Mitochondrial redox impairment and enhanced autophagy in peripheral blood mononuclear cells from type 1 diabetic patients.

Type 1 diabetes (T1D) involves critical metabolic disturbances that contribute to an increased cardiovascular risk. Leukocytes are key players in the onset of atherosclerosis due to their interaction with the endothelium. However, whether mitochondrial redox impairment, altered bioenergetics and abnormal autophagy in leukocytes contribute to T1D physiopathology is unclear. In this study we aimed to evaluate the bioenergetic and redox state of peripheral blood mononuclear cells (PBMCs) from T1D patients in comparison to those from healthy subjects, and to assess autophagy induction and leukocyte-endothelial interactions. T1D patients presented lower levels of fast-acting and total antioxidants in their blood, and their leukocytes produced higher amounts of total reactive oxygen species (ROS) and superoxide radical with respect to controls. Basal and ATP-linked respiration were similar in PBMCs from T1D and controls, but T1D PBMCs exhibited reduced spare respiratory capacity and a tendency toward decreased maximal respiration and reduced non-mitochondrial respiration, compared to controls. The autophagy markers P-AMPK, Beclin-1 and LC3-II/LC3-I were increased, while P62 and NBR1 were decreased in T1D PBMCs versus those from controls. Leukocytes from T1D patients displayed lower rolling velocity, higher rolling flux and more adhesion to the endothelium versus controls. Our findings show that T1D impairs mitochondrial function and promotes oxidative stress and autophagy in leukocytes, and suggest that these mechanisms contribute to an increased risk of atherosclerosis by augmenting leukocyte-endothelial interactions.

Oxidative and endoplasmic reticulum stress is impaired in leukocytes from metabolically unhealthy vs healthy obese individuals.

BACKGROUND: Oxidative stress and inflammation are related to obesity, but the influence of metabolic disturbances on these parameters and their relationship with endoplasmic reticulum (ER) stress is unknown. Therefore, this study was performed to evaluate whether metabolic profile influences ER and oxidative stress in an obese population with/without comorbidities. SUBJECTS AND METHODS: A total of 113 obese patients were enrolled in the study; 29 were metabolically healthy (MHO), 53 were metabolically abnormal (MAO) and 31 had type 2 diabetes (MADO). We assessed metabolic parameters, proinflammatory cytokines (TNFα and IL-6), mitochondrial and total reactive oxygen species (ROS) production, glutathione levels, antioxidant enzymes activity, total antioxidant status, mitochondrial membrane potential and ER stress marker expression levels (glucose-regulated protein (GRP78), spliced X-box binding protein 1 (XBP1), P-subunit 1 alpha (P-eIF2α) and activating transcription factor 6 (ATF6). RESULTS: The MAO and MADO groups showed higher blood pressure, atherogenic dyslipidemia, insulin resistance and inflammatory profile than that of MHO subjects. Total and mitochondrial ROS production was enhanced in MAO and MADO patients, and mitochondrial membrane potential and catalase activity differed significantly between the MADO and MHO groups. In addition, decreases in glutathione levels and superoxide dismutase activity were observed in the MADO vs MAO and MHO groups. GRP78 and CHOP protein and gene expression were higher in the MAO and MADO groups with respect to MHO subjects, and sXBP1 gene expression was associated with the presence of diabetes. Furthermore, MAO patients exhibited higher levels of ATF6 than their MHO counterparts. Waist circumference was positively correlated with ATF6 and GRP78, and A1c was positively correlated with P-Eif2α. Interestingly, CHOP was positively correlated with TNFα and total ROS production and GRP78 was negatively correlated with glutathione levels. CONCLUSIONS: Our findings support the hypothesis that both inflammation and oxidative stress are involved in the induction of ER stress signaling pathways in the leukocytes of metabolically unhealthy obese vs healthy obese subjects.

Customized stimulation enhances performance of independent binary SSVEP-BCIs.

OBJECTIVE: Brain-computer interfaces based on steady-state visual evoked potentials (SSVEP-BCIs) achieve the highest performance, due to their multiclass nature, in paradigms in which different visual stimuli are shown. Studies of independent binary SSVEP-BCIs have been previously presented in which it was not necessary to gaze at the stimuli at the cost of performance. Despite that, the energy of the SSVEPs is largely affected by the temporal and spatial frequencies of the stimulus, there are no studies in the BCI literature about its combined impact on the final performance of SSVEP-BCIs. The objective of this study is to present an experiment that evaluates the best configuration of the visual stimulus for each subject, thus minimizing the decline in performance of independent binary SSVEP-BCIs. METHODS: The participants attended and ignored a single structured stimulus configured with a combination of spatial and temporal frequencies at a time. They were instructed to gaze at a central point during the whole experiment. The best combination of spatial and temporal frequencies achieved for each subject, in terms of signal-to-noise ratio (SNR), was subsequently determined. RESULTS: The SNR showed a significant dependency on the combination of frequencies, in such a way that only a reduced set of these combinations was applicable for obtaining an optimum SNR. The selection of an inappropriate stimulus configuration may cause a degradation of the information transmission rate (ITR) as it does the SNR. CONCLUSIONS: The appropriate selection of the optimal spatial and temporal frequencies determines the performance of independent binary SSVEP-BCIs. This fact is critical to enhance its low performance; hence, they should be adjusted independently for each subject. SIGNIFICANCE: Independent binary SSVEP-BCIs can be used in patients who are unable to control their gaze sufficiently. The correct selection of the spatial and temporal frequencies has a considerable benefit on their low ITR that must be taken into account. In order to find the most suitable frequencies, a test similar to the presented in this study should be performed beforehand for each SSVEP-BCI user. This regard is not documented in studies conducted in the BCI literature.

Serum lipid responses to phytosterol-enriched milk in a moderate hypercholesterolemic population is not affected by apolipoprotein E polymorphism or diameter of low-density lipoprotein particles.

BACKGROUND/OBJECTIVES: The importance of both low-density lipoprotein cholesterol (LDLc) size and the apolipoprotein E (Apo E) in the atherogenic process is known, but there is little information with regard to the effect of phytosterols (PS) on these parameters. The aim of this study was to evaluate the influence of PS on lipid profile and LDLc size according to Apo E genotype. SUBJECTS/METHODS: This was a randomized parallel trial employing 75 mild-hypercholesterolemic subjects and consisting of two 3-month intervention phases. After 3 months of receiving a standard healthy diet, subjects were divided into two intervention groups: a diet group (n=34) and a diet+PS group (n=41) that received 2 g/day of PS. Total cholesterol (TC), triacylglycerols, LDLc, high-density lipoprotein cholesterol (HDLc), non-HDLc, Apo A-I and B-100, LDLc size and Apo E genotype were determined. RESULTS: Patients receiving PS exhibited a significant decrease in TC (5.1%), LDLc (8.1%), non-HDLc (7.4%) and Apo B-100/Apo A-I ratio (7.7%), but these effects did not depend on Apo E genotype. No significant changes were found in lipid profile according to Apo E genotype when patients following dietary recommendations were considered as a whole population or separately. No variations in LDLc size were observed in any of the intervention groups. CONCLUSION: The results of this study show that Apo E genotype does not have an impact on the lipid response to PS as a cholesterol-lowering agent in mild-hypercholesterolemic patients. Furthermore, the evidence obtained confirms that LDLc particle size is not modified when PS are added to a standard healthy diet.

Fibrinogen, plasma viscosity and blood viscosity in obesity. Relationship with insulin resistance.

Plasma viscosity (PV) and blood viscosity (BV) have been scarcely evaluated in morbid obese patients with no other concomitant cardiovascular risk factors. Contradictory results have been published regarding the influence of insulin resistance on these rheological parameters in obesity. In 67 severe or morbid obese patients without other cardiovascular risk factors (51 women and 11 men, aged 34+/-11 years), fibrinogen, PV and BV at native (nBV) and corrected 45% hematocrit (cBV) have been determined, and insulin resistance has been calculated with homeostasis model assessment (HOMA) index, in basal conditions and after a three month diet period. The same determinations were performed in 67 healthy volunteers (45 women, 22 men, aged 32+/-10 years) at baseline and three months later. When cases and controls were compared, obese patients showed higher fibrinogen levels (P<0.001), PV (P=0.050) and cBV (P=0.035), and showed a higher insulin resistance than the control group (P<0.001). Differences in PV were maintained after adjusting for BMI (P=0.001), but disappeared after adjusting for HOMA (P=0.391) fibrinogen (P=0.367) and LDL-chol (P=0.097). Differences between obese patients and the control group for cBV disappeared after adjusting for BMI (P=0.739), HOMA (P=0.744), fibrinogen (P=0.907), LDL-chol (P=0.283) and PV (P=0.112). The achieved weight loss (8.7+/-3.53%) was not accompanied by any changes in these rheological parameters (P>0.050). Obese patients show increased fibrinogen levels, PV and cBV. These rheological disturbances seem to be associated with insulin resistance and the metabolic syndrome, and do not seem to improve with moderate weight loss.

Management of diabetic ketoacidosis in a teaching hospital.

The aim of our study was to evaluate clinical management of diabetic ketoacidosis (DKA) in a teaching hospital. We followed all the patients hospitalised for DKA over six years (1995-2000), and we recorded clinical data, laboratory finding at entrance and clinical management. We compared the data to the standards set in guidelines. Our study showed an important delay of initiation of intravenous fluid (70% of cases), an under-replacement with intravenous fluid (69% of cases) and with potassium therapy (80% of cases), and an excessive use of alkali therapy. In conclusion, suboptimal management of DKA occurred in a large percentage of patients.

Tratamiento de la diabetes gestacional / Treatment of gestational diabetes mellitus

Se considera DG cualquier grado de intolerancia a la glucosa de comienzo o primer diagnóstico durante la gestación. Su diagnóstico y tratamiento disminuyen la morbimortalidad maternofetal asociadas a este trastorno. En el tratamiento es básico la elaboración de una dieta, la monitorización glucémica y la administración de insulina si los objetivos terapéuticos no han sido conseguidos con la dieta. Se recomienda una ganancia de peso al finalizar el embarazo entre los 10-12 kilos. El aporte calórico se basa en el peso ideal, recomendándose una ingesta calórica de 30 Kcal/kg/dia, con una distribución del aporte calórico en 6 tomas diarias, evitándose un ayuno nocturno mayor a 9 horas. La monitorización glucémica se realiza mediante el autoanálisis de glucemia domiciliaria, tanto basal como postprandial, con unos objetivos de glucemia basal < 90 mg/dl, 1 hora postprandial < 140 mg/dl y 2 horas postprandial < 120 mg/dl; y mediante el valor de la HbA1c, que debe ser monitorizada cada 2-4 semanas. Se recomienda la administración de insulina cuando no se alcancen dichos objetivos con la dieta, con una pauta de insulinización inicial que debe ser sencilla, con 0,15-0,30 UI/kg de insulina NHP o mezcla, dividida en 2 dosis antes del desayuno y de la cena, para pasar en caso de fracaso a pauta de insulinoterapia intensiva. Las mujeres que hayan requerido tratamiento con insulina necesitan tratamiento insulínico intensivo durante el parto, mediante perfusión de glucosa más insulina. Es recomendable un parto espontáneo y por vía vaginal, salvo que las condiciones obstétricas lo dictaminen. Es importante una reclasificación del estatus glúcemico materno entre 3 y 6 meses tras el parto o tras finalizar la lactancia, mediante una SOG con 75 g, dada la alta prevalencia de alteraciones futuras en el metabolismo glucídico en estas pacientes, especialmente de DM tipo 2 y de la aparición de DG en embarazos posteriores; esto está más relacionado con el control de peso en años sucesivos. Se recomienda un seguimiento de los hijos a largo plazo, ya que estos tienen una mayor predisposición a desarrollar en la adolescencia IHC y/obesidad (AU)

Cardiopatía isquémica en la gestación diabética / Ischemic cardiomyopathy in diabetic patients during pregnancy

Las manifestaciones cardiovasculares de la arteriosclerosis son la causa más frecuente de la morbimortalidad en los pacientes diabéticos. No existen evidencias de que el embarazo constituya por sí mismo un riesgo independiente para la cardiopatía isquémica; en la gestante diabética el factor de riesgo más asociado es la hipertensión arterial. Es de destacar que la cardiopatía isquémica en la gestante diabética suele presentarse en forma de infarto de miocardio, generalmente en el tercer trimestre y preferentemente en multigrávidas, con una media de 33 años de edad. En caso de larga evolución de la diabetes es necesario un estudio cardiológico pregestacional. Cuando la cardiopatía isquémica es conocida y se desea el embarazo, sería necesario cirugía revascularizadora previa. Durante la gestación, el tratamiento de la cardiopatía isquémica no difiere del habitual, a excepción de la precaución con el uso de determinados fármacos por su posible acción teratógena, debiendo extremar la vigilancia durante el segundo y tercer trimestre, parto y postparto por la mayor inestabilidad hemodinámica que conllevan. Podemos admitir que la gestación diabética asociada a cardiopatía isquémica representa una situación de riesgo elevado y que si bien no es contraindicación absoluta para la gestación sí es una circunstancia para evaluar el riesgo detallada e individualmente (AU)

Complicaciones metabólicas agudas en la gestante diabética / Acute metabolic complications in diabetic patients during pregnancy

La complicación aguda más frecuente de la diabetes (10 por ciento con episodios repetidos) es la hipoglucemia, que consiste en un descenso de los niveles plasmáticos de glucosa (glucemia plasmática < 45-50 mg/dl), responsable de la presentación de una serie de síntomas que desaparecen si se normaliza la glucemia. Esta complicación es mucho más frecuente en la gestante con diabetes tipo 1, en relación con el tratamiento intensivo insulínico y alteración de la contrarregulación. El esquema actual del tratamiento en las gestantes con diabetes tipo 1 durante el embarazo supone iniciar un control estricto de la glucemia antes de la concepción y durante la gestación; esto implica que tengamos que recurrir a regímenes de insulinoterapia intensiva que pueden provocar episodios más frecuentes e intensos de hipoglucemia. La clínica de la hipoglucemia es profusa, con síntomas relativamente inespecíficos, que pueden remedar diversos cuadros clínicos; pero, de una manera general, podemos distinguir dos grandes grupos: síntomas secundarios a descarga adrenérgica y a neuroglucopenia. En caso de hipoglucemia, hay varias opciones terapéuticas dependiendo de la gravedad del episodio. Por otra parte, las descompensaciones hiperglucémicas cetósicas y, especialmente, la cetoacidosis diabética (CAD), constituyen urgencias metabólicas que pueden provocar la muerte del feto y la madre. La CAD se trata de una complicación metabólica grave que se asocia con morbilidad y mortalidad materna y fetal muy elevadas. Es una complicación típica de la diabetes tipo 1, aunque también puede aparecer en gestantes con diabetes tipo 2 o con diabetes gestacional, ante situaciones de estrés o infecciones. En los últimos años se ha reducido de forma espectacular esta complicación, gracias al estricto control de la diabetes durante el embarazo (AU)

Association between diabetic ketoacidosis and thyrotoxicosis.

Three cases of diabetic ketoacidosis precipitated by thyrotoxicosis are presented. Two of them are young women with type 1 diabetes mellitus; the third case is a middle-aged woman with type 2 diabetes mellitus. All of them were diagnosed with Graves' disease. They typically showed tachycardia at rest in spite of correction of the metabolic disorder. Hyperthyroidism worsens glycemic control in diabetic patients and may precipitate diabetic ketoacidosis. On the other hand, women with diabetes have a higher prevalence of Graves' disease. Thus, in diabetic ketoacidosis without an obvious triggering factor, the presence of hyperthyroidism should be investigated, particularly in women.

[Abdominal fat assessment by magnetic resonance: comparison with biometric profiles and cardiovascular risk markers]. / Estudio de la grasa abdominal mediante resonancia magnética: comparación con parámetros antropométricos y de riesgo cardiovascular.

BACKGROUND: Obesity is associated with numerous metabolic complications and cardiovascular disease. Magnetic Resonance (MR) imaging provides fair resolution of fat distribution, its quantification by semiautomatic methods being feasible. Our purpose was to analyze abdominal fat deposition by MR imaging and quantify its relative distribution in 50 obese patients. RESULTS were then related to anthropometric measures and cardiovascular risk markers. PATIENTS AND METHOD: Six axial T1-weighted abdominal images were obtained from each patient and transferred to a PC. A software (ASYMED 3.0; Valencia) was used to analyze the images and quantify relative fat deposition. Comparison of MR results with several cardiovascular risk markers was performed using unpaired data Student t-test. Significance level was defined as a P < 0.05. RESULTS: 12% of patients showed predominant intra-abdominal fat deposition.Significant differences were found with regard to age, waist-hip ratio and average serum levels of total cholesterol, LDL, VLDL,triglycerides and apoprotein B between intra-abdominal deposition versus subcutaneous fat deposition. CONCLUSION: MR imaging allows estimation of abdominal fat deposition and its relative distribution. There is a significant relationship between a predominant intra-abdominal fat deposition and an atherogeniclipid profile.

Effect of thyroid hormone replacement on lipoprotein(a), lipids, and apolipoproteins in subjects with hypothyroidism.

OBJECTIVE: To study the effect of thyroid hormone replacement on total cholesterol, low-density lipoprotein cholesterol, triglycerides, high-density lipoprotein cholesterol (HDL-C), apolipoprotein A-I and B-100, and lipoprotein(a) [Lp(a)] in subjects with hypothyroidism. MATERIAL AND METHODS: In 17 patients with clinical primary hypothyroidism, studies were done before and after thyroid hormone replacement therapy. Free thyroxine and thyrotropin were determined by chemiluminescent assay. Total cholesterol and triglycerides were measured by enzymatic methods, and HDL-C was measured after dextran sulfate-MgCl2 precipitation. Apolipoprotein A-I and B-100 were assayed by immunonephelometry. For measurement of Lp(a), we used a sequential sandwich enzyme-linked immunosorbent assay. RESULTS: After levothyroxine treatment, the mean concentration of thyrotropin decreased from 91.4 to 3.7 microIU/mL, and free thyroxine increased from 0.5 to 1.2 ng/ dL. Total cholesterol, triglycerides, HDL-C, low-density lipoprotein cholesterol, and apolipoprotein A-I and B-100 decreased after thyroid hormone replacement therapy. Lp(a) levels also decreased significantly (P<0.05) after treatment, from a mean of 33.4 to 25.6 mg/dL. CONCLUSION: Hypothyroidism is associated with an increase in total cholesterol, triglycerides, HDL-C, apolipoprotein A-I and B-100, and Lp(a). A reduction in lipid and lipoprotein levels after thyroid hormone replacement in our study cohort resulted in a less atherogenic profile.

Cardiovascular autonomic neuropathy in type 1 diabetic patients with and without peripheral neuropathy.

One hundred Type 1 diabetic patients (54 men, 46 women) mean age 28.9+/-8.4 years, were selected from among individuals referred to our hospital, with no previous diagnosis of diabetic chronic complications including diabetic neuropathy. After clinical and physical examinations, subjects were divided into two groups: with (n = 37) and without (n = 63) peripheral neuropathy. The percentage of subjects with cardiovascular autonomic neuropathy (AN), diagnosed by positive results to at least two of the five cardiovascular tests (Valsalva ratio, EI ratio, 30/15 ratio, blood-pressure response to standing up and handgrip test), was 40%: 72.9% in the group with peripheral neuropathy and 20.6% in the group without peripheral neuropathy (P < 0.0001). The prevalence of cardiovascular AN was related to the duration of the diabetes (P < 0.0001) and to HbA1c (P < 0.02). The presence of microalbuminuria and the existence of retinopathy were higher (P < 0.01 ) in group 1 (with peripheral neuropathy). Logistic regression analysis showed that only the presence of higher excretion of albumin is independently related to the presence of peripheral neuropathy. In conclusion, cardiovascular AN is frequent in Type 1 diabetes; furthermore, prevalence increases with the existence of peripheral neuropathy and with duration of the diabetes.