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Aterosclerosis , Diabetes Mellitus Tipo 2 , Angiopatías Diabéticas , Metabolismo de los Lípidos , Lípidos/sangre , Aterosclerosis/sangre , Aterosclerosis/tratamiento farmacológico , Diabetes Mellitus Tipo 2/sangre , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Angiopatías Diabéticas/sangre , Angiopatías Diabéticas/tratamiento farmacológico , Humanos , Guías de Práctica Clínica como AsuntoRESUMEN
Serum levels of interleukin-6 (IL-6) are increased in patients with type 2 diabetes (T2D). IL-6 exerts its pleiotropic effects via the IL-6 α-receptor (IL-6R), which exists in membrane-bound and soluble (sIL-6R) forms and activates cells via the ß-receptor glycoprotein 130 (gp130). The nonsynonymous single-nucleotide polymorphism (SNP) rs2228145 (Asp358Ala) within the IL6R locus is associated with T2D. The aim of this study was to determine whether sIL-6R in combination with soluble gp130 (sgp130) is able to form an IL-6-neutralizing buffer in healthy subjects and whether this is disturbed in T2D. We found that sIL-6R-sgp130 indeed forms an IL-6-neutralizing buffer in the serum of healthy humans, whose capacity is controlled by the SNP of the IL-6R. Circulating sIL-6R-sgp130 levels were lower in T2D subjects (P < 0.001), whereas IL-6 was high and inversely correlated with sIL-6R (r = -0.57, P < 0.001), indicating a severe disturbance of the buffer. This phenomenon is also observed in sex- and age-matched patients with both T2D and atherosclerosis but not in patients with atherosclerosis alone. In conclusion, sIL-6R and sgp130 serum levels were significantly lower in T2D patients compared with healthy subjects or atherosclerosis patients, although IL-6 levels were high. These data suggest that disturbance of the protective buffer may be closely associated with T2D pathophysiology.
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Receptor gp130 de Citocinas/sangre , Diabetes Mellitus Tipo 2/sangre , Interleucina-6/antagonistas & inhibidores , Receptores de Interleucina-6/sangre , Anciano , Sustitución de Aminoácidos , Aterosclerosis/sangre , Aterosclerosis/etiología , Estudios de Casos y Controles , Receptor gp130 de Citocinas/metabolismo , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/metabolismo , Femenino , Células Hep G2 , Humanos , Interleucina-6/sangre , Interleucina-6/farmacología , Masculino , Persona de Mediana Edad , Fosforilación/efectos de los fármacos , Polimorfismo de Nucleótido Simple , Unión Proteica , Receptores de Interleucina-6/genética , Receptores de Interleucina-6/metabolismo , Factor de Transcripción STAT3/genética , Factor de Transcripción STAT3/metabolismo , Transducción de Señal/efectos de los fármacos , Transducción de Señal/genéticaRESUMEN
Lipoprotein (a) [Lp(a)] is a highly atherogenic lipid particle. Although earlier reports suggested that Lp(a) levels are mostly determined by genetic factors, several recent studies have revealed that Lp(a) induction is also caused by chronic inflammation. Therefore, we aimed to examine whether cytokine blockade by monoclonal antibodies may inhibit Lp(a) metabolism. We found that interleukin 6 (IL-6) blockade by tocilizumab (TCZ) reduced Lp(a) while TNF-α-inhibition by adalimumab in humans had no effect. The specificity of IL-6 in regulating Lp(a) was further demonstrated by serological measurements of human subjects (n = 1,153) revealing that Lp(a) levels are increased in individuals with elevated serum IL-6. Transcriptomic analysis of human liver biopsies (n = 57) revealed typical IL-6 response genes being correlated with the LPA gene expression in vivo. On a molecular level, we found that TCZ inhibited IL-6-induced LPA mRNA and protein expression in human hepatocytes. Furthermore, examination of IL-6-responsive signal transducer and activator of transcription 3 binding sites within the LPA promoter by reporter gene assays, promoter deletion experiments, and electrophoretic mobility shift assay analysis showed that the Lp(a)-lowering effect of TCZ is specifically mediated via a responsive element at -46 to -40. Therefore, IL-6 blockade might be a potential therapeutic option to treat elevated Lp(a) serum concentrations in humans and might be a noninvasive alternative to lipid apheresis in the future.
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Anticuerpos Monoclonales Humanizados/farmacología , Apoproteína(a)/sangre , Artritis Reumatoide/tratamiento farmacológico , Interleucina-6/antagonistas & inhibidores , Biosíntesis de Proteínas/efectos de los fármacos , Adalimumab/farmacología , Antirreumáticos/farmacología , Apoproteína(a)/genética , Artritis Reumatoide/metabolismo , Femenino , Células Hep G2 , Humanos , Interleucina-6/sangre , Interleucina-6/genética , Hígado/metabolismo , Masculino , Persona de Mediana Edad , Elementos de Respuesta , Factor de Transcripción STAT3/genética , Factor de Transcripción STAT3/metabolismoRESUMEN
CONTEXT AND OBJECTIVE: Investigating the effects of lipid-lowering drugs on HDL subclasses has shown ambiguous results. This study assessed the effects of ezetimibe, simvastatin, and their combination on HDL subclass distribution. DESIGN AND PARTICIPANTS: A single-center randomized parallel 3-group open-label study was performed in 72 healthy men free of cardiovascular disease with a baseline LDL-cholesterol of 111±30 mg/dl (2.9±0.8 mmol/l) and a baseline HDL-cholesterol of 64±15 mg/dl (1.7±0.4 mmol/l). They were treated with ezetimibe (10 mg/day, nâ=â24), simvastatin (40 mg/day, nâ=â24) or their combination (nâ=â24) for 14 days. Blood was drawn before and after the treatment period. HDL subclasses were determined using polyacrylamide gel-tube electrophoresis. Multivariate regression models were used to determine the influence of treatment and covariates on changes in HDL subclass composition. RESULTS: Baseline HDL subclasses consisted of 33±10% large, 48±6% intermediate and 19±8% small HDL. After adjusting for baseline HDL subclass distribution, body mass index, LDL-C and the ratio triglycerides/HDL-C, there was a significant increase in large HDL by about 3.9 percentage points (P<0.05) and a decrease in intermediate HDL by about 3.5 percentage points (P<0.01) in both simvastatin-containing treatment arms in comparison to ezetimibe. The parameters obtained after additional adjustment for the decrease in LDL-C indicated that about one third to one half of these effects could be explained by the extent of LDL-C-lowering. CONCLUSIONS: In healthy men, treatment with simvastatin leads to favorable effects on HDL subclass composition, which was not be observed with ezetimibe. Part of these differential effects may be due to the stronger LDL-C-lowering effects of simvastatin. TRIAL REGISTRATION: ClinicalTrials.gov NCT00317993.
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Azetidinas/farmacología , Voluntarios Sanos , Hipolipemiantes/farmacología , Lipoproteínas HDL/sangre , Simvastatina/farmacología , Adipoquinas/sangre , Adulto , Azetidinas/uso terapéutico , Biomarcadores/sangre , Quimioterapia Combinada , Ezetimiba , Glucosa/metabolismo , Humanos , Hipercolesterolemia/sangre , Hipercolesterolemia/tratamiento farmacológico , Hipercolesterolemia/metabolismo , Hipolipemiantes/uso terapéutico , Masculino , Simvastatina/uso terapéuticoRESUMEN
CONTEXT AND OBJECTIVE: The myokine irisin has been proposed to regulate energy homeostasis. Little is known about its association with metabolic parameters and especially with parameters influencing pathways of lipid metabolism. In the context of a clinical trial, an exploratory post hoc analysis has been performed in healthy subjects to determine whether simvastatin and/or ezetimibe influence serum irisin levels. The direct effects of simvastatin on irisin were also examined in primary human skeletal muscle cells (HSKMCs). DESIGN AND PARTICIPANTS: A randomized, parallel 3-group study was performed in 72 men with mild hypercholesterolemia and without apparent cardiovascular disease. Each group of 24 subjects received a 14-day treatment with either simvastatin 40 mg, ezetimibe 10 mg, or their combination. RESULTS: Baseline irisin concentrations were not significantly correlated with age, BMI, estimated GFR, thyroid parameters, glucose, insulin, lipoproteins, non-cholesterol sterols, adipokines, inflammation markers and various molecular markers of cholesterol metabolism. Circulating irisin increased significantly in simvastatin-treated but not in ezetimibe-treated subjects. The changes were independent of changes in LDL-cholesterol and were not correlated with changes in creatine kinase levels. In HSKMCs, simvastatin significantly increased irisin secretion as well as mRNA expression of its parent peptide hormone FNDC5. Simvastatin significantly induced cellular reactive oxygen species levels along with expression of pro- and anti-oxidative genes such as Nox2, and MnSOD and catalase, respectively. Markers of cellular stress such as atrogin-1 mRNA and Bax protein expression were also induced by simvastatin. Decreased cell viability and increased irisin secretion by simvastatin was reversed by antioxidant mito-TEMPO, implying in part that irisin is secreted as a result of increased mitochondrial oxidative stress and subsequent myocyte damage. CONCLUSIONS: Simvastatin increases irisin concentrations in vivo and in vitro. It remains to be determined whether this increase is a result of muscle damage or a protective mechanism against simvastatin-induced cellular stress. TRIAL REGISTRATION: ClinicalTrials.gov NCT00317993 NCT00317993.
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Fibronectinas/sangre , Hipolipemiantes/farmacología , Músculo Esquelético/efectos de los fármacos , Músculo Esquelético/metabolismo , Adulto , Azetidinas/farmacología , Supervivencia Celular/efectos de los fármacos , Células Cultivadas , Ezetimiba , Femenino , Humanos , Masculino , Persona de Mediana Edad , Músculo Esquelético/citología , Simvastatina/farmacología , Adulto JovenRESUMEN
OBJECTIVES: Statins decrease cardiovascular events mainly by lowering cholesterol but anti-inflammatory effects also play a role. The effects of the cholesterol absorption inhibitor ezetimibe on markers of inflammation remain unclear. We performed an exploratory post-hoc analysis whether these drugs influence the pro-inflammatory markers interleukin-6 and high-sensitivity C-reactive protein in subjects with very-low cardiovascular risk. DESIGN: Single center, randomized, parallel 3-group study in 72 healthy men without apparent cardiovascular disease (age 32 ± 9 years, BMI 25.7 ± 3.2 kg/m(2)). Each group of 24 subjects received a 14-day treatment with either simvastatin 40 mg, ezetimibe 10 mg, or their combination. RESULTS: Baseline IL-6 and hsCRP concentrations in the total cohort were 0.72 ± 0.57 ng/l and 0.40 ± 0.65 mg/l, respectively, with no differences between the 3 groups. Median changes (interquartile range) in IL-6 and hsCRP concentrations were -22% (-43 to 0%) and -30% (-44 to +19%) after simvastatin, -5% (-36 to +30%) and +9% (-22 to +107%) after ezetimibe, and +15% (-15 to +86%) and +1 (-30 to +49%) after the combination. Using a generalized linear model, the multivariable adjusted overall P-values for these changes were 0.008 (IL-6) and 0.1 (hsCRP). CONCLUSIONS: Simvastatin decreases the pro-inflammatory markers IL-6 and almost significantly hsCRP while ezetimibe monotherapy or the combination with simvastatin has no effect.
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Antiinflamatorios/administración & dosificación , Anticolesterolemiantes/administración & dosificación , Azetidinas/administración & dosificación , Proteína C-Reactiva/metabolismo , Inhibidores de Hidroximetilglutaril-CoA Reductasas/administración & dosificación , Mediadores de Inflamación/sangre , Interleucina-6/sangre , Simvastatina/administración & dosificación , Adulto , Biomarcadores/sangre , Esquema de Medicación , Combinación de Medicamentos , Ezetimiba , Combinación Ezetimiba y Simvastatina , Alemania , Humanos , Modelos Lineales , Masculino , Persona de Mediana Edad , Análisis Multivariante , Estudios Prospectivos , Factores de Tiempo , Adulto JovenRESUMEN
In brains from patients with Alzheimer's disease (AD), expression of insulin receptor (IR), insulin-like growth factor-1 receptor (IGF-1R), and insulin receptor substrate proteins is downregulated. A key step in the pathogenesis of AD is the accumulation of amyloid precursor protein (APP) cleavage products, ß-amyloid (Aß)(1-42) and Aß(1-40). Recently, we and others have shown that central IGF-1 resistance reduces Aß accumulation as well as Aß toxicity and promotes survival. To define the role of IR in this context, we crossed neuron-specific IR knockout mice (nIR(-/-)) with Tg2576 mice, a well-established mouse model of an AD-like pathology. Here, we show that neuronal IR deficiency in Tg2576 (nIR(-/-)Tg2576) mice leads to markedly decreased Aß burden but does not rescue premature mortality of Tg2576 mice. Analyzing APP C-terminal fragments (CTF) revealed decreased α-/ß-CTFs in the brains of nIR(-/-)Tg2576 mice suggesting decreased APP processing. Cell based experiments showed that inhibition of the PI3-kinase pathway suppresses endosomal APP cleavage and decreases α- as well as ß-secretase activity. Deletion of only one copy of the neuronal IGF-1R partially rescues the premature mortality of Tg2576 mice without altering total amyloid load. Analysis of Tg2576 mice expressing either a dominant negative or constitutively active form of forkhead box-O (FoxO)1 did not reveal any alteration of amyloid burden, APP processing and did not rescue premature mortality in these mice. Thus, our findings identified IR signaling as a potent regulator of Aß accumulation in vivo. But exclusively decreased IGF-1R expression reduces AD-associated mortality independent of ß-amyloid accumulation and FoxO1-mediated transcription.
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Enfermedad de Alzheimer/metabolismo , Precursor de Proteína beta-Amiloide/metabolismo , Receptor de Insulina/metabolismo , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/mortalidad , Péptidos beta-Amiloides , Animales , Modelos Animales de Enfermedad , Ensayo de Inmunoadsorción Enzimática , Genotipo , Humanos , Immunoblotting , Proteínas Sustrato del Receptor de Insulina/metabolismo , Ratones , Ratones Transgénicos , Transducción de Señal/genéticaRESUMEN
AIMS: Selenium is an antioxidant micronutrient with potential associations with hypertension. Few studies have investigated the association of serum selenium concentrations with blood pressure and hypertension in countries with low dietary selenium intake such as Germany, with inconsistent findings. METHODS: We undertook a cross-sectional analysis of participants in the Lipid Analytic Cologne (LIANCO) cohort. To reduce potential confounding, we restricted the analysis to 792 participants who were never smokers, who did not use antihypertensive medications, and who did not have diabetes or known atherosclerotic disease. Hypertension was defined as blood pressure at least 140 and/or at least 90â mmHg. About half of the cohort was diagnosed as hypertensive. Selenium was measured by inductively coupled plasma-dynamic reaction cell-mass spectrometry (ICP-DRC-MS). RESULTS: Mean ± standard deviation (SD) serum selenium concentration was 68â ±â 32 µg/l. The multivariable adjusted differences (95% confidence intervals) in blood pressure levels comparing the highest (>91.9âµg/l) to the lowest (≤ 42.8 µg/l) quartile of serum selenium were 5.2 (1.4 to 8.9), 2.8 (0.7 to 4.8), and 2.4 (-0.4 to 5.2) mmHg for systolic, diastolic, and pulse pressure, respectively (P for trend for all <0.003). The corresponding multivariable adjusted odds ratio for the presence of hypertension was 1.52 (0.98 to 2.36; P trend = 0.004). CONCLUSIONS: The data suggest that even in a population with very low serum selenium concentrations higher serum selenium concentrations are associated with higher blood pressure levels and a higher prevalence of hypertension. These findings call for careful evaluation of the effects of selenium on blood pressure endpoints in randomized clinical trials.
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Hipertensión/sangre , Lípidos/sangre , Selenio/sangre , Adulto , Estudios de Cohortes , Estudios Transversales , Femenino , Humanos , Masculino , Persona de Mediana EdadRESUMEN
Chronic peripheral hyperinsulinemia is one of the main characteristics of type 2 diabetes accompanied by impaired glucose homeostasis and obesity resulting from increased food intake and decreased physical activity. Patients with type 2 diabetes have a higher risk of cognitive decline and neurodegenerative diseases e.g. Alzheimer's disease (AD). Furthermore, obesity or hyperinsulinemia alone already increase the probability of cognitive decline possibly progressing to AD. Tau hyperphosphorylation is one of the pathological hallmarks of AD and so called tauopathies. Aim of the present study was to analyze the influence of obesity-associated hyperinsulinemia on tau phosphorylation without changes in glucose homeostasis. 15% high fat diet fed over 12-16 weeks induced 2.4-fold increased plasma insulin levels without changing glucose tolerance. However, this diet did not lead to substantial differences in tau phosphorylation in the brain of C57Bl/6 mice. Additionally, chronic hyperinsulinemia did not influence downstream insulin receptor signaling and the expression of the tau kinases (e.g. ERK-1/-2, Akt, GSK-3ß, CDK5 or JNK) and tau phosphatases (e.g. PP2A) in the murine central nervous system. Thus, we successfully induced hyperinsulinemia without causing glucose intolerance in our experimental animals but this did not influence central insulin receptor signaling or tau phosphorylation.
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Encéfalo/metabolismo , Hiperinsulinismo/complicaciones , Proteínas tau/metabolismo , Animales , Western Blotting , Enfermedad Crónica , Dieta Alta en Grasa/efectos adversos , Masculino , Ratones , Ratones Endogámicos C57BL , Obesidad/complicaciones , FosforilaciónRESUMEN
BACKGROUND: Obesity is associated with macrophage infiltration of adipose tissue. These inflammatory cells affect adipocytes not only by classical cytokines but also by the secreted glycopeptide wnt5a. Healthy adipocytes are able to release the wnt5a inhibitor sFRP5. This protective effect, however, was found to be diminished in obesity. The aim of the present study was to examine (1) whether obese human subjects exhibit increased serum concentrations of wnt5a and (2) whether wnt5a and/or sFRP5 serum concentrations in obese subjects can be influenced by caloric restriction. METHODOLOGY: 23 obese human subjects (BMI 44.1 ± 1.1 kg/m(2)) and 12 age- and sex-matched lean controls (BMI 22.3 ± 0.4 kg/m(2)) were included in the study. Obese subjects were treated with a very low-calorie diet (approximately 800 kcal/d) for 12 weeks. Body composition was assessed by impedance analysis, insulin sensitivity was estimated by HOMA-IR and the leptin-to-adiponectin ratio and wnt5a and sFRP5 serum concentrations were measured by ELISA. sFRP5 expression in human adipose tissue biopsies was further determined on protein level by immunohistology. PRINCIPAL FINDINGS: Pro-inflammatory wnt5a was not measurable in any serum sample of lean control subjects. In patients with obesity, however, wnt5a became significantly detectable consistent with low grade inflammation in such subjects. Caloric restriction resulted in a weight loss from 131.9 ± 4.0 to 112.3 ± 3.2 kg in the obese patients group. This was accompanied by a significant decrease of HOMA-IR and leptin-to-adiponectin ratio, indicating improved insulin sensitivity. Interestingly, these metabolic improvements were associated with a significant increase in serum concentrations of the anti-inflammatory factor and wnt5a-inhibitor sFRP5. CONCLUSIONS/SIGNIFICANCE: Obesity is associated with elevated serum levels of pro-inflammatory wnt5a in humans. Furthermore, caloric restriction beneficially affects serum concentrations of anti-inflammatory sFRP5 in such subjects. These findings suggest a novel regulatory system in low grade inflammation in obesity, which can be influenced by nutritional therapy.
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Proteínas del Ojo/biosíntesis , Proteínas del Ojo/genética , Regulación de la Expresión Génica , Proteínas de la Membrana/biosíntesis , Proteínas de la Membrana/genética , Ciencias de la Nutrición , Proteínas Proto-Oncogénicas/biosíntesis , Proteínas Proto-Oncogénicas/genética , Proteínas Wnt/biosíntesis , Proteínas Wnt/genética , Proteínas Adaptadoras Transductoras de Señales , Adipocitos/citología , Tejido Adiposo/metabolismo , Adulto , Composición Corporal , Índice de Masa Corporal , Estudios de Casos y Controles , Ensayo de Inmunoadsorción Enzimática/métodos , Femenino , Humanos , Inflamación , Masculino , Persona de Mediana Edad , Modelos Biológicos , Obesidad/sangre , Obesidad/genética , Proteína Wnt-5aRESUMEN
Animal and human studies suggest that a malleable protein matrix (MPM) from whey decreases plasma lipid concentrations and may positively influence other components of the metabolic syndrome such as glucose metabolism and blood pressure (BP). The primary objective of this double-blind, multi-centre trial was to investigate the effects of a low-fat yoghurt supplemented with whey MPM on fasting TAG concentrations in patients with the metabolic syndrome. A total of 197 patients were randomised to receive MPM or a matching placebo yoghurt identical in protein content (15 g/d). Patients were treated during 3 months with two daily servings of 150 g yoghurt each to compare changes from baseline in efficacy variables. MPM treatment resulted in a significantly larger reduction of TAG concentrations in comparison to placebo (relative change -16%, P=0·004). The difference was even more pronounced in subjects with elevated fasting TAG (≥200 mg/dl) at baseline (-18%, P=0·005). The relative treatment difference in fasting plasma glucose was -7·1 mg/dl (P=0·089). This effect was also more pronounced in subjects with impaired fasting glucose at baseline (-11 mg/dl, P=0·03). In patients with hypertension, the relative treatment difference in systolic BP reached -5·9 mmHg (P=0·054). The relative treatment difference in body weight was -1·7 kg (P=0·015). The most common adverse events were gastrointestinal in nature. Conclusions from the present study are that consumption of a low-fat yoghurt supplemented with whey MPM twice a day over 3 months significantly reduces fasting TAG concentrations in patients with the metabolic syndrome and improves multiple other cardiovascular risk factors.
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Errores Innatos del Metabolismo de los Carbohidratos/prevención & control , Hipolipemiantes/uso terapéutico , Síndrome Metabólico/dietoterapia , Proteínas de la Leche/uso terapéutico , Triglicéridos/sangre , Yogur , Adulto , Anciano , Errores Innatos del Metabolismo de los Carbohidratos/etiología , Enfermedades Cardiovasculares/epidemiología , Enfermedades Cardiovasculares/prevención & control , Dieta con Restricción de Grasas , Método Doble Ciego , Femenino , Fermentación , Alemania/epidemiología , Glicerol Quinasa/deficiencia , Humanos , Hiperglucemia/etiología , Hiperglucemia/prevención & control , Hipertensión/etiología , Hipertensión/prevención & control , Insuficiencia Corticosuprarrenal Familiar , Hipolipemiantes/efectos adversos , Hipolipemiantes/metabolismo , Masculino , Síndrome Metabólico/sangre , Síndrome Metabólico/fisiopatología , Persona de Mediana Edad , Proteínas de la Leche/efectos adversos , Proteínas de la Leche/metabolismo , Factores de Riesgo , Proteína de Suero de Leche , Yogur/efectos adversos , Yogur/análisisRESUMEN
The question whether lipid-lowering treatment is associated with a decrease in cardiovascular morbidity and mortality in patients with chronic kidney disease has been disputed for a while, with recent trials in patients on haemodialysis failing to show benefit. Recently, the long-awaited results of the SHARP (Study of Heart And Renal Protection) trial were published. This randomized trial compared the effects of either simvastatin 20 mg plus ezetimibe 10 mg daily or placebo on the occurrence of a first major vascular event in 9720 patients with chronic kidney disease. There was a 17% relative risk reduction but no benefit on survival. We address our concerns regarding the conclusions drawn from this trial. The trial has a major design flaw by comparing the effects of two different lipid-lowering drugs with placebo. Although the SHARP trial showed that lipid lowering may be beneficial for patients with chronic kidney disease, the clinically as well as economically important question remains unanswered as to whether it was statin therapy and/or ezetimibe that mediated this effect. A great opportunity to investigate superiority, equipoise, or potential inferiority of ezetimibe compared to statins was missed.
RESUMEN
BACKGROUND: Lipoprotein(a) [Lp(a)] is an independent risk factor for cardiovascular disease. The interleukin-6 (IL-6) receptor antagonist tocilizumab has been shown to lower serum Lp(a) concentrations. We investigated whether the IL-6 single nucleotide polymorphism -174G/C is associated with baseline serum Lp(a) concentrations. METHODOLOGY/PRINCIPAL FINDINGS: We divided 2321 subjects from the Lipid Analytic Cologne (LIANCO) cohort into 2 groups, the ones with substantially elevated Lp(a), defined as concentrations ≥60 mg/dl (nâ=â510), and the ones with Lp(a) <60 mg/dl (nâ=â1811). The association with the genotypes GG (33.7%), GC (50.75%) and CC (15.55%) was investigated. The GC and the CC genotype were associated with a significantly increased odds ratio of having substantially elevated Lp(a) concentrations (ORâ=â1.3, 95% CI 1.04 to 1.63, Pâ=â0.02 and ORâ=â1.44, 95% CI 1.06 to 1.93, Pâ=â0.018). These associations remained significant after adjusting for age, sex, smoking behavior, body mass index, serum lipoproteins, hypertension and diabetes. Of these covariates, only LDL cholesterol was significantly and independently associated with elevated Lp(a) concentrations. CONCLUSIONS/SIGNIFICANCE: The IL-6 single nucleotide polymorphism -174G/C is associated with increased odds of having elevated Lp(a). Whether this association plays a role in the Lp(a)-lowering effects of IL-6 receptor antagonists remains to be established.
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Interleucina-6/genética , Lipoproteína(a)/sangre , Polimorfismo Genético/genética , Regiones Promotoras Genéticas/genética , Anciano , Femenino , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple/genéticaRESUMEN
OBJECTIVES: To determine whether disease management programs (DMPs) for type 2 diabetes mellitus (T2DM) can improve some processes of care and intermediate outcomes. STUDY DESIGN: Two cross-sectional registries of patients with T2DM were used for data extraction before (previous cohort) and after (recent cohort) introduction of DMPs in Germany (N = 78,110). METHODS: In the recent cohort, 15,293 patients were treated within the DMPs and 9791 were not. Processes of care, medications, and intermediate outcomes (achievement of treatment targets for low-density lipoprotein [LDL] cholesterol, blood pressure, and glycosylated hemoglobin [A1C]) were analyzed using multi- variable, multilevel logistic regression, adjusting for patient case-mix and physician-level clustering to derive odds ratios and 95% confidence intervals (CIs). RESULTS: Availability of structured diabetes education and of lipid, blood pressure, and A1C measurements increased over time. In DMP patients, availability was significantly higher for blood pressure and A1C but not for lipid measurements. Prescription of angiotensin-converting enzyme inhibitors, oral antidiabetic drugs, and insulin increased over time and was more common in DMP patients. Statin prescription increased over time but was not influenced by DMP status. Intermediate outcomes improved over time, but DMPs had no influence on intermediate outcomes except for reaching LDL cholesterol targets (odds ratio 1.12 [95% CI 1.06, 1.19] in favor of DMPs). CONCLUSIONS: While there may be some unmeasured confounding, our data suggest that improvement in processes of care by DMPs, as implemented in Germany, only partially translates into improvement of intermediate outcomes.
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Diabetes Mellitus Tipo 2/terapia , Manejo de la Enfermedad , Calidad de la Atención de Salud/normas , Anciano , Análisis de Varianza , Índice de Masa Corporal , Enfermedades Cardiovasculares/epidemiología , Comorbilidad/tendencias , Estudios Transversales , Diabetes Mellitus Tipo 2/epidemiología , Femenino , Alemania , Humanos , Masculino , Evaluación de Procesos y Resultados en Atención de Salud , Pacientes Ambulatorios , Educación del Paciente como Asunto , Calidad de la Atención de Salud/tendencias , Fumar/epidemiología , Fumar/tendenciasRESUMEN
Hyperglycemia in patients with type 2 diabetes causes multiple neuronal complications, e.g., diabetic polyneuropathy, cognitive decline, and embryonic neural crest defects due to increased apoptosis. Possible mechanisms of neuronal response to increased glucose burden are still a matter of debate. Insulin and insulin-like growth factor-1 (IGF-1) receptor signaling inhibits glucose-induced caspase-3 activation and apoptotic cell death. The insulin receptor substrates (IRS) are intracellular adapter proteins mediating insulin's and IGF-1's intracellular effects. Even though all IRS proteins have similar function and structure, recent data suggest different actions of IRS-1 and IRS-2 in mediating their anti-apoptotic effects in glucose neurotoxicity. We therefore investigated the role of IRS-1/-2 in glucose-induced caspase-3 activation using human neuroblastoma cells. Overexpression of IRS-1 or IRS-2 caused complete resistance to glucose-induced caspase-3 cleavage. Inhibition of PI3-kinase reversed this protective effect of IRS-1 or IRS-2. However, MAP-kinases inhibition had only minor impact. IRS overexpression increased MnSOD abundance as well as BAD phosphorylation while Bim and BAX levels remained unchanged. Since Akt promotes cell survival at least partially via phosphorylation and inhibition of downstream forkhead box-O (FoxO) transcription factors, we generated neuroblastoma cells stably overexpressing a dominant negative mutant of FoxO1 mimicking activation of the insulin/IGF-1 pathway on FoxO-mediated transcription. Using these cells we showed that FoxO1 is not involved in neuronal protection mediated by increased IRS-1/-2 expression. Thus, overexpression of both IRS-1 and IRS-2 induces complete resistance to glucose-induced caspase-3 activation via PI3-kinase mediated BAD phosphorylation and MnSOD expression independent of FoxO1.
Asunto(s)
Caspasa 3/metabolismo , Glucosa/farmacología , Proteínas Sustrato del Receptor de Insulina/metabolismo , Neuroblastoma/metabolismo , Edulcorantes/farmacología , Apoptosis/efectos de los fármacos , Proteínas Reguladoras de la Apoptosis/genética , Proteínas Reguladoras de la Apoptosis/metabolismo , Proteína 11 Similar a Bcl2 , Western Blotting , Activación Enzimática , Proteína Forkhead Box O1 , Factores de Transcripción Forkhead/genética , Factores de Transcripción Forkhead/metabolismo , Humanos , Inmunoprecipitación , Proteínas Sustrato del Receptor de Insulina/genética , Proteínas de la Membrana/genética , Proteínas de la Membrana/metabolismo , Neuroblastoma/tratamiento farmacológico , Neuroblastoma/patología , Fosfatidilinositol 3-Quinasas/metabolismo , Proteínas Proto-Oncogénicas/genética , Proteínas Proto-Oncogénicas/metabolismo , Proteínas Proto-Oncogénicas c-akt , ARN Mensajero/genética , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Transducción de Señal/efectos de los fármacos , Superóxido Dismutasa/genética , Superóxido Dismutasa/metabolismo , Células Tumorales Cultivadas , Proteína Letal Asociada a bcl/genética , Proteína Letal Asociada a bcl/metabolismoRESUMEN
BACKGROUND: Interleukin-6 (IL-6) is a pro-inflammatory cytokine that has been found to be increased in type 2 diabetic subjects. However, it still remains unclear if these elevated IL-6 levels are co-incidental or if this cytokine is causally related to the development of insulin resistance and type 2 diabetes in humans. Therefore, in the present study we examined insulin sensitivity, serum adipokine levels and lipid parameters in human subjects before and after treatment with the IL-6 receptor antibody Tocilizumab. METHODOLOGY/PRINCIPAL FINDINGS: 11 non-diabetic patients with rheumatoid disease were included in the study. HOMA-IR was calculated and serum levels for leptin, adiponectin, triglycerides, LDL-cholesterol, HDL-cholesterol and lipoprotein (a) (Lp (a)) were measured before as well as one and three months after Tocilizumab treatment. The HOMA index for insulin resistance decreased significantly. While leptin concentrations were not altered by inhibition of IL-6 signalling, adiponectin concentrations significantly increased. Thus the leptin to adiponectin ratio, a novel marker for insulin resistance, exhibited a significant decrease. Serum triglycerides, LDL-cholesterol and HDL-cholesterol tended to be increased whereas Lp (a) levels significantly decreased. CONCLUSIONS/SIGNIFICANCE: Inhibition of IL-6 signalling improves insulin sensitivity in humans with immunological disease suggesting that elevated IL-6 levels in type 2 diabetic subjects might be causally involved in the pathogenesis of insulin resistance. Furthermore, our data indicate that inhibition of IL-6 signalling decreases Lp (a) serum levels, which might reduce the cardiovascular risk of human subjects.