Angelos A. Evangelopoulos

Alpha-Lipoic Acid and Diabetic Neuropathy

Diabetic neuropathy presents a major public health problem. It is defined by the symptoms and signs of peripheral nerve dysfunction in diabetic patients, in whom other causes of neuropathy have been excluded. Pathogenetic mechanisms that have been implicated in diabetic neuropathy are: a) increased flux through the polyol pathway, leading to accumulation of sorbitol, a reduction in myo-inositol, and an associated reduced Na+-K+-ATPase activity, and b) endoneurial microvascular damage and hypoxia due to nitric oxide inactivation by increased oxygen free radical activity. Alpha-lipoic acid seems to delay or reverse peripheral diabetic neuropathy through its multiple antioxidant properties. Treatment with alpha-lipoic acid increases reduced glutathione, an important endogenous antioxidant. In clinical trials, 600 mg alpha-lipoic acid has been shown to improve neuropathic deficits. This review focuses on the relationship of alpha-lipoic acid and auto-oxidative glycosylation. It discusses the impact of alpha-lipoic acid on hyperglycemia-induced oxidative stress, and examines the role of alpha-lipoic acid in preventing glycation process and nerve hypoxia.

An inverse relationship between cumulating components of the metabolic syndrome and serum magnesium levels

Metabolic syndrome has been defined as the presence of abdominal obesity combined with 2 of the following factors: hypertension, dyslipidemia, and impaired glucose tolerance, or diabetes mellitus. Magnesium is an essential cofactor for more than 300 enzymes involved in carbohydrate and lipid metabolism. In this study, we enrolled 117 consecutive overweight and obese patients and we measured serum magnesium levels together with fasting serum glucose, high-density lipoprotein cholesterol, and triacylglycerols. A strong inverse relationship between magnesium levels in serum and the presence of metabolic syndrome was noticed. Moreover, magnesium levels decreased as the number of components of metabolic syndrome increased. Also, there is an inverse relationship between serum magnesium levels and high-sensitivity C-reactive protein. We concluded that decreased levels of serum magnesium are associated with increased risk for metabolic syndrome, perhaps by a low-grade inflammation process.

Neck circumference is correlated with triglycerides and inversely related with HDL cholesterol beyond BMI and waist circumference.

Neck circumference, beyond a measure of obesity, is a unique fat depot with increasing significance. This study aimed to investigate the association between neck circumference and biomarkers, indicators of cardiovascular risk.

Metformin and cancer.

Metformin is well-known as an anti-diabetic drug, but it seems to possess anti-cancerous properties as well. Adenosine monophosphate-activated protein kinase (AMPK) is a highly conserved regulator of the cellular response to the presence of low energy in all eukaryotic cells. It is considered a key sensor of the balance of cellular ATP and AMP concentrations. LKB1 serine/threonine kinase is a divergent yet evolutionarily well-conserved kinase, biochemically sufficient to activate AMPK in vitro and genetically required for AMPK activation. Because of this potent connection to AMPK, LKB1 may act as a central regulator of metabolism in vivo. Once activated, AMP kinase phosphorylates the transcriptional activator TorC2, thereby blocking its nuclear translocation and inhibiting the expression of genes involved in gluconeogenesis. Data suggest that LKB1/AMPK signaling plays a role in protection from apoptosis, specifically in response to agents that increase the cellular AMP/ATP ratio. Active AMPK signaling offers a protective effect by providing the cell with time to reverse the aberrantly high ratio of AMP/ATP. If unable to reverse this ratio, the cell will eventually undergo cell death. These observations offer the provocative suggestion of a potential therapeutic window in which LKB1-deficient tumor cells may be acutely sensitive to AMP analogues or sensitized to cell death by other stimuli when treated in combination with agents that increase the AMP/ATP ratio. LKB1 therefore is a classical tumor suppressor. AMPK is a direct LKB1 substrate. A consequence of AMPK activation by LKB1 is the inhibition of the mammalian target of rapamycin (mTOR) C1 pathway. Metformins anti-cancerous properties have been demonstrated in various cancer cells in vitro, such as lung, pancreatic, colon, ovarian, breast, prostate, renal cancer cells, melanoma, and even in acute lymphoblastic leukemia cells. To test metformins action in vivo, mice were implanted with transformed mammary epithelial cells and treated with three cycles of metformin and with the anthracycline doxorubicin. When combined with doxorubicin, metformin wiped out tumors and prevented recurrence. Metformin alone had no effect, and doxorubicin as a single agent initially shrank tumors, but they regrew later. Virtually no cancer stem cells were recovered immediately after treatment and the complete response was sustained for nearly two months. Further studies are needed to assess the anti-cancerous potentials of metformin in vivo. This article reviews the current knowledge on the actions of LKB1/AMPK and the effectiveness of metformin in cancer, specifically in diabetes patients.

Resveratrol and diabetes.

Resveratrol is a stilbene compound, and a phytoalexin, synthesized by plants in response to stressful stimuli, usually caused by infection. It is abundantly present in red wine, ports and sherries, red grapes, blueberries, peanuts, itadori tea, as well as hops, pistachios, and in grape and cranberry juices. The anti-hyperglycemic effects of resveratrol seem to be the result of an increased action of the glucose transporter in the cytoplasmic membrane. Studies on rats with streptozotocin-induced diabetes have demonstrated that the expression of the insulin-dependent glucose transporter, GLUT4, is increased after resveratrol ingestion. Also, resveratrol enhances adiponectin levels, which could be one of the potential mechanisms by which it improves insulin sensitivity. Another important observation is that resveratrol induces the secretion of the gut incretin hormone, glucagon-like peptide-1. Resveratrol is also reported to activate Sir2 (silent information regulatory 2), a SIRT1 homolog, thus mimicking the benefits of calorie restriction. It produces a wide variety of effects in mammalian cells, including activation of AMP-activated protein kinase, which is involved in some of the same metabolic pathways as SIRT1, which may influence other mechanisms via the involvement of nuclear factor kappa B (NF-κB). In the near future, resveratrol-based therapies with either resveratrol or its analogs that have better bioavailability could be useful in the treatment of diabetes and its complications, either alone or in combination with other anti-diabetic drugs.

The Therapeutic Potential of Milk Thistle in Diabetes

Milk thistle has been known for more than 2.000 years as a herbal remedy for a variety of disorders. It has mainly been used to treat liver and gallbladder diseases. Silibum marianum, the Latin term for the plant, and its seeds contain a whole family of natural compounds, called flavonolignans. Silimarin is a dry mixture of these compounds; it is extracted after processing with ethanol, methanol, and acetone. Silimarin contains mainly silibin A, silibin B, taxifolin, isosilibin A, isosilibin B, silichristin A, silidianin, and other compounds in smaller concentrations. Apart from its use in liver and gallbladder disorders, milk thistle has recently gained attention due to its hypoglycemic and hypolipidemic properties. Recently, a substance from milk thistle has been shown to possess peroxisome proliferator-activated receptor γ (PPARγ) agonist properties. PPARγ is the molecular target of thiazolidinediones, which are used clinically as insulin sensitizers to lower blood glucose levels in diabetes type 2 patients. The thiazolidinedione type of PPARγ ligands is an agonist with a very high binding affinity. However, this ligand type demonstrates a range of undesirable side effects, thus necessitating the search for new effective PPARγ agonists. Interestingly, studies indicate that partial agonism of PPARγ induces promising activity patterns by retaining the positive effects attributed to the full agonists, with reduced side effects. In this review, the therapeutic potential of milk thistle in the management of diabetes and its complications are discussed.

Vertebral osteomyelitis and native valve endocarditis due to Staphylococcus simulans: a case report

BackgroundStaphylococcus simulans is a common animal pathogen that occasionally can colonize human skin. Unlike other coagulase-negative staphylococci, S. simulans tends to cause more severe infections that resemble those caused by S. aureus. We present a case of vertebral osteomyelitis and endocarditis due to S. simulans. To the best of our knowledge, this is the first report of vertebral osteomyelitis associated with native valve endocarditis rather than orthopedic surgery.Case presentationA 46-year-old male butcher was admitted to the hospital with a 4-week history of high fever with profound sweating. He reported weakness in his legs and low back pain that compromised his walking ability. Blood cultures yielded Gram-positive cocci on Gram stain. These cocci were identified to the species level as S. simulans, a coagulase-negative staphylococcus. The patient was treated with antibiotics, which were discontinued after 6 months.ConclusionThis case illustrates the importance of identifying coagulase-negative staphylococci to the species level. Accurate identification of S. simulans would further help investigations defining its pathogenic role in human infections.

Association of butyrylcholinesterase with cardiometabolic risk factors among apparently healthy adults.

Background Although butyrylcholinesterase is widely distributed in different tissues of the human body, its physiological role has not yet been defined. This study aimed to explore the relationship between butyrylcholinesterase and lipids levels, among apparently healthy adults. Methods During 2009, 490 volunteers (46 ± 16 years, 40% men) who visited the outpatients’ office of our hospital for routine examinations were consecutively enrolled in the study (participation rate 85%). Biochemical analyses were performed through established procedures, after 12 h fasting, and haematological as well as biochemical parameters were measured. Anthropometric, lifestyle and dietary characteristics were also recorded to account for potential confounding. Results Butyrylcholinesterase activity was positively correlated with glucose, low-density lipoprotein (LDL)-cholesterol, total cholesterol, triglycerides, uric acid, haptoglobin and platelet count, after age–sex adjustments (all Ps < 0.05). Further adjustment for a series of anthropometric, lifestyle and clinical characteristics revealed that only BMI, LDL-cholesterol, total cholesterol and triglycerides were positively associated with serum butyrylcholinesterase activity. Conclusions This study demonstrated the positive association of serum butyrylcholinesterase activity with BMI, LDL-cholesterol, total cholesterol and triglycerides, a fact that could state a hypothesis for a novel marker of atherosclerotic disease that could – together with other biomarkers – improve our potential to assess cardiovascular disease risk.

The Impact of Demographic Characteristics and Lifestyle in the Distribution of Cystatin C Values in a Healthy Greek Adult Population

Background. The aim of the present study was to examine sources of variation for serum cystatin C in a healthy Greek population. Methods. Cystatin C together with basic clinical chemistry tests was measured in a total of 490 adults (46 ± 16 yrs, 40% males) who underwent an annual health check. Demographic, anthropometric, and lifestyle characteristics were recorded. Results. Higher values of cystatin C were observed among males (P = .04), participants aged over 65 years (P < .001), current smokers (P = .001) and overweight/obese participants (P = .03). On the contrary, alcohol consumption and physical activity seemed to have no influence on cystatin C levels (P = .61; P = .95, resp.). Conclusions. In interpreting serum cystatin C values in a healthy adult population, age, gender, Body Mass Index, and cigarette smoking need to be considered, and determination of reference ranges among distinct subpopulations seem to be prudent.

N-terminal ProBNP distribution and correlations with biological characteristics in apparently healthy Greek population: ATTICA study.

Brain natriuretic peptides are widely used as biomarkers of cardiovascular diseases and mainly heart failure. However, these markers are often found to be high even in apparently healthy participants, and little is known about which factors contribute to physiological change in plasma brain natriuretic peptide (BNP) and amino-terminal pro-B-type natriuretic peptide (NTproBNP) concentration in general populations. In this study, a random subsample of the ATTICA study was used (486 individuals) and serum NT-proBNP was measured. Approximately 20% of the participants had no detectable NT-proBNP values. Women had higher values of NT-proBNP than men (median [25th-75th percentiles]: 30.2 [15.8-54.3] vs 14.9 [4.0-28.1] pg/mL, P < .001]. Amino-terminal pro-B-type natriuretic peptide values were positively correlated with age (ρ = .140, P = .006) and inversely with body mass index (BMI; ρ = —.142, P = .005), creatinine (Cr) clearance (ρ = —.349, P < .001), and hemoglobin (ρ = —.249, P < .001) values. Linear regression analysis revealed that gender is the main contributor of NT-proBNP levels, followed by age, BMI, and Cr values.