Randomized Evaluation of Glycemic Control in the Medical Intensive Care Unit Using Real-Time Continuous Glucose Monitoring (REGIMEN Trial).

BACKGROUND AND OBJECTIVE: Hyperglycemia occurs commonly in patients admitted to medical intensive care units (MICUs). Whether real-time (RT) continuous glucose monitoring (CGM) improves glycemic control and variability and reduces hypoglycemia in severely ill MICU patients with an Acute Physiology and Chronic Health Evaluation II (APACHE-II) score of ≥20 has not been studied. SUBJECTS AND METHODS: Thirty-five patients (66 ± 10 years of age; APACHE-II score, 28 ± 6) were randomly assigned to RT-CGM (n = 16) using the GlucoDay(®)S (A. Menarini Diagnostics, Florence, Italy) device or to blinded CGM. Insulin was infused using a modified Yale protocol targeting a blood glucose level between 80 and 120 mg/dL. Outcome measures were percentage of time in normoglycemia (80-110 mg/dL) and in hypoglycemia (<60 mg/dL), glycemic variability (SD, coefficient of variation, mean amplitude of glucose excursions, and mean of daily differences), and CGM accuracy (error grid analyses, Bland-Altman bias plot, and mean absolute relative deviation). RESULTS: During 96 h of monitoring, glycemia reached target (80-110 mg/dL) in 37 ± 15%, was between 70 and 180 mg/dL in 91 ± 10%, and <60 mg/dL in 2 ± 2% of the time. In the RT-CGM group glycemia averaged 119 ± 17 mg/dL versus 122 ± 11 mg/dL in the control group. Parameters of glucose variability and percentages of time at target glycemia and in hypoglycemia were similar between groups. GlucoDayS values and arterial glycemia correlated well, with 98.6% of data falling in Zones A and B of the error grid analysis. Mean absolute relative devation was 11.2%. CONCLUSIONS: RT-CGM did not ameliorate glucose control or variability; neither did it reduce the number of hypoglycemic events, but our insulin infusion protocol led to overall good glucose control without a significant hypoglycemia risk, making further improvement difficult.

Ferritin levels and risk of metabolic syndrome: meta-analysis of observational studies.

BACKGROUND: Elevated ferritin levels have been associated with single cardiovascular risk factors but the relationship to the presence of metabolic syndrome is inconclusive.The aim of this systematic review and meta-analysis of published observational studies was to estimate the association between serum ferritin levels and metabolic syndrome in adults. METHODS: The Pubmed, SCOPUS and the Cochrane Library databases were searched for epidemiological studies that assessed the association between ferritin levels and metabolic syndrome and were published before September 2013. There were no language restrictions. Two investigators independently selected eligible studies. Measures of association were pooled by using an inverse-variance weighted random-effects model. The heterogeneity among studies was examined using the I2 index. Publication bias was evaluated using the funnel plot. RESULTS: Twelve cross-sectional, one case-control and two prospective studies met our inclusion criteria including data from a total of 56,053 participants. The pooled odds ratio (OR) for the metabolic syndrome comparing the highest and lowest category of ferritin levels was 1.73 (95% CI: 1.54, 1.95; I2 = 75,4%). Subgroup analyses indicate that pooled OR was 1.92 (95% CI: 1.61, 2.30; I2 = 78%) for studies adjusting for C-reactive protein (CRP), and 1.52 (95% CI:1. 36, 1.69; I2 = 41%) for studies that did not adjust for CRP (P = 0.044). This finding was remarkably robust in the sensitivity analysis. We did not find publication bias. CONCLUSIONS: The meta-analysis suggests that increased ferritin levels are independently and positively associated with the presence of the metabolic syndrome with an odds ratio higher than 1.73.

Influencia del peso corporal en el pronóstico de las supervivientes de cáncerde mama; abordaje nutricional tras el diagnóstico / Influence of body weight on the prognosis of breast cancer survivors; nutritional approach after diagnosis

La obesidad combinada con el cáncer de mama constituye un problema de salud pública dada la gran incidencia y prevalencia de ambas enfermedades. El objetivo de esta revisión es conocer el estado actual de las investigaciones sobre la relación entre el peso de las pacientes con cáncer de mama y su pronóstico. El sobrepeso y la obesidad en el momento del diagnóstico se asocian con un peor pronóstico en las mujeres supervivientes de cáncer de mama. Estudios observacionales muestran un aumento del 33% de la mortalidad entre las supervivientes obesas en comparación con las no obesas. Además, el aumento de peso en estas pacientes es común tras del diagnóstico y es mayor aún en las que reciben quimioterapia. Se observan ganancias de 2 - 8kg de peso en el 68% de las pacientes a los tres años del diagnóstico. Cada aumento de 5 kg de peso se relaciona con un aumento del 13% en la mortalidad por cáncer de mama. Se desconocen los mecanismos que producen este aumento de peso, pero sí se observa que cuanto mayor es éste, mayor es el riesgo de padecer enfermedades cardiometabólicas asociadas lo que conduce a una peor calidad de vida y menor supervivencia global. Por otro lado, el exceso de tejido adiposo actúa como promotor indirecto de la proliferación celular tumoral y del aumento de los estrógenos circulantes. De ahí la importancia de prevenir un exceso de peso en estas pacientes. Ante las limitaciones que supone la poca cantidad de estudios controlados aleatorios que estudien específicamente la dieta a aplicar en casos de cáncer de mama, los estudios actuales señalan que una dieta saludable, baja en grasa y azúcares simples, con alta proporción de frutas, vegetales y productos integrales tiene el potencial de reducir significativamente la morbilidad y el riesgo de recurrencia, mejorando por tanto, el pronóstico y la calidad de vida a largo plazo (AU)

Obesity combined with breast cancer is a public health problem, given the high incidence and prevalence of both diseases. The aim of this review is to determine the current status of research on the relationship between the body weight of breast cancer patients and their prognosis. Overweight and obesity at the time of diagnosis are associated with a worse prognosis in breast cancer survivors. Observational studies show that breast cancer mortality is 33% higher in obese than in non-obese survivors. Furthermore, weight gain after diagnosis is common in these patients and is even greater in those receiving chemotherapy. Weight gains of 2-8 kg are observed in 68% of patients 3 years after diagnosis. Each 5kg increase in body weight is associated with a 13% increase in breast cancer specific mortality. The mechanisms that cause this weight gain are not totally known. A higher weight gain is also associated with higher the risk of co-morbid cardiometabolic diseases, which worsen the quality of life and shorten overall survival. On the other hand, excess adipose tissue is an indirect promoter of tumor cell proliferation and releases circulating estrogens. Hence, preventing excess weight is important in these patients. An important limitation is the small number of randomised controlled trials investigating the type of diet that could be recommended specifically to breast cancer survivors. The evidence from current studies suggests that a healthy diet, low in fat and simple sugars and with a high proportion of fruit, vegetables and wholegrain products, has the potential to reduce morbidity and the risk of recurrence significantly, thus improving prognosis and quality of life in the long term (AU)

Adverse effects of low occupational cadmium exposure on renal and oxidative stress biomarkers in solderers.

OBJECTIVES: Recent studies suggest adverse health effects after low exposure to cadmium (Cd). Brazing with Cd-containing solder exposes workers to Cd. The purpose of this study was to assess: (1) indicators of Cd exposure in blood (Cd-B)/ urine (Cd-U); (2) the association between Cd-B, Cd-U and renal and oxidative stress biomarkers. METHODS: In this cross-sectional study Cd-B, Cd-U, renal (ie, N-acetyl-ß-D-glucosaminidase/urinary intestinal alkaline phosphatase (IAP)/microalbumin/beta-2-microglobulin/retinol binding protein and oxidative stress markers (ie, derivatives of reactive oxygen metabolites/glutathione peroxidase/superoxide dismutase (SOD)/ advanced oxidation protein products/8-hydroxy-2'-deoxyguanosin/8-isoprostanes) were determined in 36 solderers. RESULTS: Multiple linear regression analysis adjusting for age and pack-years of smoking show that IAP is statistically significantly associated with Cd-B (B=0.24; SE=0.11) and Cd-U (B=0.15; SE=0.07). Also SOD is statistically significantly associated with Cd-B (B=62.96; SE=29.62). The association between SOD and Cd-U is of borderline statistical significance (B=37.69; SE=19.59). CONCLUSIONS: While there is still some debate as whether the Cd-induced tubular effects are reversible or not, IAP and SOD appear as sensitive and potentially useful early biomarkers for the health surveillance of workers exposed to low levels of Cd.

Prevalence of overweight and obesity among 6-to 9-year-old school children in Cuenca, Ecuador: relationship with physical activity, poverty, and eating habits.

BACKGROUND: The high prevalence of childhood overweight and obesity is a health problem worldwide. In developing countries, we lack information on the extent of the problem and the risk factors involved. OBJECTIVE: To determine the prevalence rates of overweight and obesity and of abdominal obesity, and their relationship with physical activity, poverty, and eating habits in schoolchildren in Cuenca, Ecuador. METHODS: A cross-sectional survey in a representative sample (n = 743) schoolchildren aged 6 to 9 years was conducted. Overweight and obesity were detected using the International Obesity Task Force cutoffs according to body mass index (BMI), and abdominal obesity was detected according to waist circumference. Poverty, physical activity, and eating habits were assessed with validated questionnaires. RESULTS: The prevalence rates of overweight and obesity and of abdominal obesity were 26.0% and 10.6%, respectively. There were no differences between the sexes, but the prevalence of overweight and obesity was 1.5- to 2-fold higher in 9-year-old than in 6-year-old children (p < .05). Multivariate models demonstrated that higher BMI and waist circumference were significantly related to low physical activity and nonpoverty. Insufficient physical activity (in 75% of children) was associated with a 13% to 18% increased risk of overweight and obesity and abdominal obesity. Eating breakfast and eating more than three meals per day (in 96.7% and 85.9% of children, respectively) were not related to the prevalence of overweight and obesity. Eating fruits during school break was associated with a lower BMI.L CONCLUSIONS: The high prevalence of overweight and obesity observed in schoolchildren increased from the ages of 6 to 9 years and was associated with insufficient physical activity and nonpoverty. Promoting physical activity and fruit consumption in school snacks should be explored as intervention measures to prevent and reduce overweight and obesity in Cuenca schoolchildren.

[Influence of body weight on the prognosis of breast cancer survivors; nutritional approach after diagnosis]. / Influencia del peso corporal en el pronóstico de las supervivientes de cáncer de mama; abordaje nutricional tras el diagnóstico.

Obesity combined with breast cancer is a public health problem, given the high incidence and prevalence of both diseases. The aim of this review is to determine the current status of research on the relationship between the body weight of breast cancer patients and their prognosis. Overweight and obesity at the time of diagnosis are associated with a worse prognosis in breast cancer survivors. Observational studies show that breast cancer mortality is 33% higher in obese than in non-obese survivors. Furthermore, weight gain after diagnosis is common in these patients and is even greater in those receiving chemotherapy. Weight gains of 2-8 kg are observed in 68% of patients 3 years after diagnosis. Each 5 kg increase in body weight is associated with a 13% increase in breast cancer specific mortality. The mechanisms that cause this weight gain are not totally known. A higher weight gain is also associated with higher the risk of co-morbid cardiometabolic diseases, which worsen the quality of life and shorten overall survival. On the other hand, excess adipose tissue is an indirect promoter of tumor cell proliferation and releases circulating estrogens. Hence, preventing excess weight is important in these patients. An important limitation is the small number of randomised controlled trials investigating the type of diet that could be recommended specifically to breast cancer survivors. The evidence from current studies suggests that a healthy diet, low in fat and simple sugars and with a high proportion of fruit, vegetables and wholegrain products, has the potential to reduce morbidity and the risk of recurrence significantly, thus improving prognosis and quality of life in the long term.

La obesidad combinada con el cáncer de mama constituye un problema de salud pública dada la gran incidencia y prevalencia de ambas enfermedades. El objetivo de esta revisión es conocer el estado actual de las investigaciones sobre la relación entre el peso de las pacientes con cáncer de mama y su pronóstico. El sobrepeso y la obesidad en el momento del diagnóstico se asocian con un peor pronóstico en las mujeres supervivientes de cáncer de mama. Estudios observacionales muestran un aumento del 33% de la mortalidad entre las supervivientes obesas en comparación con las no obesas. Además, el aumento de peso en estas pacientes es común tras del diagnóstico y es mayor aún en las que reciben quimioterapia. Se observan ganancias de 2 ­ 8kg de peso en el 68% de las pacientes a los tres años del diagnóstico. Cada aumento de 5 kg de peso se relaciona con un aumento del 13% en la mortalidad por cáncer de mama. Se desconocen los mecanismos que producen este aumento de peso, pero sí se observa que cuanto mayor es éste, mayor es el riesgo de padecer enfermedades cardiometabólicas asociadas lo que conduce a una peor calidad de vida y menor supervivencia global. Por otro lado, el exceso de tejido adiposo actúa como promotor indirecto de la proliferación celular tumoral y del aumento de los estrógenos circulantes. De ahí la importancia de prevenir un exceso de peso en estas pacientes. Ante las limitaciones que supone la poca cantidad de estudios controlados aleatorios que estudien específicamente la dieta a aplicar en casos de cáncer de mama, los estudios actuales señalan que una dieta saludable, baja en grasa y azúcares simples, con alta proporción de frutas, vegetales y productos integrales tiene el potencial de reducir significativamente la morbilidad y el riesgo de recurrencia, mejorando por tanto, el pronóstico y la calidad de vida a largo plazo.

Diet and paraoxonase 1 enzymatic activity in diabetic foot patients from Romania and Belgium: favorable association of high flavonoid dietary intake with arylesterase activity.

BACKGROUND/AIMS: The antiatherosclerotic enzyme paraoxonase (PON1) is affected by disease and lifestyle. We investigated the impact of diet in diabetic foot patients from 2 European countries. METHODS: Dietary intake and serum PON1 activity, using as substrate paraoxon (paraoxonase) or phenylacetate (arylesterase), were assessed in patients from Bucharest (n = 40) and Antwerp (n = 30) and in 34 healthy controls. RESULTS: The diabetic patients had lower paraoxonase and arylesterase activities than the controls. Arylesterase was lowest in the Bucharest patients, 116 +/- 42 U/ml, versus 141 +/- 43 and 184 +/- 49 U/ml in the Antwerp patients and controls, respectively (p < 0.0005). The Bucharest patients had worse glycemic control, higher blood pressure, lower HDL cholesterol and a diet richer in cholesterol and poorer in monounsaturated fats and fish. In contrast, their median intake of vitamins E and C, folic acid and flavonoids was higher, 82 mg (range: 4-259 mg), versus 28 mg (range: 5-169 mg) aglycone units in Antwerp (p = 0.005). Flavonoid intake predicted arylesterase independently of HDL cholesterol, region and sex (beta = 0.27; p = 0.03), and patients with high intake achieved normal levels of arylesterase (30.1 +/- 10.0 U/micromol in the highest versus 21.0 +/- 8.2 U/micromol total cholesterol in the lowest tertile; p = 0.02). CONCLUSION: A flavonoid-rich diet is positively associated with PON1 arylesterase activity in diabetic foot patients.

Minimally-invasive and non-invasive continuous glucose monitoring systems: indications, advantages, limitations and clinical aspects.

Accurate and reliable devices sensing glucose on a (near)-continuous basis may facilitate specific therapeutic adjustments that need to be made to avoid hypo- and hyperglycaemic excursions, thereby improving metabolic control. Current continuous glucose monitoring (CGM) systems indicate the glucose level, the direction and magnitude of change of glucose levels, and can be used to assess glycaemic variability. In addition, real-time CGM sensors can serve as a tool to predict impending glucose excursions, thereby providing alarm signals of hypo- and hyperglycaemic values warning the patient to take preventative actions. Quality of life may also improve by using CGM via reducing the fear of hypoglycaemia. Particularly patients with brittle diabetes, hypoglycaemia unawareness, gastroparesis, pregnant women, or pump users, who are motivated to participate in their diabetes care and are technologically adept, may benefit from CGM. However, to successfully implement CGM in daily practice, these devices must be accurate and reliable, and one must be aware of the limitations of current CGM systems, that originate from physiological and technical aspects. Whether CGM succeeds in improving metabolic control, reducing hypoglycaemic episodes, and improving quality of life in the majority of patients remains to be proven. Should this be the case, real-time CGM may reduce chronic diabetic complications, and avoid hospitalisations, thereby reducing health care costs. In this article we will review indications, advantages, limitations, clinical and technical aspects of current minimally-invasive and non-invasive CGM sensors.

Glucose control and use of continuous glucose monitoring in the intensive care unit: a critical review.

Stress hyperglycemia recently became a major therapeutic target in the Intensive Care Unit (ICU) since it occurs in most critically ill patients and is associated with adverse outcome, including increased mortality. Intensive insulin therapy to achieve normoglycemia may reduce mortality, morbidity and the length of ICU and in-hospital stay. However, obtaining normoglycemia requires extensive efforts from the medical staff, including frequent glucose monitoring and adjustment of insulin dose. Current insulin titration is based upon discrete glucose measurements, which may miss fast changes in glycemia and which does not give a full picture of overall glycemic control. Recent evidence suggests that continuous monitoring of glucose levels may help to signal glycemic excursions and eventually to optimize insulin titration in the ICU. In this review we will summarise monitoring and treatment strategies to achieve normoglycemia in the ICU, with special emphasis on the possible advantages of continuous glucose monitoring.

A review of current evidence with continuous glucose monitoring in patients with diabetes.

Devices that measure glucose on a near-continuous basis may provide a better insight into glycemic profiles, allowing patients with diabetes to make therapeutic adjustments to improve metabolic control, thereby reducing the risk of diabetic complications. Motivated and technologically adept patients with brittle diabetes, hypoglycemia unawareness, diabetic pregnancy, or who use pumps might benefit.Current evidence of continuous glucose monitoring (CGM) on health outcome in patients with diabetes is critically reviewed. No data are available on chronic complications or mortality. Therefore, surrogate endpoints need to be investigated, particularly HbA1c, number of hypo- and hyperglycemic episodes, time within normal, high, or low glucose concentrations, glycemic variability, and quality of life.Randomized controlled trials (RCTs) using CGM in a retrospective way did not show metabolic improvement. In contrast, most RCTs applying real-time CGM showed a decrease in HbA1c, reduced glycemic variability, and a diminished number and length of hypo- and hyperglycemic events. Using accurate, real-time CGM devices improves quality of life by reducing the fear of unexpected hypoglycemic events. These beneficial effects were observed despite the fact that in most studies no clear treatment algorithm based on CGM results was provided to the patients. However, most trials were too short in duration, with a variable use of CGM, and were performed in small study samples.In conclusion, real-time CGM systems can improve metabolic control, reduce hypoglycemic episodes, and improve quality of life. Whether this holds true for longer time periods and in the majority of patients remains to be proven. In the long term, CGM might help to reduce chronic diabetes complications and perhaps also mortality, thereby reducing health care costs.

Iron-induced oxidative stress in haemodialysis patients: a pilot study on the impact of diabetes.

BACKGROUND: Administration of intravenous iron preparations in haemodialysis patients may lead to the appearance of non-transferrin bound iron which can catalyse oxidative damage. We investigated this hypothesis by monitoring the oxidative stress of haemodialysis patients and the impact of iron and diabetes mellitus herein. MATERIALS AND METHODS: Baseline values of serum iron and related proteins, transferrin glycation, non-transferrin bound iron, antioxidant capacity and lipid peroxidation (malondialdehyde) of 11 haemodialysis patients (six non-diabetic and five type 2 diabetes) were compared to those of non-haemodialysis control subjects (non-diabetic and type 2 diabetes). Changes in these parameters were monitored during haemodialysis before and after iron administration. RESULTS: Baseline values of malondialdehyde correlated with ferritin concentration (r = 0.664, P = 0.036) and were elevated to the same extent in non-diabetic and diabetic haemodialysis patients (median of 1.09 compared to 0.60 mumol/l in control persons, P < 0.02). After iron infusion, transferrin saturation increased more markedly in non-diabetic subjects from 28% to 185% vs. from 33% to 101% in diabetic patients (P = 0.008). This increase was accompanied by the appearance of non-transferrin bound iron (5.91 +/- 1.33 micromol/l), a loss in plasma iron-binding antioxidant capacity and a further increase in malondialdehyde which was more pronounced in diabetic patients (from 0.93 +/- 0.30 micromol/l to 2.21 +/- 0.69 micromol/l vs. from 1.21 +/- 0.42 micromol/l to 1.86 +/- 0.56 micromol/l in the non-diabetic subjects, P = 0.046). CONCLUSIONS: In haemodialysis patients, higher lipid peroxidation is determined by higher body iron stores. The increase induced by iron infusion is accompanied by a loss in iron-binding antioxidant capacity and is more pronounced in diabetes mellitus.

Impact of oxidative stress on the endothelial dysfunction of children and adolescents with type 1 diabetes mellitus: protection by superoxide dismutase?

Diabetes mellitus is associated with endothelial dysfunction and oxidative stress (OS). We investigated whether these abnormalities are interrelated in children and adolescents with type 1 diabetes mellitus (T1DM) and if early OS markers predictive of vascular dysfunction can be identified. Thirty-five T1DM patients were matched for sex, age, height, and weight with nondiabetic subjects as healthy controls (CO). Flow-mediated dilatation (FMD), carotid intima media thickness (IMT), and OS status in fasting blood were measured. Diabetic children had impaired FMD (6.68+/-1.98 versus 7.92+/-1.60% in CO, p=0.004), which was more pronounced in boys. The degree of FMD impairment was not related to the lower plasma levels of antioxidants or to the higher glucose, glycation, lipids, and peroxidation products. Erythrocyte superoxide dismutase activity, copper/zinc superoxide dismutase (Cu/Zn SOD), was higher in diabetic subjects (1008+/-224 versus 845+/-195 U/g Hb in CO, p=0.003) and was positively associated with FMD. After correcting for diabetes and gender, the subgroup of children with high Cu/Zn SOD (>955 U/g Hb) had a significantly better FMD (p=0.035). These results suggest that higher circulating Cu/Zn SOD could protect T1DM children and adolescents against endothelial dysfunction. Low Cu/Zn SOD is a potential early marker of susceptibility to diabetic vascular disease.

Intensive insulin therapy in the intensive care unit: assessment by continuous glucose monitoring.

OBJECTIVE: Hyperglycemia occurs in most critically ill patients. Using continuous glucose monitoring (CGM), we investigated whether intensive insulin therapy based on discontinuous glucose monitoring can achieve normoglycemia (80-110 mg/dl) in a medical intensive care unit (MICU). RESEARCH DESIGN AND METHODS: Fifty adults (men/women 31/19, age 62 +/- 16 years, nondiabetic/diabetic 30/20, intravenous/subcutaneous insulin 22/28, and Acute Physiology and Chronic Health Evaluation II score 22 +/- 7) were prospectively recruited. Forty-eight-hour CGM was performed using a subcutaneous glucose sensor (GlucoDay) and compared with arterial glycemia. Main outcome measures were percent of time in normoglycemia and accuracy/applicability of CGM. RESULTS: During 48-h CGM, glycemia reached target (80-110 mg/dl) in only 22 +/- 18%, was >140 mg/dl in 39 +/- 27%, and was <60 mg/dl in 5 +/- 10% of the time. Patients on subcutaneous versus intravenous insulin had more glycemia readings >110 mg/dl (P = 0.016). Glycemia was higher in diabetic patients (170 +/- 77 vs. 129 +/- 35 mg/dl, P = 0.013). BMI was an independent determinant for bad glycemic control (beta = 0.73, P < 0.0001). Diabetic state (beta = 0.47, P < 0.0001), septic shock (beta = 0.22, P = 0.045), sequential organ failure assessment score (beta = 0.40, P = 0.001), and use of corticoids (beta = 0.28, P = 0.014) and inotropics (beta = -0.24, P = 0.035) were independent determinants of insulin dose. GlucoDay values and arterial glycemia correlated well (r = 0.85, P < 0.0001, n = 555 after six-point calibration), with 97% of data falling in regions A and B of error grid analysis. There were no adverse events using GlucoDay. CONCLUSIONS: GlucoDay, a well-tolerated 48-h CGM system, revealed that normoglycemia was only achieved 22% of the time in MICU patients. Further studies should investigate whether application of CGM to titrate insulin therapy can improve patient outcome.

Iron-binding antioxidant capacity is impaired in diabetes mellitus.

Increased lipid peroxidation contributes to diabetic complications and redox-active iron is known to play an important role in catalyzing peroxidation reactions. We aimed to investigate if diabetes affects the capacity of plasma to protect against iron-driven lipid peroxidation and to identify underlying factors. Glycemic control, serum iron, proteins involved in iron homeostasis, plasma iron-binding antioxidant capacity in a liposomal model, and non-transferrin-bound iron were measured in 40 type 1 and 67 type 2 diabetic patients compared to 100 nondiabetic healthy control subjects. Iron-binding antioxidant capacity was significantly lower in the plasma of diabetic subjects (83 +/- 6 and 84 +/- 5% in type 1 and type 2 diabetes versus 88 +/- 6% in control subjects, p < 0.0005). The contribution of transferrin, ceruloplasmin, and albumin concentrations to the iron-binding antioxidant capacity was lost in diabetes (explaining only 4.2 and 6.3% of the variance in type 1 and type 2 diabetes versus 13.9% in control subjects). This observation could not be explained by differences in Tf glycation, lipid, or inflammatory status and was not associated with higher non-transferrin-bound iron levels. Iron-binding antioxidant capacity is decreased in diabetes mellitus.

A novel method to quantify in vivo transferrin glycation: applications in diabetes mellitus.

BACKGROUND: In vitro glycation of transferrin leads to increased oxidative stress by impairing iron-binding antioxidant capacity. The aim of this study is to develop a method to evaluate in vivo transferrin glycation in diabetes. METHODS: We adapted the nitroblue tetrazolium assay to measure in micro-well plates the fructosamine content of transferrin isolated from serum by immunocomplexation. RESULTS: Introduction of the immunocomplexation step did not affect the analytical performance of the fructosamine measurement and analytical variability was lower than 7%. The diabetic group (n=107) had significantly higher transferrin glycation (1.39+/-1.12 versus 0.79+/-1.09 micromol fructosamine/g transferrin in the non-diabetic group, n=91, p<0.0005) and this was most pronounced in type 1 diabetes (1.95+/-1.02 versus 1.06+/-1.04 micromol fructosamine/g transferrin in type 2, p<0.0005). Transferrin glycation was associated with parameters of glycaemic control but did not correlate with serum iron or total iron-binding capacity. Total iron-binding capacity was lower in type 1 diabetes (63+/-9 versus 69+/-12 micromol/l in type 2, p<0.05) and was mainly determined by transferrin concentration. CONCLUSIONS: These results indicate that the adapted nitroblue tetrazolium assay combined with immunocomplexation of serum transferrin is suitable to detect differences in in vivo transferrin glycation between non-diabetic, type 1 and type 2 diabetic subjects.

Impact of diabetes mellitus on the relationships between iron-, inflammatory- and oxidative stress status.

BACKGROUND: Diabetes is an inflammatory condition associated with iron abnormalities and increased oxidative damage. We aimed to investigate how diabetes affects the interrelationships between these pathogenic mechanisms. METHODS: Glycaemic control, serum iron, proteins involved in iron homeostasis, global antioxidant capacity and levels of antioxidants and peroxidation products were measured in 39 type 1 and 67 type 2 diabetic patients and 100 control subjects. RESULTS: Although serum iron was lower in diabetes, serum ferritin was elevated in type 2 diabetes (p = 0.02). This increase was not related to inflammation (C-reactive protein) but inversely correlated with soluble transferrin receptors (r = - 0.38, p = 0.002). Haptoglobin was higher in both type 1 and type 2 diabetes (p < 0.001) and haemopexin was higher in type 2 diabetes (p < 0.001). The relation between C-reactive protein and haemopexin was lost in type 2 diabetes (r = 0.15, p = 0.27 vs r = 0.63, p < 0.001 in type 1 diabetes and r = 0.36, p = 0.001 in controls). Haemopexin levels were independently determined by triacylglycerol (R(2) = 0.43) and the diabetic state (R(2) = 0.13). Regarding oxidative stress status, lower antioxidant concentrations were found for retinol and uric acid in type 1 diabetes, alpha-tocopherol and ascorbate in type 2 diabetes and protein thiols in both types. These decreases were partially explained by metabolic-, inflammatory- and iron alterations. An additional independent effect of the diabetic state on the oxidative stress status could be identified (R(2) = 0.5-0.14). CONCLUSIONS: Circulating proteins, body iron stores, inflammation, oxidative stress and their interrelationships are abnormal in patients with diabetes and differ between type 1 and type 2 diabetes.

Effect of N-acetylcysteine on neutrophil activation markers in healthy volunteers: in vivo and in vitro study.

BACKGROUND AND AIMS: Neutrophil activation is implicated in the pathogenesis of inflammatory processes such as chronic obstructive pulmonary disease (COPD). We wished to evaluate both in vivo and in vitro whether N-acetylcysteine (NAC) has an effect on the response of activated neutrophils. METHODS: Ten healthy volunteers took NAC (600 mg daily) for 14 days. The effects on basal and fMLP-induced respiratory burst and chemotaxis were assessed at baseline, 2 h and 14 days after NAC intake. Neutrophils from healthy volunteers (NAC naïve) were pre-incubated with NAC for 30 min and the effects on the release of elastase and IL-8, the respiratory burst in response to fMLP and PMA, on TNFalpha-induced NFkappaB activation and on the migration across an endothelial-epithelial bilayer were investigated. RESULTS: PMA and fMLP-induced neutrophil respiratory burst and chemotaxis were lower after 14 days of NAC intake but not after 2 h. In vitro incubation with NAC inhibited release of elastase (p < 0.05), IL-8 (p < 0.05), respiratory burst and NFkappaB activation at 10 mM but not at lower concentrations. This was accompanied by a decrease in cellular ATP content. CONCLUSIONS: Our results suggest that acute in vitro addition of NAC can modulate neutrophil activity only when used at the high concentrations which directly affect cellular metabolism. On the other hand, the lower doses of NAC given in vivo might require longer times in order to achieve sustained effects on the cellular thiols which lead to changes in the redox status.

Time course of oxidative stress status in the postprandial and postabsorptive states in type 1 diabetes mellitus: relationship to glucose and lipid changes.

OBJECTIVE: The aim of this study was to compare oxidative stress status (OSS) with blood glucose and lipid changes during the fasting, postprandial and postabsorptive phases in type 1 diabetes mellitus. METHODS: Twenty-three patients on intensive insulin treatment received a standard fat-rich breakfast and lunch. OSS was monitored at fasting (F), just after the post-breakfast glycemia peak (BP) (identified by continuous subcutaneous glucose monitoring), 3.5-h post-breakfast (B3.5), just after the post-lunch peak (LP), just after the post-lunch dale (LD) and 5 hours after lunch (L5). RESULTS: Whereas whole blood glutathione and plasma protein thiols increased in the postprandial period (from 6.52 +/- 1.20 (F) to 7.08 +/- 1.45 micromol/g Hb (BP), p = 0.005), ascorbate decreased gradually from 44 +/- 17 (F) to 39 +/- 19 micromol/L (LD), p = 0.015. Retinol and alpha-tocopherol also decreased from 27.1 +/- 7.0 (F) to 25.3 +/- 5.2 micromol/L (BP), p = 0.005. Uric acid decreased later, from 213 +/- 77 (BP) to 204 +/- 68 micromol/L (B3.5), p = 0.01, but then increased in LP (231 +/- 70 micromol/L) and LD to values higher than F (215 +/- 64, micromol/L, p = 0.01). Malondialdehyde increased gradually from 1.02 +/- 0.36 (F) to a maximum of 1.14 +/- 0.40 micromol/L (LP). In the postabsorptive phase (L5) all parameters except for thiols reverted to fasting concentrations. CONCLUSIONS: In type 1 diabetes lipid peroxidation increases during the postprandial phase in parallel to glucose and triglyceride changes. Blood antioxidants, however, followed diverse patterns of change.

Cell-mediated LDL oxidation: the impact of transition metals and transferrin.

Activated monocytes release oxygen radicals by respiratory burst and oxidative damage can be accelerated by transition metals. We investigated the cell-mediated and metal-catalysed in vitro oxidation of low-density lipoproteins (LDL), as well as the impact of the metal-binding protein transferrin (Tf). LDL oxidation was measured by monitoring the increase in fluorescence (350/440 nm excitation/emission). Maximal respiratory burst by U937 cells was achieved after 96 h differentiation with retinoic acid and dihydroxyvitamin D3 followed by stimulation with opsonised zymosan. Addition of activated cells resulted in the LDL oxidation, even in the absence of transition metals. Moreover, activated cells greatly enhanced metal-catalysed oxidative modifications, especially in the presence of copper. By binding metals, Tf was able to strongly impair this process. In conclusion, by generating oxygen radicals, activated U937 cells were able to oxidise LDL. The oxidising process was most pronounced in the presence of copper and could be blocked by Tf.

Postprandial glucose monitoring in type 1 diabetes mellitus: use of a continuous subcutaneous monitoring device.

BACKGROUND: Pre-prandial glucose gives insufficient information on glycemic excursions throughout the day. We aimed to test a continuous subcutaneous glucose-monitoring device (GlucoDay) to describe postprandial glucose changes. METHODS: In 23 T1DM patients, 24-h GlucoDay registrations were started about 14 h before receiving a standard breakfast B and 3 h later lunch L. RESULTS: The 3-min glucose values were computed into parameters describing the postprandial changes after B and L. Two-hour glucose was higher after B (243 +/- 69 vs 180 +/- 79 mg/dL after L, p < 0.0001). Maximum glycemia (313 +/- 105 mg/dL after B and 304 +/- 119 after L, p < 0.0001) was higher and was reached after 78 and 57 min respectively. Three-hour AUC was higher but 30-min AUC was lower after B (5725 +/- 2414 vs 7488 +/- 2208 min mg/dL after L, p = 0.004). Glucose spikes (maximum peak minus fasting plasma glucose) were similar after B and L but the difference between maximum and minimum values was smaller after B (165 +/- 110 vs 219 +/- 115 mg/dL after L, p = 0.020). Duration of hyperglycemic periods >200, 140 or 126 mg/dL were not different after B or L, but time spent at glucose <100 mg/dL was longer after L (p < 0.0001). CONCLUSIONS: These results illustrate the use of subcutaneous glucose registration to characterize postprandial glycemia patterns in T1DM. Application of such methods to evaluate this and other clinical situations in DM can lead to therapeutic and dietary adjustments and ultimately improve glycemic control.