Erifili Hatziagelaki

IL6 gene promoter polymorphisms and type 2 diabetes: joint analysis of individual participants' data from 21 studies

Several lines of evidence indicate a causal role of the cytokine interleukin (IL)-6 in the development of type 2 diabetes in humans. Two common polymorphisms in the promoter of the IL-6 encoding gene IL6, −174G>C (rs1800795) and −573G>C (rs1800796), have been investigated for association with type 2 diabetes in numerous studies but with results that have been largely equivocal. To clarify the relationship between the two IL6 variants and type 2 diabetes, we analyzed individual data on >20,000 participants from 21 published and unpublished studies. Collected data represent eight different countries, making this the largest association analysis for type 2 diabetes reported to date. The GC and CC genotypes of IL6 −174G>C were associated with a decreased risk of type 2 diabetes (odds ratio 0.91, P = 0.037), corresponding to a risk modification of nearly 9%. No evidence for association was found between IL6 −573G>C and type 2 diabetes. The observed association of the IL6 −174 C-allele with a reduced risk of type 2 diabetes provides further evidence for the hypothesis that immune mediators are causally related to type 2 diabetes; however, because the association is borderline significant, additional data are still needed to confirm this finding.

Body mass index in acute heart failure: association with clinical profile, therapeutic management and in‐hospital outcome

Increased body mass index (BMI) is a risk factor for heart failure, but evidence regarding BMI in acute heart failure (AHF) remains inconclusive. We sought to compare the clinical profile, treatment and in‐hospital outcome across BMI categories in a large international AHF cohort.

Short Term, Low Dose Thyroxin Treatment of Euthyroid Patients with Type 2 Diabetes improves Peripheral Blood Flow and Overall Insulin Sensitivity

Purpose: Variation of plasma thyroid hormone levels influences insulin sensitivity and peripheral glucose disposal. High thyroxin dose administration to healthy humans induces insulin resistance, whereas moderate doses increase peripheral glucose disposal. An open-labeled, randomized and placebo-controlled intervention was performed in euthyroid type 2-diabetic patients, to examine the effect of a small thyroxin dose within the euthyroid range on postprandial forearm muscle glucose uptake, insulin sensitivity, in vitro glucose uptake and GLUT4 recruitment in the plasma membrane of monocytes. Methods: A meal was given to eleven euthyroid, treatment-naive, type-2 diabetic patients (aged 43 ± 3.8 yrs, BMI 27.48 ± 1.39 kg/m2, T3 119 ± 5.7 ng/dl, T4 8,13 ± 0.46 μg/dl, TSH 1.51 ± 0.14 μU/ml, FT4 1.272 ± 0.047 ng/dl) before and after administration of 50 μg of thyroxin once daily for 2 months. Similarly, a placebo was given to eleven age, sex and BMI-matched euthyroid, type-2 diabetic patients. Blood was drawn for 300 min from a forearm deep vein and the radial artery for measurements of glucose, insulin, and GLUT4 abundance in peripheral monocytes. Forearm blood flow (BF) was measured with strain-gauge-plethysmography. Forearm glucose-uptake, and insulin sensitivity were assessed. After the first meal-tolerance-test, daily treatment with 50 μg of thyroxin or placebo was initiated for a 2-month period. Then a second identical test was repeated. Results: TSH, glucose, insulin levels and HbA1c reduced significantly in the treatment group. Peak-baseline BF and Glucose-uptake (AUC0-300 min) increased significantly (1.685 ± 0.3 vs. 3.07 ± 0.15 ml/min per 100 cc tissue, p=0.0018) and (587 ± 68 vs. 1015 ± 131 μmol per 100 cc tissue, p=0.0051), respectively. All insulin-sensitivity indices improved post-treatment. Glucose uptake and GLUT4 abundance in monocytes also improved. The placebo group exhibited no change in all variables. Conclusion: Administration of small, subthyrotoxic doses of thyroxin to euthyroid diabetic patients improves peripheral glucose disposal, blood flow responses and overall insulin sensitivity. This could be of therapeutic importance by reducing the burden of hyperglycaemia and possibly the long term complications of diabetes.

Peripheral blood lymphocytes from patients with bipolar disorder demonstrate apoptosis and differential regulation of advanced glycation end products and S100B

Abstract Background: This study addresses the expression of the glycosylated proteins known as advanced glycation end products (AGEs), the calcium binding protein S100B and the apoptotic parameters cytochome c and caspase-3 activity in peripheral lymphocyte cytosolic extracts from a sample of bipolar disorder (BD) patients and healthy (control) subjects. Methods: Cross-sectional study of 35 patients with a clinical diagnosis of bipolar disease (10 euthymic, 12 depressed, 13 manic) and 10 healthy control subjects. Lymphocytes were used as a surrogate model in BD diagnosis and treatment. AGEs and S100B in lymphocyte cell extracts were measured by commercially available enzyme-linked immunosorbent assay. Results: AGEs were lower in all BD patients compared to healthy subjects. Depressed patients had approximately two-fold higher S100B levels compared to healthy subjects. Manic and depressed BD patients had increased superoxide dismutase mRNA levels. Apoptosis as measured by BAX/Bcl2 ratio, cytochrome c release, caspase-3 activity was increased in manic and depressed patients compared to healthy subjects. In the depressed patients, S100B levels correlated with cytochrome c release. Conclusions: In conclusion, our study shows decreased AGEs and increased S100B levels and caspase down-stream apoptosis in peripheral lymphocytes of BD patients that may underlie disease etiopathogenesis.

Predictors of Impaired Glucose Regulation in Patients with Non-Alcoholic Fatty Liver Disease

Introduction. Many patients with non-alcoholic fatty liver disease (NAFLD) have impaired glucose regulation or type 2 diabetes mellitus (DM). We investigated characteristics of NAFLD patients associated with hyperglycemia. Methods. During a 2-hour oral glucose tolerance test (OGTT), serum glucose and insulin were measured in 152 NAFLD patients. Results. 48.7% of NAFLD patients had hyperglycemia. Age (odds ratio (OR) = 1.08, 95% confidence interval (CI): 1.03–1.13), body mass index (BMI) (OR = 1.12, 95% CI: 1.01–1.25), and lower high-density lipoprotein cholesterol (HDL-C) (OR = 0.95, 95% CI: 0.92–0.98) proved to be independent predictors of hyperglycemia. After OGTT, 30 min insulin was lower in hyperglycemic patients (74.2 ± 49.7 versus 94.5 ± 53.9 μIU/mL, P = 0.02), while 90 min insulin (170.1 ± 84.6 versus 122.9 ± 97.7 μU/mL, P = 0.01) and 120 min insulin (164.0 ± 101.2 versus 85.3 ± 61.9 μIU/mL, P < 0.01) were higher. Conclusions. NAFLD patients with higher BMI, lower HDL-C, or older age were more likely to have impaired glucose metabolism. An OGTT could be of value for early diagnosis of DM among this population.

Association of mineralocorticoid receptor antagonist use and in-hospital outcomes in patients with acute heart failure

Mineralocorticoid receptor antagonists (MRAs) constitute a beneficial therapy in chronic heart failure, but their use in the acute heart failure (AHF) setting remains rather unexplored. To assess the effect of MRAs administered during hospitalization on in-hospital outcomes of patients with AHF, we performed a post-hoc analysis of the Acute Heart Failure Global Registry of Standard Treatment (ALARM-HF). Patients of the original study cohort (n = 4953) were categorized according to in-hospital MRA treatment status as MRA-treated (n = 1439) and untreated (n = 3514) subjects. Nearest-neighbor propensity score with 1:1 matching yielded a subsample of pairs of MRA-treated and MRA-untreated patients (n = 1003 in each treatment group) that were balanced in an extensive list of baseline characteristics. In-hospital mortality between MRA-treated and untreated patients were assessed by Cox regression analysis before and after adjustment for known prognostic factors and other concomitantly administered intravenous and oral HF specific therapies. In the matched cohort, in-hospital mortality was 4.2 vs 10.8% in MRA-treated vs untreated patients. Treatment with MRAs was associated with a reduction of in-hospital mortality [HR 0.372 (95% CI, 0.261–0.532), p < 0.001]. This association remained significant after adjustment for known prognostic factors and co-administered intravenous and oral HF therapies [HR: 0.618 (95% CI, 0.383–0.995), p = 0.048]. In conclusion, MRA therapy administered during hospitalization for AHF was associated with reduced in-hospital mortality. The role of MRAs in AHF deserves further examination in adequately powered randomized controlled studies.

Metabolic syndrome, independent of its components, affects adversely cardiovascular morbidity in essential hypertensives.

BACKGROUND The metabolic syndrome (MS) is widespread among hypertensive patients. However, the net impact of MS on major atherosclerotic events beyond the cardiovascular risk imposed by its individual components remains controversial in this group. We sought to assess both the independent and incremental prognostic role of MS for unfavorable cardiovascular events in a cohort of essential hypertensives. METHODS We followed up 2176 essential hypertensives free of cardiovascular disease for a median period of 40 months. All subjects had at least one annual visit. MS was defined according to the updated NCEP III criteria. Endpoint of interest was the incidence of stroke, coronary artery disease (CAD) and their composite. RESULTS MS was present at baseline in 819 hypertensives (37.6%). MS group presented increased prevalence of resistant hypertension in comparison to MS free group (18.4% versus 10.6%, p < 0.001). The incidence of the composite end-point was 3.1% (69 events) across the follow-up period. Patients with MS were more likely to experience major adverse cardiovascular events (MACE) in comparison to reference category (3.7% versus 1.9%, log rank p = 0.024). While MS was an independent predictor for MACE, none of the individual components of the syndrome was associated independently with the endpoint. MS provided incremental discriminative value (Harrells c, p < 0.05 for all) over individual risk factors for the incidence of MACE. CONCLUSIONS MS predicts adverse cardiovascular events in hypertensives incrementally of its individual components. Early identification of MS in this population may enable more accurate prediction of future cardiovascular risk and could implement more efficient strategies in terms of primary prevention.

A Longitudinal Study of Alterations of S100B, sRAGE and Fas Ligand in Association to Olanzapine Medication in a Sample of First Episode Patients with Schizophrenia

BACKGROUND & OBJECTIVE Neuroinflammation has been proposed as a major mechanism in schizophrenic disorder. Specifically, an increase in the inflammatory response in the central nervous system is capable of activating microglial cells, leading to the release of pro-inflammatory cytokines and thus activating apoptotic signaling. An increase in apoptosis may underlie a potential role of immune neuropathology in the etiopathogenesis of schizophrenia and specifically, the onset of the disorder. We analyzed in whole blood, levels of S100B, the receptor for advanced glycation end products (RAGE) and the apoptotic marker Fas Ligand in a sample of 13 first episode of schizophrenia twice at baseline before the initiation of any antipsychotic medication (A) and 6 weeks later following an antipsychotic monotherapy with olanzapine (B) and in a sample of 10 healthy controls. The S100B, RAGE and Fas Ligand showed statistically significant differences before and after treatment; the S100B measurements yielded a p-value of 0.004 while the soluble RAGE and Fas Ligand measurements yielded a p=0.03, and p=0.04 respectively. The differences between cases and controls were not statistically significant for all measurements, with the only exception being the S100B values where both samples A and B showed significantly higher values than the controls with p=8.5x10-8 and p=2.9x10-10 respectively. CONCLUSION The levels of S100B, RAGE, and Fas Ligand of drug-naive first episode psychosis patients with schizophrenia were significantly higher than that of the same medicated first episode psychosis patients, indicating that an increase of apoptotic signaling is present at the onset of schizophrenia and is also associated with treatment progress.

Short-term administration of a small thyroxine dose to euthyroid type 2 diabetic patients improves the fasting lipoprotein profile#

ABSTRACT Background: Although several studies have assessed the association between thyroid hormones and dyslipidaemia, whether influencing thyroid function improves the lipid profile in euthyroid diabetic patients has not been studied. Methods: Fasting lipids were assessed in 11 euthyroid, treatment naive patients with type 2 diabetes (T2DM) and a micronodular texture of the thyroid gland (age: 43 ± 3.8 years, body mass index (BMI) 27.5 ± 1.4 kg/m2, triiodothyronine (T3) 119 ± 5.7 ng/dl, thyroxine (T4) 8.13 ± 0.46 μg/dl, thyroid- stimulating hormone (TSH) 1.51 ± 0.14 μIU/ml, free thyroxine (FT4) 1.272 ± 0.047 ng/dl) before and after administration of 50 μg of T4 once daily for 2 months. A placebo was given to 11 age, sex and BMI-matched euthyroid, treatment naive patients with T2DM. Care was taken to avoid even subclinical hyperthyroidism. Results: TSH fell significantly post-treatment (1.51 ± 0.11 vs. 0.79 ± 0.11 μIU/ml, p < 0.0001), but remained within the reference range. Total cholesterol (212 ± 21 vs. 158 ± 10 mg/dl, p = 0.003), low-density lipoprotein cholesterol (146 ± 17 vs. 112 ± 9 mg/dl, p = 0.007), high density lipoprotein cholesterol (51 ± 4 vs. 40 ± 3 mg/dl p = 0.001), triglycerides (93 ± 13 vs. 72 ± 8 mg/dl, p = 0.015), apolipoprotein A1 (167 ± 15 vs. 127 ± 8 mg/dl, p = 0.004), apolipoprotein B (101 ± 13 vs. 72 ± 7 mg/dl, p = 0.009) and lipoprotein (a) (60 ± 15 vs. 41 ± 11 mg/dl p = 0.009) all fell significantly after T4 administration for 2 months. No changes were observed in the placebo group. Conclusions: Small doses of T4 administered to euthyroid patients with T2DM significantly improved lipid levels. This could contribute to a reduced risk of macrovascular complications.

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome—Metabolic Disease or Disturbed Homeostasis due to Focal Inflammation in the Hypothalamus?

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a complex disease characterized by debilitating fatigue, lasting for at least 6 months, with associated malaise, headaches, sleep disturbance, and cognitive impairment, which severely impacts quality of life. A significant percentage of ME/CFS patients remain undiagnosed, mainly due to the complexity of the disease and the lack of reliable objective biomarkers. ME/CFS patients display decreased metabolism and the severity of symptoms appears to be directly correlated to the degree of metabolic reduction that may be unique to each individual patient. However, the precise pathogenesis is still unknown, preventing the development of effective treatments. The ME/CFS phenotype has been associated with abnormalities in energy metabolism, which are apparently due to mitochondrial dysfunction in the absence of mitochondrial diseases, resulting in reduced oxidative metabolism. Such mitochondria may be further contributing to the ME/CFS symptomatology by extracellular secretion of mitochondrial DNA, which could act as an innate pathogen and create an autoinflammatory state in the hypothalamus. We propose that stimulation of hypothalamic mast cells by environmental, neuroimmune, pathogenic and stress triggers activates microglia, leading to focal inflammation in the brain and disturbed homeostasis. This process could be targeted for the development of novel effective treatments.