (3) do increased plasma Lp(a) concentrations in patients with diabetes contribute to the vascular complications of this disease; and (4) can the atherogenicity of Lp(a) in diabetes be enhanced in the absence of elevated levels of this lipoprotein due to biochemical modifications.
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Complicaciones de la Diabetes , Lipoproteína(a)/sangre , Arteriosclerosis/sangre , Arteriosclerosis/fisiopatología , Enfermedad Coronaria/epidemiología , Diabetes Mellitus/sangre , Diabetes Mellitus Tipo 1/sangre , Angiopatías Diabéticas/sangre , Angiopatías Diabéticas/fisiopatología , Humanos , Factores de RiesgoRESUMEN
In order to characterize the lipoprotein abnormalities in familial combined hyperlipidemia (FCHL) and to describe factors associated with the stability of the FCHL phenotype during 20-year follow-up, 287 individuals from 48 families with FCHL originally identified in the early 1970s (baseline) were studied. Hyperlipidemia was defined as lipid-lowering medication use, or > or =age- and sex-specific 90th percentile for triglycerides or cholesterol. Triglyceride, cholesterol and medical history data were obtained at baseline and 20-year follow-up. Additional follow-up measures included HDL-C, LDL-C, LDL particle size, lipoprotein(a), apolipoprotein (apo) A-I, apoB, and apoE polymorphism. Longitudinally, two-thirds of relatives were consistently normolipidemic or hyperlipidemic, and one third were discordant for hyperlipidemic status at baseline and 20-year follow-up. Individuals with hyperlipidemia at baseline and/or follow-up had higher apoB levels than those with consistently normal lipids (P<0.05), whereas small LDL size was associated with concurrent hyperlipidemia. Among individuals who were normolipidemic at baseline, the following variables were independently associated with development of hyperlipidemia over 20 years: older age at baseline, male sex, greater increase in BMI during follow-up, and apoE alleles epsilon 2 or epsilon 4. In conclusion, apoB is associated with hyperlipidemia and apoE polymorphism is associated with later onset of hyperlipidemia in FCHL.
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Apolipoproteínas/genética , Hiperlipidemia Familiar Combinada/genética , Lipoproteínas/genética , Polimorfismo Genético , Adulto , Distribución por Edad , Apolipoproteína A-I/análisis , Apolipoproteína A-I/genética , Apolipoproteínas/sangre , Niño , HDL-Colesterol/sangre , HDL-Colesterol/genética , LDL-Colesterol/sangre , LDL-Colesterol/genética , Femenino , Estudios de Seguimiento , Humanos , Hiperlipidemia Familiar Combinada/epidemiología , Incidencia , Lipoproteínas/sangre , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Linaje , Probabilidad , Estudios Prospectivos , Valores de Referencia , Factores de Riesgo , Distribución por SexoRESUMEN
Lipoprotein(a) [Lp(a)] is a unique lipoprotein which resembles low-density lipoprotein (LDL) both in lipid composition and the presence of apolipoprotein B-100 (apo B-100). Lp(a) is, however, distinguishable from LDL by the presence of an additional glycoprotein apolipoprotein(a) [apo(a)], which is covalently attached to apo B-100 by a single disulfide bond. It is now generally accepted that Lp(a) assembly is a two-step process in which the initial non-covalent interaction between apo(a) and apo B-100 is mediated by the weak lysine binding sites present in kringle IV types 6, 7 and 8 of apo(a). In the present study, we have investigated the effect of LDL heterogeneity on Lp(a) assembly in a group of 111 individuals. The three parameters of LDL composition assessed in this study were the cholesterol content, the apo B content, and the relative flotation rate (a measure of LDL buoyancy and thus size). We found no correlation between the size of LDL particles and the extent of Lp(a) formation; a weak negative correlation was observed between cholesterol content of LDL and Lp(a) formation (P=0.042). This may suggest a role for free (i.e., surface-associated) cholesterol in the ability of LDL to form Lp(a) particles.
Asunto(s)
Colesterol/química , Lipoproteína(a)/química , Lipoproteínas LDL/químicaRESUMEN
Most but not all epidemiologic studies have shown that lipoprotein(a) [Lp(a)] is a risk factor for cardiovascular disease (CVD). Lp(a) levels are also strongly genetically influenced. The purpose of this study was to evaluate the association between Lp(a) levels in adult offspring and parental CVD mortality in 61 kindreds with familial forms of hyperlipidemia. The study sample consisted of offspring-parent pairs in which offspring had fasting Lp(a) measurements and parents had 20-year vital status data and standardized cause-of-death classification if deceased. Linear regression analyses, using a robust variance estimator, were performed separately for 241 offspring with known maternal history (114 mothers) and 194 offspring with known paternal history (93 fathers). Maternal history of CVD mortality was significantly (p=0.004) associated with 2.4-fold higher median Lp(a) levels in offspring compared with those with no maternal history, independent of diabetes, lipid-lowering medications and hormone use. No association was observed between paternal CVD mortality and offspring Lp(a) levels (p=0.505). Adjusting for apolipoprotein(a) kringle 4 number did not alter these parent-specific associations. In conclusion, Lp(a) levels in offspring may be associated with maternal but not paternal history of CVD mortality. This parent-specific finding needs to be confirmed in other samples of high-risk families.
Asunto(s)
Enfermedades Cardiovasculares/diagnóstico , Enfermedades Cardiovasculares/etiología , Hiperlipidemia Familiar Combinada/diagnóstico , Hiperlipidemia Familiar Combinada/genética , Hipertrigliceridemia/diagnóstico , Hipertrigliceridemia/genética , Lipoproteína(a)/biosíntesis , Lipoproteína(a)/química , Lipoproteína(a)/genética , Adolescente , Adulto , Enfermedades Cardiovasculares/mortalidad , Colesterol/metabolismo , Relación Dosis-Respuesta a Droga , Salud de la Familia , Padre , Femenino , Estudios de Seguimiento , Humanos , Hiperlipidemia Familiar Combinada/mortalidad , Kringles , Modelos Lineales , Masculino , Persona de Mediana Edad , Madres , Linaje , Polimorfismo Genético , Factores de Riesgo , Factores de TiempoRESUMEN
Lipoprotein(a) is composed of low-density lipoprotein linked both covalently and noncovalently to apolipoprotein(a). The structure of lipoprotein(a) and the interactions between low-density lipoprotein and apolipoprotein(a) were investigated by electron microscopy and correlated with analytical ultracentrifugation. Electron microscopy of rotary-shadowed and unidirectionally shadowed lipoprotein(a) prepared without glycerol revealed that it is a nearly spherical particle with no large projections. After extraction of both lipoprotein(a) and low-density lipoprotein with glycerol prior to rotary shadowing, the protein components were observed to consist of a ring of density made up of nodules of different sizes, with apolipoprotein(a) and apolipoprotein B-100 closely associated with each other. However, when lipoprotein(a) was treated with a lysine analogue, 6-aminohexanoic acid, much of the apolipoprotein(a) separated from the apolipoprotein B-100. In 6-aminohexanoic acid-treated preparations without glycerol extraction, lipoprotein(a) particles had an irregular mass of density around the core. In contrast, lipoprotein(a) particles treated with 6-aminohexanoic acid in the presence of glycerol had a long tail, in which individual kringles could be distinguished, extending from the ring of apolipoprotein B-100. The length of the tail was dependent on the particular isoform of apolipoprotein(a). Dissociation of the noncovalent interactions between apolipoprotein(a) and low-density lipoprotein as a result of shear forces or changes in the microenvironment may contribute to selective retention of lipoprotein(a) in the vasculature.
Asunto(s)
Lipoproteína(a)/química , LDL-Colesterol/química , LDL-Colesterol/ultraestructura , Ligandos , Lipoproteína(a)/ultraestructura , Lisina/química , Unión Proteica , Conformación Proteica , Isoformas de Proteínas/química , Isoformas de Proteínas/ultraestructura , UltracentrifugaciónRESUMEN
We have previously shown that lipoprotein(a) (Lp(a)) assembly involves an initial noncovalent interaction between sequences within apolipoprotein(a) (apo(a)) kringle IV types 5-8 and the amino terminus of apolipoprotein B-100 (sequences between amino acids 680 and 781 in apoB-100), followed by formation of a disulfide bond. In the present study, citraconylation of lysine residues in apoB-100 abolished the ability of the modified low density lipoprotein to associate with apo(a), thereby demonstrating a direct role for lysine residues in apoB in the first step of Lp(a) assembly. To identify specific lysine residues in the amino terminus of apoB that are required for the noncovalent interaction, we initially used an affinity chromatography method in which recombinant forms of apo(a) (r-apo(a)) were immobilized on Sepharose beads. Assessment of the ability of carboxyl-terminal truncations of apoB-18 to bind to r-apo(a)-Sepharose revealed that a 25-amino acid sequence in apoB (amino acids 680-704) bound specifically to apo(a) in a lysine-dependent manner; citraconylation of the lysine residues in the apoB derivative encoding this sequence abolished the binding interaction. Using fluorescence spectrometry, we found that a synthetic peptide corresponding to this sequence bound directly to apo(a); the peptide also reduced covalent Lp(a) formation. Lysine residues present in this sequence (Lys(680) and Lys(690)) were mutated to alanine in the context of apoB-18. We found that the apoB-18 species containing the Lys(680) mutation was incapable of binding to r-apo(a)-Sepharose columns, whereas the apoB-18 species containing the Lys(690) mutation exhibited slightly reduced binding to these columns. Taken together, our data indicate that Lys(680) is critical for the noncovalent interaction of apo(a) and apoB-100 that precedes covalent Lp(a) formation.
Asunto(s)
Apolipoproteínas B/química , Lisina/química , Alanina/química , Apolipoproteína B-100 , Apolipoproteínas B/aislamiento & purificación , Apolipoproteínas B/metabolismo , Cromatografía de Afinidad , Cromatografía en Agarosa , Anhídridos Citracónicos/farmacología , Disulfuros , Relación Dosis-Respuesta a Droga , Ensayo de Inmunoadsorción Enzimática , Humanos , Cinética , Lipoproteínas LDL/química , Lipoproteínas LDL/metabolismo , Mutación , Unión Proteica , Proteínas Recombinantes/metabolismo , Espectrometría de Fluorescencia , Factores de TiempoRESUMEN
This cross-sectional study was undertaken to examine the relationship between plasma lipoprotein(a) [Lp(a)] level and peritoneal dialysis (PD) albumin clearance while controlling for the influence of the apolipoprotein(a) [apo(a)] phenotype. Plasma Lp(a) level, PD albumin clearance, and apo(a) phenotype (high vs. low molecular weight, HMW vs. LMW) were determined in 54 PD patients. Apo(a) phenotypes were 24 LMW and 30 HMW. The plasma Lp(a) level was high (> 65 nmol/l) in 17 of 24 patients with LMW phenotype versus 2 of 30 with HMW phenotype (chi2, p < 0.01). Spearman correlation coefficients of Lp(a) with PD, urine, and total albumin clearances were -0.05 (p = 0.74), -0.04 (p = 0.80), and -0.09 (p = 0.51), respectively. The apo(a) isoform size was the only significant predictor of Lp(a) in multivariate analysis. In this study, there was no association between PD albumin clearance and Lp(a) level. The association between apo(a) phenotype and Lp(a) level is in keeping with studies in the general population. There is a strong genetic influence on Lp(a) level in PD patients.
Asunto(s)
Albúminas/metabolismo , Apolipoproteínas A/genética , Lipoproteína(a)/metabolismo , Diálisis Peritoneal , Estudios Transversales , Ensayo de Inmunoadsorción Enzimática , Femenino , Humanos , Masculino , Persona de Mediana Edad , Peso Molecular , FenotipoRESUMEN
BACKGROUND: The relation between a family history of heart attack and the occurrence of early myocardial infarction (MI) has not been studied extensively in women. In addition, whether recognized and newly-identified coronary heart disease (CHD) risk factors account for the familial aggregation of these events remains unknown. We therefore examined these questions in a population-based case-control study among female 18- to 44-year-old residents of western Washington State. METHODS AND RESULTS: The patients consisted of 107 women with first acute MI, and the control subjects comprised 526 women similar in age identified from the community and without a history of recognized clinical coronary heart disease or stroke. Trained interviewers used a structured questionnaire to elicit a detailed history of heart attack in first-degree relatives. Information about other known MI risk factors was collected and biochemical measurements performed, and common polymorphisms in various candidate genes were determined. The rate of MI among first-degree relatives of MI cases was twice as high as among first-degree relatives of controls (relative risk, 1.96; 95% confidence interval (CI), 1.46-2.48); this association was present for each familial relationship. Sibling history of MI but not parental history was associated with MI, after controlling for established CHD risk factors. In a subsample of subjects with blood measurements, further adjustment for lipids, lipoproteins and specific genetic risk factors slightly reduced the association with sibling MI history (from odds ratio (OR), 5.17; 95% CI, 1.93-13.85 to OR, 3.97; 95% CI, 0.92-17.17). CONCLUSION: Family history of MI is positively associated with the risk of early MI in women. While the association with parental history of MI is mediated through the clustering of other common risk factors, the association of sibling history of MI with early-onset MI in young women is only partially explained by the clustering of established and newly-identified risk factors.