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Obesity is a chronic disease and a major public health problem due to its association with non-communicable diseases and all-cause mortality. An increased energy intake and decreased physical activity have been long recognized as the classical parameters that contribute to the development of obesity. However, several other, non-classical factors have also been associated with obesity through various complex mechanisms. Some of them are diet related, such as diet quality, dietary habits and speed of eating. Other factors are non-dietary, such as endocrine-disrupting chemicals, sleep quality and quantity, psychotropic medications and light at night. The scope of the present narrative review is to address these non-classical factors that are implicated in the pathogenesis of obesity, to clarify their potential role in the management of obesity and, where possible, to provide some practical clinical recommendations.

Hydroxytyrosol (HT) is a natural antioxidant found in olive products and characterized by well-documented beneficial effects on human health. Several research studies are ongoing that aim to investigate its potency and molecular mechanism of action. The present study aimed to investigate the potential effect of HT on human obesity through a randomized double-blind prospective design. HT in two different doses (15 and 5 mg/day) and a placebo capsule was administered to 29 women with overweight/obesity for six months and their weight and fat mass were monitored at three time points (baseline, 4, 12 and 24 weeks). Statistically significant weight and visceral fat mass loss (%weight loss: p = 0.012, %visceral fat loss: p = 0.006) were observed in the group receiving the maximum HT dosage versus placebo after 4 weeks of the intervention, with attenuation of these findings at 12 and 24 weeks of the study. Urine samples were collected during the intervention and analyzed via liquid chromatography-high-resolution mass spectrometry for untargeted metabolomic purposes and comparisons between study groups were performed. HT administration was safe and well-tolerated. To the best of our knowledge, this is the first human cohort investigating the effects of HT on obesity for a prolonged study period.

Ketone bodies are low chain organic substances with four carbon atoms, with β-hydroxybutyric acid and acetone being the main ketone bodies in blood circulation. Under physiological conditions their levels are low while during conditions of oxidative stress, such as exercise, fasting state and acute illness, ketone body levels are increased. Recent findings have shown that in patients with heart failure their plasma concentration is increased. There is a positive correlation between increased energy metabolism of myocardial cells and the levels of β-hydroxybutyric acid and acetone. Furthermore, it has been hypothesized that the mild ketosis caused by sodium glucose cotransporter 2 inhibitors is one of the possible pathogenetic mechanisms explaining the significant cardiovascular and renal benefits observed in patients with type 2 diabetes treated with these agents. The aim of the present review is to summarize the role of ketone bodies in both normal and pathological conditions, such as heart failure., Competing Interests: The authors declare no conflict of interest., (Copyright: © 2021 Termedia & Banach.)

Aims: Prevalence and risk factors of pre-symptomatic left ventricular systolic dysfunction (LVSD) in individuals with type 1 diabetes (T1D) have not been adequately studied. The present cross-sectional study assessed the prevalence of early LVSD in asymptomatic patients with type 1 diabetes and investigated potential risk factors., Methods: Consecutive patients with T1D, free of cardiovascular disease and significant evident microvascular complications were examined. LVSD was assessed by speckle-tracking echocardiography and calculation of global longitudinal strain (GLS). Abnormal GLS was defined as a value>-18.7%. We looked for possible associations between the presence of LVSD and patient demographic, clinical and laboratory characteristics, as well as with autonomic nervous system (ANS) function and arterial stiffness., Results: We enrolled 155 T1D patients (29.7% men, age 36.7 ± 13.1 years, diabetes duration 19.1 ± 10.0 years, HbA1c 7.5 ± 1.4% [58 ± 15 mmol/mol]). Early LVSD was prevalent in 53 (34.2%) patients. Multivariable analysis identified male gender (OR:4.14; 95% CI:1.39-12.31, p = 0.011), HbA1c (OR:1.59 per 1% increase; 95% CI:1.11-2.28, p = 0.011), glomerular filtration rate (GFR, OR:0.97; 95% CI:0.95-0.99, p = 0.010) and BMI (OR:1.19; 95% CI:1.06-1.34, p = 0.003) as independent predictors of LVSD presence., Conclusions: Early subclinical LVSD is a common finding in asymptomatic patients with T1D, free of macrovascular and significant microvascular complications. Apart from chronic hyperglycemia, increased adiposity may be implicated in its etiology. Further investigation is warranted to identify patients at high risk for whom early screening is required and to determine possible associations between risk markers identified in the present analysis and long-term outcomes., Competing Interests: Declaration of competing interest None. Drs Kapelios and Liatis take full responsibility for the contents of the article., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Aims: To study the impact of diabetic neuropathy, both peripheral sensorimotor (DPN) and cardiac autonomic neuropathy (CAN), on transcutaneous oxygen tension (TcPO 2 ) in patients with type 2 diabetes mellitus (T2DM)., Methods: A total of 163 participants were recruited; 100 with T2DM and 63 healthy individuals. Peripheral arterial disease (PAD) was defined as ankle-brachial index (ABI) values ≤0.90. Diagnosis of DPN was based on neuropathy symptom score and neuropathy disability score (NDS), while diagnosis of CAN on the battery of the cardiovascular autonomic function tests. TcPO 2 was measured using a TCM30 system., Results: Patients with T2DM had lower TcPO 2 levels when compared with healthy individuals. Among the diabetic cohort, those who had either PAD, DPN or CAN had significantly lower TcPO 2 values than participants without these complications. Multivariate linear regression analysis, after controlling for diabetes duration, diastolic blood pressure, HbA1c, albumin to creatinine ratio and CAN score, demonstrated that TcPO 2 levels were significantly and independently associated with current smoking (p = 0.013), ABI (p = 0.003), and NDS (p = 0.013)., Conclusion: Presence of DPN is independently associated with impaired cutaneous perfusion. Low TcPO 2 in subjects with DPN may contribute to delay in healing of diabetic foot ulcers, irrespectively of PAD., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Irisin is a myokine that increases energy expenditure. In this cross-sectional study, we examined for differences in plasma irisin concentrations between subjects with type 1 diabetes mellitus and healthy individuals and searched for associations between plasma irisin levels and clinical and biochemical characteristics as well as self-reported physical activity. A total of 79 subjects with type 1 diabetes [age 38.2±12.5 years, men/women (n): 27/52], were consecutively recruited. Moreover, 53 healthy controls, matched for age and body mass index with those with diabetes were recruited. Plasma irisin was measured with ELISA. Participants were asked about their physical activity during the last week. We also measured trunk and visceral fat. Circulating irisin levels were lower in subjects with diabetes than in controls [median value (interquartile range): 53.0 (35.2, 106.3) vs. 178.1 (42.6, 641.6) ng/ml, respectively, p<0.001]. In the group of diabetes, univariate analysis showed that irisin levels were associated with waist circumference (beta=-0.283, p=0.023), serum triglycerides (beta=-0.282, p=0.031), and trunk fat (beta=-0.324, p=0.012). In multivariate analysis after adjustment for potential confounders, irisin levels were associated independently only with waist circumference (beta=-0.403, p=0.005). Among controls, multivariate analysis demonstrated that irisin levels were associated with pack-years of smoking (beta=-0.563, p=0.012) and fasting triglycerides (beta=-0.338, p=0.041). Circulating irisin levels were lower in subjects with diabetes in comparison with healthy-matched controls. In conclusion, plasma irisin concentrations in subjects with diabetes were associated with waist circumference, while in controls with serum triglycerides and pack-years of smoking., Competing Interests: The authors declare that they have no conflict of interest., (© Georg Thieme Verlag KG Stuttgart · New York.)

Lipotest ® is a standardized fat-rich meal designed for use as a test meal during a fat tolerance test (FTT) for the study of postprandial triacylglycerol (TAG) concentrations. Herein we examined the precision and reproducibility of examination using Lipotest ® on postprandial TAG levels. A total of 26 healthy consenting subjects were examined twice after 8-10 h fasting with an interval of approximately 1 week apart. Blood samples were collected at baseline and 1, 2, 3, and 4 h after consumption of the test meal for measurement of plasma total TAG levels. We examined agreement, precision, and accuracy between the two visits using the Altman plots and correlation coefficient. Reproducibility was tested using the coefficient of variation (CV) and intraclass correlation coefficient (ICC). Moreover, the area under the curve (AUC) as a summary measure of the overall postprandial TAG levels was calculated. The agreement, precision (r ≥ 0.74, p < 0.001), and accuracy (≥0.99) between the measurements in plasma TAG during Lipotest ® testing in the two visits were high. In terms of reproducibility, the values of CV were 15.59-23.83% while those of ICC were ≥0.75. The values of the AUCs in the visits were not different (p = 0.87). A single measurement of plasma TAG levels at 4 h after Lipotest ® consumption depicted peak postprandial TAG concentration. A FTT using Lipotest ® as a standardized meal has good precision and reproducibility for the study of postprandial TAG levels in healthy individuals. A single determination of plasma TAG concentration at 4 h after Lipotest ® consumption captures peak postprandial TAG response.

For thousands of years, Chios Gum Mastic (CGM), the resin produced by the trunk of Pistachia lentiscus var Chia, has been used for culinary and medicinal purposes and several therapeutic properties have been attributed to it. CGM has been used in traditional medicine of various nations in the eastern Mediterranean area. This survey was carried out to identify biological mechanisms that could explain traditional usage and recent pharmacological findings. We reviewed the related scientific literature available from the NCBI PUBMED database on CGM studies and on natural products showing peroxisome proliferator-activated receptor (PPAR) agonist effects. We investigated whether CGM qualifies as a PPAR modulator. A large number of studies demonstrate that CGM has antioxidant, anti-inflammatory, hypolipidemic, and anticancer properties. Recently, the first evidence of CGM antidiabetic effect became known. CGM chemical composition has been extensively analyzed and the presence of several compounds, especially triterpenoids is well documented. Some of them, oleanonic acid, oleanolic acid, and gallic acid are considered to act as PPAR modulators. PPARs are nuclear receptors functioning as transcription factors and thereby controlling cellular functions at the level of gene expression. PPARs are involved in the pathways of significant diseases, such as metabolic syndrome, diabetes mellitus, dyslipidemia, inflammation, atheromatosis, and neoplasias, constituting a key target for pharmacological interventions. This article proposes that the synergistic action of some constituents of CGM on PPARs and more precisely on both PPARs isotypes-α and -γ, may be one of the major biological mechanisms via which CGM exerts its multiple effects.

Chios mastic gum (MG), a resin produced from Pistacia lentiscus var. Chia, is reported to possess beneficial cardiovascular and hepatoprotective properties. This study investigated the effect of crude Chios MG on metabolic parameters in diabetic mice. Streptozotocin-induced diabetic 12-week-old male C57bl/6 mice were assigned to three groups: NC (n=9) control; LdM (n=9) animals receiving low dose mastic for 8 weeks (20 mg/kg body weight [BW]); and HdM (n=9) animals receiving high dose mastic (500 mg/kg BW) for the same period. Serum lipid and glucose levels were determined at baseline, at 4 and 8 weeks. Serum total protein, adiponectin, and resistin levels were also measured at the end of the experiment. Histopathological examination for liver, kidney, aorta, and heart lesions was performed. After 4 weeks, MG administration resulted in decreased serum glucose and triglyceride levels in both LdM and HdM, whereas BW levels were reduced in LdM group compared with controls. At the end of the experiment, LdM presented significantly lower serum glucose, cholesterol, low-density lipoprotein cholesterol, and triglyceride levels and improved high-density lipoprotein cholesterol levels compared with control group. HdM group had ameliorated serum triglyceride levels. Hepatic steatosis observed in control group was partially reversed in LdM and HdM groups. MG administered in low dosages improves glucose and lipid disturbances in diabetic mice while alleviating hepatic damage.

Obesity is a condition in which excess or abnormal fat accumulation may present with adverse effects on health and decreased life expectancy. Increased body weight and adipose tissue accumulation amplifies the risk of developing various age-related diseases, such as cardiovascular disease, type 2 diabetes mellitus, musculoskeletal disorders, respiratory diseases and certain types of cancer. This imbalance in body composition and body weight is now recognized as a state of increased oxidative stress and inflammation for the organism. Increasing oxidative stress and inflammation affect telomeres. Telomeres are specialized DNA-protein structures found at the ends of eukaryotic chromosomes and serve as markers of biological aging rate. They also play a critical role in maintaining genomic integrity and are involved in age-related metabolic dysfunction. Erosion of telomeres is hazardous to healthy cells, as it is a known mechanism of premature cellular senescence and loss of longevity. The association of telomeres and oxidative stress is evident in cultured somatic cells in vitro, where oxidative stress enhances the process of erosion with each cycle of replication. Shorter telomeres have been associated with increasing body mass index, increased adiposity, and more recently with increasing waist to hip ratio and visceral excess fat accumulation. Furthermore, many of the metabolic imbalances of obesity (e.g. glycemic, lipidemic, etc.) give rise to organ dysfunction in a way that resembles the accelerated aging process. This article is a non-systematic review of the evidence linking obesity and accelerated aging processes as they are regulated by telomeres., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Aims: The aim of the present study was to evaluate the impact on dietary and activity habits of a non-intensive, community based lifestyle intervention for type 2 diabetes prevention, in high-risk Greek individuals., Methods: A total of 191 high-risk persons were invited to participate in a one-year lifestyle intervention program, consisting of six bi-monthly sessions with a dietician. The dietary aims of the intervention were: reduction of saturated fat, sugars and refined cereals intake and at least five servings of fruits and vegetables, daily. Demographic, dietary, anthropometric, medical and biochemical indices were recorded at baseline and at the end of the intervention., Results: The intervention was completed by 126 participants. At study end, participants reported decreased whole fat dairies and processed meats consumption (p=0.018 and 0.016, respectively), sugars (p=0.006) and refined cereals (p=0.045). Participants who improved their diet, decreased body weight (p=0.040), plasma triglycerides (p=0.020) and 2-h post-load plasma glucose (p=0.05) compared to those who had worsened their dietary habits. Total time spent daily on physical activity, remained unchanged throughout the intervention., Conclusions: The implementation of a group-based, non-intensive dietary counseling proved to be practical and feasible in "real-world" community settings and was accompanied by favorable dietary changes and health benefits., (Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.)

Background: Previous studies in different clinical settings have established heart rate variability (HRV) as a significant independent risk factor for higher mortality and cardiac death. The aim of this study was to examine the effect of chronic haemodialysis therapy on time- and frequency-domain parameters of HRV in diabetic and non-diabetic patients with chronic kidney disease (CKD)., Methods: We studied 25 patients with stage 4 CKD and type 2 diabetes mellitus (CKD4+DM), 25 patients with stage 4 CKD without diabetes (CKD4), 25 patients with type 2 diabetes mellitus (DM) and 25 healthy subjects (HS). The study was performed in two phases. In the first phase, a 24-h Holter electrocardiographic (ECG) monitoring was performed in all subjects. The patients with stage 4 CKD were followed up until they progressed to stage 5, and in the second phase of the study, they underwent a 24-h Holter ECG monitoring after completion of 3 months of conventional haemodialysis treatment., Results: In the first phase of the study, a reduction in cardiac sympathetic activity in CKD4 patients (significantly lower SDNN, SDANN/5 min, SD and VLF vs. HS) and worse autonomic function in CKD4+DM patients (significantly lower SDNN, SDANN/5 min, SD, VLF and LF/HF) vs. HS, DM and CKD4 was observed. After 3 months of dialysis therapy, the patients with CKD+DM showed a significant improvement only in the time-domain parameter SDANN/5 min, while the time-domain parameters SDNN, SDANN/5 min and SD were improved in CKD patients without diabetes. Frequency-domain parameters of HRV remained unchanged in both groups., Conclusions: CKD is associated with worse cardiac autonomic function. Haemodialysis therapy for 3 months improves some indices of HRV, and this effect is more pronounced in non-diabetic subjects. Our findings suggest that the improvement of HRV after the initiation of chronic dialysis therapy can ameliorate clinical outcomes and survival in patients with end-stage renal disease.

Background and Aims: Although whole-body insulin resistance in obesity is established, information on insulin action in peripheral tissues, especially adipose tissue (AD), is limited. This study was undertaken in morbid obesity to investigate insulin action on glucose disposal in AD and muscle (M)., Subjects and Methods: A meal was given to 30 obese (age 34 +/- 1 yr, body mass index 47 +/- 1 kg/m(2)) and 10 nonobese women (age 39 +/- 4 yr, body mass index 23 +/- 1 kg/m(2)). Samples for glucose and insulin were taken for 360 min from veins draining the abdominal subcutaneous AD and forearm muscles and from the radial artery. Blood flow (BF) was measured in AD ((133)Xe) and M (plethysmography)., Results: The area under the curve divided by time (AUC(0-360 min)/360 min) in obese vs. nonobese was as follows: 1) arterial glucose was similar 6.04 +/- 0.2 vs. 5.67 +/- 0.1 mm), but insulin was increased (65.5 +/- 6.6 vs. 28.7 +/- 1.7 mU/liter, P = 0.0004); 2) BF was decreased (3 +/- 0.2 vs. 4.4 +/- 0.3 ml/min per 100 ml tissue in M, P = 0.002 and 1.8 +/- 0.1 vs. 3.7 +/- 0.3 ml/min per 100 ml tissue in AD, P < 0.0001); 3) glucose uptake was decreased (0.9 +/- 0.1 vs. 2.3 +/- 0.4 micromol/min per 100 ml tissue in M, P = 0.002 and 0.45 +/- 0.1 vs. 1.1 +/- 0.17 micromol/min per 100 ml tissue in AD, P = 0.01); 4) fractional glucose extraction was decreased in M (5 +/- 1 vs. 9 +/- 1%, P = 0.03), but was similar in AD (3 +/- 1 vs. 3.6 +/- 1.4%); 5) glucose uptake (per total fat mass) was increased (0.275 +/- 0.04 vs. 0.12 +/- 0.02 mmol/min, P = 0.027)., Conclusion: In morbid obesity, the sensitivity of glucose metabolism to insulin is impaired in M, due to defects in insulin-stimulated glucose use and decreased BF, and in AD, at least in part, due to decreased BF. However, increased total fat mass provides a sink for the excess of glucose and compensates for insulin resistance.

Aim: The aim of the study was to investigate: a) the differential effect of the three main macronutrients on food intake, fat depots and serum leptin levels and b) the impact of sibutramine on the above parameters in rats fed ad libitum with three isocaloric diets., Methods: Three groups of male Wistar rats (n = 63) were fed with a high fat diet (HFD), a high carbohydrate diet (HCD) or a high protein diet (HPD) for 13 weeks. In the last three weeks, each group was divided into three subgroups and received sibutramine (S) either at 5 mg/kg or 10 mg/kg, or vehicle. Food intake was measured daily during the last week of the experiment; perirenal and epididymal fat and fat/lean ratio were calculated and serum leptin was assayed., Results: HFD-fed rats demonstrated elevated food intake and higher regional fat depots. S at 10 mg/kg decreased food intake in the HFD and epididymal fat in the HCD group. S also reduced perirenal fat in the HCD and HPD groups. Leptin levels were higher in rats fed with either the HFD or the HPD compared to those fed with the HCD. Moreover, S at 10 mg/kg decreased serum leptin levels in the HPD group., Conclusions: Results suggest a preferential effect of S on perirenal visceral fat and support the view that body fat loss is greater when its administration is accompanied by a HCD diet. No effect of S on leptin levels was found, besides that expected as a result of the decrease in body fat.

Diabetes mellitus type 2 (DM type 2) is associated with depressive symptomatology and intermittent hyperfunction of the hypothalamic-pituitary-adrenal (HPA) axis. DM type 2 is also accompanied by increased tissue levels of angiotensin II (Ang II), which stimulates the HPA axis through the Ang II type 1 receptors (AT1). We investigated the effect of candesartan, an angiotensin receptor blocker (ARB) that crosses the blood brain barrier, on the activity of the HPA axis and on the affect of 17 patients with DM type 2, aged 40-65 years, who were treated with 4 mg/day candesartan per os for at least 3 months. Before and after candesartan administration, a corticotropin-releasing hormone (CRH) stimulation test and psychological tests were performed. In response to hCRH, time-integrated secretion of ACTH was not altered by candesartan administration, however, the cortisol response was decreased significantly compared to baseline (mean +/- SEM, 2327 +/- 148.3 vs. 1943 +/- 131.9 microg/dl, P = 0.005) suggesting reduced sensitivity of the adrenals to ACTH. In parallel, there was a significant improvement in interpersonal sensitivity (0.91 +/- 0.16 vs. 0.70 +/- 0.15, P = 0.027) and depression scores (0.96 +/- 0.15 vs. 0.71 +/- 0.10, P = 0.026). We suggest that candesartan resets the HPA axis of patients with DM type 2 and improves their affect.

Background: Type-1 diabetes mellitus (DM) is a lifelong serious condition which often renders the application of standard treatment options for patients' comorbid conditions, such as bipolar disorder I, risky - especially for acute manic episodes. We present such a case whereby the application of standard anti-manic treatments would have jeopardized a patient whose physical condition was already compromised by DM., Methods: We report the case of a 55-year-old female with a history of type-1 DM since the age of 11, and severe ocular and renal vascular complications thereof. While on the waiting list for pancreatic islet cell transplantation, she developed a manic episode that proved recalcitrant to a treatment with gabapentin, lorazepam and quetiapine. Moreover, her mental state affected adversely her already compromised glycemic control, requiring her psychiatric hospitalization. Her psychotropic medication was almost discontinued and replaced by oxcarbazepine (OXC) up to 1800 mg/day for 10 days., Results: The patient's mental state improved steadily and on discharge, 3 weeks later, she showed an impressive improvement rate of over 70% on the YMRS. Moreover, she remains normothymic 6 months after discharge, with OXC at 1200 mg/day., Conclusion: Standard prescribing guidelines for acute mania recommend a combination of an antipsychotic with lithium or, alternatively, a combination of an antipsychotic with valproate or carbamazepine. However, in our case, administration of lithium was at least relatively contra-indicated because of patient's already compromised renal function. Furthermore, antipsychotics increase glucose levels and thus were also relatively contra-indicated. Moreover, the imminent post-transplantation immunosuppressant treatment with immuno-modulating medicines also contra-indicated both valproate and carbamazepine. Despite the severe methodological limitations of case reports in general, the present one suggests that OXC as monotherapy might be both safe and efficacious in the treatment of acute mania in patients with early-onset type-1 DM, whose already compromised physical condition constitutes an absolute or relative contra-indication for the administration of standard treatments, though there are no, as yet, randomized clinical trials attesting to its efficacy unambiguously.

A prospective observational study was conducted to identify factors associated with bloodstream infections (BSIs) caused by integron-carrying Enterobacteriaceae and to evaluate the clinical significance of integron carriage. Consecutive patients with Enterobacteriaceae BSIs were identified and followed up until discharge or death. Identification of blood isolates and susceptibility testing were performed by the Wider I automated system. int-1-specific PCR, conserved-segment PCR, and DNA sequencing were used to determine the presence, length, and content of integrons. The relatedness among the isolates was examined by pulsed-field gel electrophoresis. Two hundred fifty episodes of Enterobacteriaceae BSI occurred in 233 patients; 109 (43.6%) were nosocomial, 82 (32.8%) were community acquired, and 59 (23.6%) were health care associated. Integrons were detected in 11 (13.4%) community-acquired, 24 (40.7%) health care-associated, and 46 (42.2%) nosocomial isolates. Integron-carrying organisms were more likely to exhibit resistance to three or more classes of antimicrobials (odds ratio [OR], 9.84; 95% confidence interval [95% CI], 5.31 to 18.23; P < 0.001) or to produce extended-spectrum beta-lactamases (OR, 5.75; 95% CI, 2.38 to 13.89; P < 0.001) or a VIM-type metallo-beta-lactamase (P, 0.003). Inter- or intraspecies integron transfer and cross-transmission of integron-carrying clones were observed. Use of cotrimoxazole (OR, 4.77; 95% CI, 1.81 to 12.54; P < 0.001) and a nosocomial or other health care setting (OR, 3.07; 95% CI, 1.30 to 7.22; P, 0.01) were independently associated with BSIs caused by integron-carrying Enterobacteriaceae. Patients with a nonurinary source of bacteremia (OR, 9.46; 95% CI, 2.77 to 32.32; P < 0.001) and a Pitt bacteremia score of > or =4 (OR, 23.36; 95% CI, 7.97 to 68.44; P < 0.001) had a significantly higher 14-day mortality rate, whereas integron carriage did not affect clinical outcomes. These findings may have implications affecting antibiotic policies and infection control measures.

Introduction: GLUTs are specific membrane proteins that transport glucose down a concentration gradient. There have been few studies on their expression in the kidney. The aim of this study was to identify the expression of GLUTs 1, 3, and 4 in HGEC and their regulation under diabetic milieu., Material and Methods: An immortalized cell line of HGEC was used. Cells were cultured in medium containing 5 or 25 mM D-glucose. Western blotting and flow cytometry were used to examine the presence of GLUTs (1, 3, 4) and alterations in expression., Results: Western blotting analysis revealed that GLUT-1 levels were increased by 53% in HGEC cultured under experimental diabetes compared to cells grown in 5mM glucose. GLUT-3 levels were also increased by 15% under diabetic conditions. GLUT-4 levels were decreased by 20% in diabetes. Fluorescence Activated Cell Sorting (FACS) analysis demonstrated that cell surface expression of GLUT-1 was increased by 28% in cells grown in 25mM glucose. High glucose concentration did not affect cell surface expression of GLUT-3 and GLUT-4., Discussion: These findings suggest that depressed GLUT4 expression in glomerulus and overexpression of GLUT-1 and in a lesser extent of GLUT-3 may alter the glucose uptake in these cells. It has been suggested that the overexpression of GLUT-1 in glomerulus, being the major isoform, may lead to the initial pathologic hallmarks of diabetic nephropathy.

Introduction: The QT interval on the resting electrocardiogram (ECG) expresses the myocardial depolarisation and repolarisation time. Elevated values of QT dispersion (QTd) are associated with cardiovascular mortality in diabetics. Cardiac autonomic neuropathy (CAN) is a common complication of diabetes that is also associated with increased morbidity and mortality. However, there are no data in the literature concerning the relation between CAN and QTd in diabetics. The aim of this study was to investigate: 1) the differences in QTd between diabetics and non-diabetics; 2) the differences in QTd between those with type 1 and type 2 diabetes; 3) the relation between QTd and CAN., Methods: The study population included 184 diabetics (63 type 1, group D1; 121 type 2, group D2) and 100 healthy controls who had similar age and sex distribution to D1 (n=44) and D2 (n=56) subjects. CAN assessment was made using the standard Ewing and Clarke tests. The QT interval was measured on the 12-lead resting ECG. QTd was calculated automatically using special software., Results: QTd values did not differ significantly between controls and D1 (p=0.15) or D2 (p=0.27). QTd was significantly greater in D2 than in D1 (p=0.02). There was no significant difference in QTd between those with and without CAN in either group of diabetics., Conclusions: QTd values do not differ between individuals with and without diabetes. Type 2 diabetes is associated with higher QTd values than is type 1 diabetes. CAN does not affect QTd in diabetics.

Background: Women with polycystic ovary syndrome (PCOS) have an increased prevalence of insulin resistance (IR) and related disorders. Elevated serum levels of cellular adhesion molecules (CAMs) reflect low-grade chronic inflammation and have been associated with several insulin-resistant states. The objective of this study is to investigate whether soluble inflammatory markers [soluble intercellular adhesion molecule-1 (sICAM-1), soluble endothelial leukocyte adhesion molecule-1 (sE-selectin), soluble vascular cell adhesion molecule-1 (sVCAM-1) and C-reactive protein (CRP)] are altered in PCOS and to further elucidate the effect of metformin treatment on their levels., Methods: Two young populations were studied [62 women with PCOS and 45 normal women of similar age, BMI and waist-to-hip ratio (WHR)]. Plasma levels of sICAM-1, sVCAM-1, sE-selectin and high-sensitivity CRP (hsCRP) were measured in both groups. Additionally, the effect of metformin on these molecules was investigated in 22 women with PCOS who accepted to metformin protocol (1700 mg daily for a 6-month period)., Results: In the total population studied, plasma levels of hsCRP (mg/l), sICAM-1 (ng/ml) and sE-selectin (ng/ml) were higher in the PCOS group compared with those in controls (hsCRP 1.31 +/- 0.22 versus 0.92 +/- 0.27, P = 0.014, sICAM-1 301.21 +/- 24.80 versus 209.86 +/- 17.05, P = 0.025, sE-selectin 57.37 +/- 4.08 versus 45.67 +/- 4.62, P = 0.045, respectively). sVCAM-1 (ng/ml) did not differ statistically among the two groups (P = 0.896). A significant reduction in hsCRP and sVCAM-1 was achieved after 6 months of metformin administration: PCOS pretreatment hsCRP 1.92 +/- 0.60 versus PCOS post-treatment hsCRP 0.52 +/- 0.26, P = 0.005; PCOS pretreatment sVCAM-1 668.09 +/- 98.38 versus PCOS post-treatment sVCAM-1 365.82 +/- 99.77, P = 0.039., Conclusion: These findings imply the presence of chronic inflammation in women with PCOS. Metformin decreases the levels of plasma inflammatory indices. Further investigation is required to determine whether these findings may prove to be of clinical significance for PCOS patients.

Exogenous advanced glycation endproducts (AGEs, known atherogenic molecules) abundant in everyday precooked, rich in fat, overheated meals can possibly contribute to the increased risk for diabetes and cardiovascular disease in women with polycystic ovary syndrome (PCOS). The aim of the present study was to investigate the effect of a lipase inhibitor on absorbed food glycotoxins in healthy women and those with PCOS. A 2-day protocol was followed. In the first day, a meal rich in AGE was provided, which on the second day was followed by two 120-mg capsules of lipase inhibitor, orlistat. Serum AGE levels were evaluated at baseline (0 hours), and at 3 and 5 hours postmeal during the study. Thirty-six women were studied, 15 controls (mean age, 28.80 +/- 5.47 years; body mass index, 25.85 +/- 6.73 kg/m(2)) and 21 with PCOS (mean age, 25.29 +/- 5.06 years; body mass index, 30.40 +/- 7.51 kg/m(2)) (University Hospital, Athens, Greece, institutional practice). Serum AGE levels, on day 1, were significantly increased both in the control group and in the PCOS group as compared with basal values (control group, 14.1%; PCOS group, 6.0%; P < .001). The corresponding rise was significantly lower on day 2 when the same meal was combined with orlistat (control group, 4.1%; PCOS group, 2.0%; P < .01). A limitation of the study is that it is a nonplacebo, nonrandomized therapeutic trial where each subject is considered as its own control. In conclusion, this study demonstrated the beneficial effect of orlistat on the absorption of food glycotoxins.

Objective: This study assessed the efficacy and safety of combination (COMB) of cyclosporine (CSA) and leflunomide (LEF) versus each drug alone, in the treatment of severe rheumatoid arthritis (RA)., Methods: One hundred six patients with active RA refractory to at least one disease modifying antirheumatic drug (methotrexate obligatorily) were entered into a 12-month open, prospective trial and were randomly allocated to receive either CSA 2.5 to 5 mg/kg/day, or LEF 20 mg/day, or the combination of both at the same initiating dose., Results: The American College of Rheumatology 50% (ACR50) response rates for the 3 groups were COMB 80%, CSA 40%, and LEF 42% (p = 0.001). Combination therapy was also significantly better than CSA and LEF at the more stringent 70% response rate (69% vs 34% vs 30%, respectively; p = 0.001). Comparable Disease Activity Score 28 reduction rates were noted at trial termination for all 3 treatment arms: COMB -2.74 vs CSA -2.53 vs LEF -2.28 (p nonsignificant). Discontinuation rates were more common in LEF vs CSA arm (p = 0.046). No unexpected or serious adverse drug effects were identified in the combination group during the 12-month period., Conclusion: The combination of CSA and LEF in patients with refractory RA provided statistically significant benefit in ACR50 and ACR70. Adverse events were not substantially increased.

In the present study we investigated whether acute glucose administration could be protective against hypoxic stress. H9c2 cells were exposed to either 4.5 mM or 22 mM of glucose for 15,min and then were submitted to simulated ischemia. Cell death was microscopically assessed by combined staining with propidium iodide (PI) and Hoeschst 33358. Intracellular content of glucose was measured by enzymatic analysis. Clucose content of H9c2 cells was 48.24+/- 7.94 micromol/L in the 22 mM vs 23.86+/- 4.8 micromol/L in the 4.5 mM group (p < 0.05). PKCepsilon expression was increased 1.6 fold in the membrane fraction after pretreatment with high glucose (p < 0.05), while was decreased 1.6 fold in the cytosol (p < 0.05). In addition, no difference to PKCdelta translocation was observed after pretreatment with low glucose. After hypoxia, in the 22 mM group, cell death was found to be 17.36+/- 2.66% vs 38.2+/- 5.4% in the 4.5 mM group (p < 0.05). In the presence of iodoacetic acid, a glycolytic inhibitor, cell death was not different between the two groups (23.54+/- 3.2% in 22 mM vs 22.06+/- 5.3% in 4.5 mM). Addition of chelerythrine did not change the protective effect of high glucose (13.4+/- 1.7% cell death in 22 mM vs 27.5+/- 5.5% in 4.5 mM, p < 0.05). In conclusion, short pretreatment with high glucose protects H9c2 cells against hypoxia. Although this protective effect is associated with translocation of PKCepsilon and increased glucose uptake, it was abrogated only by inhibition of glycolysis.

The development of obesity is caused by a disturbance of energy balance, with energy intake exceeding energy expenditure. As the autonomic nervous system (ANS) has a role in the regulation of both these variables, it has become a major focus of investigation in the fields of obesity pathogenesis. The enhanced cardiac sympathetic drive shown in most of the studies in obese persons might be due to an increase in their levels of circulating insulin. The role of leptin needs further investigation with studies in humans. There is a blunted response of the cardiac sympathetic nervous system (SNS) activity in obese subjects after consumption of a carbohydrate-rich meal as well as after insulin administration. This might be due to insulin resistance. It is speculated that increased SNS activity in obesity may contribute to the development of hypertension in genetically susceptible individuals. It is also speculated that the increase in cardiac SNS activity under fasting conditions in obesity may be associated with high cardiovascular morbidity and mortality.

Background: The prevalence of type-2 diabetes is increasing dramatically, primarily being driven by environmental factors, like dietary and exercise habits. In this study we investigated the association of physical activity and acute coronary events in diabetic patients, an issue that has not been adequately studied so far., Design: Cross-sectional, case-control study., Methods: We studied demographic, lifestyle, dietary and clinical information in 216 hospitalized diabetic patients (171 men, 45 women) with a first event of an acute coronary syndrome and 196 frequency matched (by age and sex) diabetic controls (154 men, 42 women) without any evidence of coronary heart disease. Physical activity was evaluated according to the kcal/min expended and the weekly frequency of exercise. Physically active were considered those who reported non-occupational physical activity >once/week (at least 30 min/time)., Results: Seventy-eight (36%) of 216 patients and 110 (56%) of 196 controls were classified as physically active (P<0.001). Multivariate conditional logistic regression analysis revealed that the odds ratio for developing an acute coronary event in diabetic subjects who reported moderate levels of physical activity was 0.22 [95% confidence interval (CI): 0.12-0.47], while in those who reported vigorous physical activity it was 0.33 (95% CI: 0.21-0.59), after adjusting for age, sex, and the conventional cardiovascular risk factors., Conclusions: Physical activity (moderate and vigorous) seems to be associated with a lower prevalence of acute coronary events in the investigated group of diabetic subjects. Light physical activity does not seem to have any significant association with the development of acute coronary events.

Background/aims: Based on former studies in experimental animals on the effect of octreotide on serum and ascitic levels of tumor necrosis factor-alpha and interleukin-6 in the field of necrotizing pancreatitis, the present study was designed to investigate the effect of octreotide on serum interleukin-6 of patients with acute edematous pancreatitis., Methodology: A total of 36 patients with acute edematous pancreatitis and initiation of symptoms 12 hours before their admission were enrolled in the study; 20 were treated with octreotide 200 microg tid and 16 with octreotide 500 microg tid for five days. Blood was sampled at regular time intervals. Interleukin-6 was determined by an enzyme-immunoassay and C-reactive protein by nephelometry., Results: Mean concentrations of interleukin-6 of patients treated with octreotide 200 microg tid were 59.52 pg/mL before and 94.08, 46.25, 49.94, 58.16 and 26.08 pg/mL at 3, 6, 24, 48 and 72 hours after the start of therapy respectively. Respective values of patients treated with octreotide 500 microg tid were 57.19, 53.07, 57.83, 36.06, 54.29 and 65.49 pg/mL. Mean C-reactive protein of patients treated with octreotide 200 microg tid were 67.37 mg/L before and 48.51, 106.08 and 95.58 mg/L at 24, 48 and 72 hours after the start of therapy respectively. Respective values of patients treated with octreotide 500 microg tid were 65.51, 60.56, 90.68 and 64.22 mg/L., Conclusions: A transient, but not statistically significant, decrease of serum interleukin-6 levels was documented after administration of octreotide in the field of acute edematous pancreatitis. That decrease was earlier after the application of the 500 microg tid dose than the 200 microg tid dose. Studies with a greater number of patients are mandatory to fully clarify the effect of octreotide, if any, on acute pancreatitis.

Objective: To investigate the role of dietary factors in the development of type 2 diabetes., Research Design and Methods: In the context of the Multinational MGSD Nutrition Study, three groups of subjects were studied: 204 subjects with recently diagnosed diabetes (RDM), 42 subjects with undiagnosed diabetes (UDM) (American Diabetes Association criteria-fasting plasma glucose [FPG] > or =126 mg/dl), and 55 subjects with impaired fasting glucose (IFG) (FPG > or =110 and <126 mg/dl). Each group was compared with a control group of nondiabetic subjects, matched one by one for center, sex, age, and BMI. Nutritional habits were evaluated by a dietary history method, validated against the 3-day diet diary. In RDM, the questionnaire referred to the nutritional habits before the diagnosis of diabetes. Demographic data were collected, and anthropometrical and biochemical measurements were taken., Results: Compared with control subjects, RDM more frequently had a family history of diabetes (49.0 vs. 14.2%; P < 0.001), exercised less (exercise index 53.5 vs. 64.4; P < 0.01), and more frequently had sedentary professions (47.5 vs. 27.4%; P < 0.001). Carbohydrates contributed less to their energy intake (53.5 vs. 55.1%; P < 0.05), whereas total fat (30.2 +/- 0.5 vs. 27.8 +/- 0.5%; P < 0.001) and animal fat (12.2 +/- 0.3 vs. 10.8 +/- 0.3%; P < 0.01) contributed more and the plant-to-animal fat ratio was lower (1.5 +/- 0.1 vs. 1.8 +/- 0.1; P < 0.01). UDM more frequently had a family history of diabetes (38.1 vs. 19.0%; P < 0.05) and sedentary professions (58.5 vs. 34.1%; P < 0.05), carbohydrates contributed less to their energy intake (47.6 +/- 1.7 vs. 52.8 +/- 1.4%; P < 0.05), total fat (34.7 +/- 1.5 vs. 30.4 +/- 1.2%; P < 0.05) and animal fat (14.2 +/- 0.9 vs. 10.6 +/- 0.7%; P < 0.05) contributed more, and the plant-to-animal fat ratio was lower (1.6 +/- 0.2 vs. 2.3 +/- 0.4; P < 0.05). IFG differed only in the prevalence of family history of diabetes (32.7 vs. 16.4%; P < 0.05)., Conclusions: Our data support the view that increased animal fat intake is associated with the presence of diabetes.

Background/aims: To define whether bacterial translocation occurs over the course of acute edematous pancreatitis and to correlate its presence to the advent of an infection since data in humans are lacking., Methods: Thirty-three patients hospitalized over the period January 2000-January 2001 were subjected to venipuncture at regular time intervals for the collection of blood samples for blood culture and for determination of endotoxins and of C-reactive protein. Endotoxins were measured by the Limulus assay and C-reactive protein by nephelometry., Results: A wide range of concentrations of endotoxins was observed over the first 3 days of the disease. Mean (+/-SE) of endotoxins was 4.01 +/- 1.36 and 2.42 +/- 0.95 EU/ml 3 and 6 h, respectively, after admission of afebrile patients. Respective values 3 and 6 h after admission of febrile patients were 3.03 +/- 1.14 and 5.84 +/- 2.28 EU/ml (normal <0.1 EU/ml); these values gradually decreased after the second day. No correlation was found between endotoxins and C-reactive protein. Endotoxins were increased as a result of the occurrence of an infection on the third day., Conclusions: A significant level of endotoxemia is observed over the course of acute edematous pancreatitis, which might be correlated to the advent of the systemic inflammatory response., (Copyright 2003 S. Karger AG, Basel and IAP)

Type 2 diabetes mellitus is one of the most costly and burdensome chronic diseases of our time and a condition that is increasing in epidemic proportions worldwide. Its complications are a significant cause of morbidity and mortality and a tremendous economic burden to the society. Effective prevention programs are therefore urgently needed. Some of the risk factors for the development of type 2 diabetes, such as obesity, physical inactivity and high-fat diet, can potentially be modified. Compelling evidence now exists from well designed randomized studies that the disease can be prevented or delayed in subjects at high risk for its development, i.e. subjects with impaired glucose tolerance (IGT) or impaired fasting glucose (IFG). The interventions studied include lifestyle modifications (with diet and exercise) and drug treatment. Weight loss with lifestyle modification seems to be the most effective way so far, given the fact that it addresses other cardiovascular disease risk factors as well. The big challenge we are facing now is to try to implement these findings in our society or among our high-risk patients, taking into consideration the great difficulties involved in changing lifestyle and in maintaining lifestyle modifications.

Background/aims: Acute pancreatitis may be accompanied by alterations of the secretion of pancreatic and gastrointestinal peptides as a result of pancreatic inflammation. These changes, that may constitute targets of therapeutic manipulation, led to the study of the serum levels of various pancreatic and gastrointestinal peptides over the course of acute pancreatitis before and after the administration of octreotide and ranitidine., Methodology: Concentrations of gastrin, glucagon, vasoactive intestinal peptide, neurotensin and pancreatic polypeptide were determined by radioimmunoassay in the plasma of 22 patients with acute pancreatitis on the first, sixth and 11th day of the disease. All patients were treated with octreotide s.c. while 14 of them were also administered ranitidine i.v. Treatment was initiated after taking the first blood sample., Results: Mean gastrin levels in patients receiving ranitidine was 56.76 ng/L and in patients not receiving ranitidine 47.16 ng/L on the first day (pNS) remaining stable throughout the course of acute pancreatitis. Mean glucagon, vasoactive intestinal peptide, neurotensin and pancreatic polypeptide levels on the first day were 52.05 pmol/L, 8.90 pmol/L, 9.80 pmol/L and 22.06 pmol/L, respectively, and no changes were found through the course of acute pancreatitis., Conclusions: Plasma levels of gastrointestinal peptides remain constant over time and they are not significantly affected by the administration of octreotide or ranitidine. However more studies are necessary to document the significance of these findings.