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Objective: Unlike visceral adipose tissue (VAT), the association between subcutaneous adipose tissue (SAT) and obesity-related morbidity is controversial. In patients with type 2 diabetes, we assessed whether this variability can be explained by a putative favorable, distinct association between abdominal superficial SAT (SSAT) (absolute amount or its proportion) and cardiometabolic parameters.Research Design and Methods: We performed abdominal magnetic resonance imaging (MRI) in 73 patients with diabetes (mean age 58 years, 83% were men) and cross-sectionally analyzed fat distribution at S1-L5, L5-L4, and L3-L2 levels. Patients completed food frequency questionnaires, and subgroups had 24-h ambulatory blood pressure monitoring and 24-h ambulatory electrocardiography.Results: Women had higher %SSAT (37 vs. 23% in men; P < 0.001) despite a similar mean waist circumference. Fasting plasma glucose (P = 0.046) and HbA(1c) (P = 0.006) were both lower with increased tertile of absolute SSAT. In regression models adjusted for age, waist circumference, and classes of medical treatments used in this patient population, increased %SSAT was significantly associated with decreased HbA(1c) (β = -0.317; P = 0.013), decreased daytime ambulatory blood pressure (β = -0.426; P = 0.008), and increased HDL cholesterol (β = 0.257; P = 0.042). In contrast, increased percent of deep SAT (DSAT) was associated with increased HbA(1c) (β = 0.266; P = 0.040) and poorer heart rate variability parameters (P = 0.030). Although total fat and energy intake were not correlated with fat tissue distribution, increased intake of trans fat tended to be associated with total SAT (r = 0.228; P = 0.05) and DSAT (r = 0.20; P = 0.093), but not with SSAT.Conclusions: Abdominal SAT is composed of two subdepots that associate differently with cardiometabolic parameters. Higher absolute and relative distribution of fat in abdominal SSAT may signify beneficial cardiometabolic effects in patients with type 2 diabetes. [ABSTRACT FROM AUTHOR]

OBJECTIVE: In a randomized controlled trial, we assessed the effect of daily moderate alcohol intake on glycemic control in the fasting and postprandial states in patients with type 2 diabetes who previously had abstained from alcohol. RESEARCH DESIGN AND METHODS: We randomly assigned 109 patients (41-74 years old) with established type 2 diabetes who abstained from alcohol to receive 150 ml wine (13 g alcohol) or nonalcoholic diet beer (control) each day during a 3-month multicenter trial. The beverages were consumed during dinner. Diet and alcohol consumption were monitored. RESULTS: During the intervention, 17% of participants (12% from the alcohol group) dropped out, leaving 91 who completed the trial. Within the alcohol group, fasting plasma glucose (FPG) decreased from 139.6 +/- 41 to 118.0 +/- 32.5 mg/dl after 3 months compared with 136.7 +/- 15.4 to 138.6 +/- 27.8 mg/dl in the control subjects (P(v) = 0.015). However, alcohol consumption had no effect on 2-h postprandial glucose levels (difference of 18.5 mg/dl in the control group vs. 17.7 mg/dl in the alcohol group, P(v) = 0.97). Patients in the alcohol group with higher baseline A1C levels had greater reductions in FPG (age-adjusted correlation -0.57, P(v) < 0.001). No significant changes were observed in the levels of bilirubin, alkaline phosphatase, alanine aminotransferase, or aspartate aminotransferase, and no notable adverse effects were reported. Participants in the alcohol group reported an improvement in the ability to fall asleep (P(v) < 0.001). CONCLUSIONS: Among patients with type 2 diabetes who had previously abstained from alcohol, initiation of moderate daily alcohol consumption reduced FPG but not postprandial glucose. Patients with higher A1C may benefit more from the favorable glycemic effect of alcohol. Further intervention studies are needed to confirm the long-term effect of moderate alcohol intake. [ABSTRACT FROM AUTHOR]

The present study was designed to study RBC aggregability in type 1 and type 2 DM by a new method based on the dielectric properties of disperse systems. This dielectric method has a significantly higher sensitivity to detect enhanced RBC aggregation in DM than other methods. Aggregability is increased in type 1 DM and even more markedly in type 2 diabetic patients. The enhanced RBC aggregation in type 1 diabetes was significantly correlated with the levels of HbA1C, cholesterol and triglycerides. However, no correlation between metabolic control and RBC aggregability was found in type 2 DM. The in vitro addition of non-toxic, low molecular weight dextran improves the high RBC aggregation in diabetes type 2. In the future, low molecular weight dextran may be used in DM patients clinically to lower the risk for vascular complications, after the problem of filtration is solved. [ABSTRACT FROM AUTHOR]

HIV protease inhibitors (HPIs) are potent antiretroviral agents clinically used in the management of HIV infection. Recently, HPI therapy has been linked to the development of a metabolic syndrome in which adipocyte insulin resistance appears to play a major role. In this study, we assessed the effect of nelfinavir on glucose uptake and lipolysis in differentiated 3T3-L1 adipocytes. An 18-h exposure to nelfinavir resulted in an impaired insulin-stimulated glucose uptake and activation of basal lipolysis. Impaired insulin stimulation of glucose up take occurred at nelfinavir concentrations >10 micromol/l (EC(50) = 20 micromol/l) and could be attributed to impaired GLUT4 translocation. Basal glycerol and free fatty acid (FFA) release were significantly enhanced with as low as 5 micromol/l nelfinavir, displaying fivefold stimulation of FFA release at 10 micromol/l. Yet, the antilipolytic action of insulin was preserved at this concentration. Potential underlying mechanisms for these metabolic effects included both impaired insulin stimulation of protein kinase B Ser 473 phosphorylation with preserved insulin receptor substrate tyrosine phosphorylation and decreased expression of the lipolysis regulator perilipin. Troglitazone pre- and cotreatment with nelfinavir partly protected the cells from the increase in basal lipolysis, but it had no effect on the impairment in insulin-stimulated glucose uptake induced by this HPI. This study demonstrates that nelfinavir induces insulin resistance and activates basal lipolysis in differentiated 3T3-L1 adipocytes, providing potential cellular mechanisms that may contribute to altered adipocyte metabolism in treated HIV patients. [ABSTRACT FROM AUTHOR]

Diabetic retinopathy (DR) is the most common of the microvascular complications of diabetes. Left unchecked and untreated, it could progresses from a non-proliferative phase to a proliferative, sight-threatening phase. Macular edema which also threatens sight can appear at any stage. The pathophysiological mechanisms underlying its appearance and progression include the accumulation of plyols, advanced glycation endproducts (AGE) reactive oxygen species, release of local growth factors and activation of protein kinase C, all of which lead to structural and functional changes in the retina which can progress to threaten sight. Tight glucose and blood pressure control can prevent the appearance and progression of retinopathy. Novel PKC inhibitors, inhibitors of growth factors, blockers of the reninDSangiotensin system (RAS) as well as statins can slow the progression of DR and protect sight. [ABSTRACT FROM AUTHOR]

BACKGROUND: The incidence of type 2 diabetes mellitus (DM) is rapidly increasing worldwide. Results from large-scale studies show that tight blood glucose (BG) control improves the outcome of patients with type 2 DM. OBJECTIVE: This trial assessed the short-term efficacy and tolerability of adding a thiazolidinedione (rosiglitazone [ROS]) to existing sulfonylurea (SU) therapy (glibenclamide) compared with switching to combination treatment with a premixed insulin (biphasic insulin aspart 30 [BIAsp 30], a rapid-acting insulin analog) and the thiazolidinedione in a select group of patients with type 2 DM whose metabolic control was inadequate with SU monotherapy. METHODS: In this 6-week, multicenter, open-label, parallel-group trial, patients with type 2 DM whose BG level was not adequately controlled with glibenclamide monotherapy (glycosylated hemoglobin [HbA1c] 8%-13%) were randomized either to replace glibenclamide with BIAsp 30 (individually titrated dosages starting with 6-8 U BID) plus rosiglitazone (4 mg once daily) (BIAsp 30 + ROS group) or to add rosiglitazone (4 mg once daily) to their pretrial doses of glibenclamide (GLIB + ROS group). Patients measured their BG levels immediately before each of the 3 main meals, 90 minutes after the start of each meal, and at bedtime, and mean BG levels were calculated at weeks 0 (baseline), 1, 2, 4, 6, and at 2-week follow-up (week 8). The primary end point was change in mean daily BG level during treatment. Secondary end points included preprandial, postprandial, and bedtime BG levels, serum fructosamine level HbA, and fasting BG level, which were measured at each study visit. Tolerability was assessed using hematologic and biochemical parameters, vital signs, and physical examination. RESULTS: Forty-nine patients (32 men, 17 women; mean [SD] age, 59.1 [8.9] years; mean [SD] body mass index, 27.7 [3.7] kg/m2) participated in the study. A significant difference was found between treatments in the change in mean daily BG level from baseline to week 6 (P=0.01). After the 6-week treatment period, change in mean serum fructosamine level was significantly greater for BIAsp 30 + ROS compared with GLIB + ROS (P=0.02). HbA1c decreased in both treatment groups from baseline to study end, but the difference between groups was nonsignificant. The changes in fasting BG from baseline to study end also were nonsignificant between groups. Both combinations were well tolerated. CONCLUSIONS: This short-term study in patients with type 2 DM whose BG level was poorly controlled with glibenclamide monotherapy suggests that switching to a combination of BIAsp 30 + ROS was efficacious and well tolerated and provided an alternative to adding rosiglitazone to existing glibenclamide treatment. The study also suggests that BIAsp 30 may be associated with greater improvements in short-term metabolic control. [ABSTRACT FROM AUTHOR]

Objectives: The prevalence of type 2 diabetes in Israel is increasing in all ethnic groups but most markedly in the Bedouin population. We aimed to assess the effects of a lifestyle change intervention on risk markers for type 2 diabetes after gestational diabetes mellitus (GDM)., Methods: One hundred eighty Jewish and Bedouin post-GDM women were randomly assigned to a lifestyle intervention group (IG) or a control group (CG) starting 3-4 months after delivery. The IG participated in healthy lifestyle sessions led by a dietician and a sports instructor for 24 months after delivery. The IG participants had three individual 45-min counseling sessions and four 90-min group meetings (10 women each). The dietary and exercise recommendations were culturally adapted. The primary outcome of the study was HOMA-IR. We monitored clinical and chemical biomarkers 1 and 2 years after delivery., Results: After 1 and 2 years of intervention, the metabolic measures improved substantially. The intervention reduced the insulin, glucose and HOMA-IR levels in the IG compared with those in the CG (p < 0.001)., Conclusions: This novel culturally tailored lifestyle intervention program significantly improved the metabolic and morphometric indices measured 1 and 2 years after delivery. These results highlight and underscore the importance of effective lifestyle change education following GDM.

Background/objectives: The progression of carotid-plaque volume in patients with type 2 diabetes is common. Previous observational studies showed an association between moderate alcohol and reduced risk of coronary disease. We examined whether consuming moderate wine affects the progression of carotid atherosclerosis., Subjects/methods: In the CASCADE (CArdiovaSCulAr Diabetes and Ethanol), a 2-year randomized controlled trial, we randomized abstainers with type 2 diabetes were to drink 150 ml of either red wine, white wine, or water, provided for 2 years. In addition, groups were guided to maintain a Mediterranean diet. We followed 2-year changes in carotid total plaque volume (carotid-TPV) and carotid vessel wall volume (carotid-VWV), using three-dimensional ultrasound., Results: Carotid images were available from 174 of the 224 CASCADE participants (67% men; age = 59 yr; HbA1C = 6.8%). Forty-five percent had detectable plaque at baseline. After 2 years, no significant progression in carotid-TPV was observed (water, -1.4 (17.0) mm 3 , CI (-2.7, 5.5), white-wine, -1.2 (16.9) mm 3 , CI (-3.8, 6.2), red wine, -1.3 (17.6) mm 3 , CI (-3.4, 6.0; p = 0.9 between groups)). In post hoc analysis, we divided the 78 participants with detectable baseline carotid plaque into tertiles. Those with the higher baseline plaque burden, whom were assigned to drink wine, reduced their plaque volume significantly after 2 years, as compared to baseline. Two-year reductions in Apo(B)/Apo(A) ratio(s) were independently associated with regression in carotid-TPV (β = 0.4; p < 0.001). Two-year decreases in systolic blood pressure were independently associated with regression in carotid-VWV (β = 0.2; p = 0.005)., Conclusions: No progression in carotid-TPV was observed. In subgroup analyses, those with the greatest plaque burden assigned to drink wine may have had a small regression of plaque burden.

Objective: To examine whether risk tolerance is associated with adherence to oral hypoglycemic agents (OHAs)., Methods: We performed a cross-sectional study among adult patients with type 2 diabetes mellitus (n = 308) presenting for routine out-patient visits, using validated questionnaires to estimate: risk preferences (risk-seeking, risk averse, risk neutral), motivation, self-efficacy, impulsivity, perception of the disease and of the interpersonal process of care, demographic and socioeconomic characteristics; computerized patient medical records to estimate disease severity and a computerized database for retrieval of medication adherence, 1 year before the interview. Adherence was estimated using prescription-based measures of proportion of days covered (PDC). Concurrent adherence was calculated as: PDC with ≥1 OHAs; average PDC; PDC of ≥80% for all OHAs., Results: Multivariable ordered logit model revealed that compared to others, risk-seeking patients had lower PDC with ≥1 OHAs (β = -0.50, p ≤ .1). Specifically, risk-seeking patients were 11.2 percentage points less likely to have ≥80% of the follow-up period covered with ≥1 OHAs available (p ≤ .1). In addition, risk-seeking patients had lower average PDC (β = -0.85, p ≤ .05). Specifically, these patients were 19.5 percentage points less likely to have an average PDC of ≥80% (p ≤ .05). Multivariable logistic model revealed that risk-seeking was associated with lower probability of having PDC ≥80% for all OHAs in the follow-up period (OR; 90% CI: 0.59; 0.35-0.97)., Conclusions: Risk-seeking patients are less adherent to OHA medications. Identifying these patients may enable practitioners to proactively tailor strategies to improve their adherence and health outcomes.

Objective: Obesity variably disrupts human health, but molecular-based patients' health-risk stratification is limited. Adipose tissue (AT) stresses may link obesity with metabolic dysfunction, but how they signal in humans remains poorly-characterized. We hypothesized that a transcriptional AT stress-signaling cascade involving E2F1 and ASK1 (MAP3K5) molecularly defines high-risk obese subtype., Methods: ASK1 expression in human AT biopsies was determined by real-time PCR analysis, and chromatin immunoprecipitation (ChIP) adopted to AT explants was used to evaluate the binding of E2F1 to the ASK1 promoter. Dual luciferase assay was used to measure ASK1 promoter activity in HEK293 cells. Effects of E2F1 knockout/knockdown in adipocytes was assessed utilizing mouse-embryonal-fibroblasts (MEF)-derived adipocyte-like cells from WT and E2F1 -/- mice and by siRNA, respectively. ASK1 depletion in adipocytes was studied in MEF-derived adipocyte-like cells from WT and adipose tissue-specific ASK1 knockout mice (ASK1-ATKO)., Results: Human visceral-AT ASK1 mRNA (N = 436) was associated with parameters of obesity-related cardio-metabolic morbidity. Adjustment for E2F1 expression attenuated the association of ASK1 with fasting glucose, insulin resistance, circulating IL-6, and lipids (triglycerides, HDL-cholesterol), even after adjusting for BMI. Chromatin-immunoprecipitation in human-AT explants revealed BMI-associated increased occupancy of the ASK1 promoter by E2F1 (r 2  = 0.847, p < 0.01). In adipocytes, siRNA-mediated E2F1-knockdown, and MEF-derived adipocytes of E2F1 -knockout mice, demonstrated decreased ASK1 expression and signaling to JNK. Mutation/truncation of an E2F1 binding site in h ASK1 promoter decreased E2F1-induced ASK1 promoter activity, whereas E2F1-mediated sensitization of ASK1 promoter to further activation by TNFα was inhibited by JNK-inhibitor. Finally, MEF-derived adipocytes from adipocyte-specific ASK1 -knockout mice exhibited lower leptin and higher adiponectin expression and secretion, and resistance to the effects of TNFα., Conclusions: AT E2F1 -ASK1 molecularly defines a metabolically-detrimental obese sub-phenotype. Functionally, it may negatively affect AT endocrine function, linking AT stress to whole-body metabolic dysfunction.

Objective: To generate evidence-based conclusions about the effect of wine consumption on weight gain and abdominal fat accumulation and distribution in patients with type 2 diabetes., Design: In the 2-year randomized controlled CASCADE (CArdiovaSCulAr Diabetes & Ethanol) trial, patients following a Mediterranean diet were randomly assigned to drink 150 ml of mineral water, white wine or red wine with dinner for 2 years. Visceral adiposity and abdominal fat distribution were measured in a subgroup of sixty-five participants, using abdominal MRI., Setting: Ben-Gurion University of the Negev, Soroka-Medical Center and the Nuclear Research Center Negev, Israel., Subjects: Alcohol-abstaining adults with well-controlled type 2 diabetes., Results: Forty-eight participants (red wine, n 27; mineral water, n 21) who completed a second MRI measurement were included in the 2-year analysis. Similar weight losses (sd) were observed: red wine 1·3 (3·9) kg; water 1·0 (4·2) kg (P=0·8 between groups). Changes (95 % CI) in abdominal adipose-tissue distribution were similar: red wine, visceral adipose tissue (VAT) -3·0 (-8·0, 2·0) %, deep subcutaneous adipose tissue (DSAT) +5·2 (-1·1, 11·6) %, superficial subcutaneous adipose tissue (SSAT) -1·9 (-5·0, 1·2) %; water, VAT -3·2 (-8·9, 2·5) %, DSAT +2·9 (-2·8, 8·6) %, SSAT -0·15 (-3·3, 2·9) %. No changes in antidiabetic medication and no substantial changes in energy intake (+126 (sd 2889) kJ/d (+30·2 (sd 690) kcal/d), P=0·8) were recorded. A 2-year decrease in glycated Hb (β=0·28, P=0·05) was associated with a decrease in VAT., Conclusions: Moderate wine consumption, as part of a Mediterranean diet, in persons with controlled diabetes did not promote weight gain or abdominal adiposity.

Objectives: To examine whether the degree of risk aversion is associated with adherence to disease self-management among adults with type 2 diabetes., Methods: This was a cross-sectional study of patients with type 2 diabetes (n = 408) aged 21 to 70 years who presented for routine visits in the diabetes clinic at a university medical center in Beer-Sheva, Israel. The authors used validated questionnaires to estimate adherence, risk preferences, motivation, self-efficacy, impulsivity, perceptions about the disease and the interpersonal process of care, and demographic and socioeconomic characteristics, in addition to retrieving data from computerized patient medical records of clinical indicators of disease severity. Multivariable linear and ordered-logit models examined predictors of adherence to each self-care behavior., Results: Multivariable analyses revealed that, compared with others, risk-seeking patients reported lower general adherence (β = -0.32; P ≤ 0.05), and specifically, lower adherence to healthful eating plan (β = -0.48; P ≤ 0.1), consumption of low-fat food (β = -0.47; P ≤ 0.1), exercise (β = -0.73; P ≤ 0.05), blood glucose monitoring (β = -0.69; P ≤ 0.05), and foot care (β = -0.36; P ≤ 0.1). Risk-seeking patients did not report lower consumption of fruits and vegetables (β = -0.19; P > 0.1). Because 96% of the study population reported optimal adherence to medication, determinants of this behavior could not be analyzed., Conclusions: Risk preference is associated with adherence to self-care behaviors. Identifying risk seekers may enable practitioners to target these patients with tailored strategies to improve adherence, thus more efficiently allocating scarce health care resources., (Copyright © 2016 International Society for Pharmacoeconomics and Outcomes Research (ISPOR). Published by Elsevier Inc. All rights reserved.)

Background: Visceral adipose tissue foam cells are increased in human obesity, and were implicated in adipose dysfunction and increased cardio-metabolic risk. In the circulation, non-classical monocytes (NCM) are elevated in obesity and associate with atherosclerosis and type 2 diabetes. We hypothesized that circulating NCM correlate and/or are functionally linked to visceral adipose tissue foam cells in obesity, potentially providing an approach to estimate visceral adipose tissue status in the non-surgical obese patient., Methods: We preformed ex-vivo functional studies utilizing sorted monocyte subclasses from healthy donors. Moreover, we assessed circulating blood monocyte subclasses and visceral fat adipose tissue macrophage (ATM) lipid content by flow-cytometry in paired blood and omental-fat samples collected from patients (n = 65) undergoing elective abdominal surgery., Results: Ex-vivo, NCM and NCM-derived macrophages exhibited lower lipid accumulation capacity compared to classical or intermediate monocytes/-derived macrophages. Moreover, of the three subclasses, NCM exhibited the lowest migration towards adipose tissue conditioned-media. In a cohort of n = 65, increased %NCM associated with higher BMI (r = 0.250,p<0.05) and ATM lipid content (r = 0.303,p<0.05). Among patients with BMI≥25Kg/m2, linear regression models adjusted for age, sex or BMI revealed that NCM independently associate with ATM lipid content, particularly in men., Conclusions: Collectively, although circulating blood NCM are unlikely direct functional precursor cells for adipose tissue foam cells, their increased percentage in the circulation may clinically reflect higher lipid content in visceral ATMs.

Objective: The presence of a foot ulcer increases the self-treatment burden imposed on the individual with diabetes. Additionally, this condition increases the cognitive demands needed for adherence to medical recommendations. A potential gap could exist between medical recommendations and the individual's ability to implement them. Hence, the goal of this study was to examine whether the cognitive profile of people with diabetic foot ulcers differs from that of people with diabetes without this complication., Research Design and Methods: This was a case-control study. Ninety-nine individuals with diabetic foot ulcers (case patients) and 95 individuals with type 2 diabetes (control subjects) (age range 45-75 years), who were matched for diabetes duration and sex, underwent extensive neuropsychological evaluation using a NeuroTrax computerized battery, digit symbol, and verbal fluency tests. A global cognitive score after standardization for age and education was computed as well as scores in the following six cognitive domains: memory, executive function, reaction time, attention, psychomotor abilities, and estimated premorbid cognition., Results: Individuals with diabetic foot ulcers had significantly (P < 0.001) lower cognitive scores than individuals with diabetes without this complication, in all tested cognitive domains, excluding estimated premorbid cognition. Individuals with diabetic foot ulcers demonstrated a significant difference between precognitive and current cognitive abilities, as opposed to the nonsignificant difference among control subjects. The differences persisted in multivariable analysis after adjusting for depression and smoking., Conclusions: Individuals with diabetic foot ulcers were found to possess fewer cognitive resources than individuals with diabetes without this complication. Thus, they appear to face more self-treatment challenges, while possessing significantly fewer cognitive resources., (© 2016 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.)

Introduction: The aim of this study was to assess the total frequency of self-treated hypoglycemia in type 2 diabetes mellitus patients using regimens including basal insulin analogs, and to describe the psychological impact and behavioral response to these events from the perspective of patients and prescribers (i.e., hospital specialists and primary care physicians)., Methods: The global attitude of patients and physicians 2 (GAPP2) survey was an online multinational, cross-sectional survey of patients with type 2 diabetes mellitus treated with basal insulin analogs, with or without bolus insulin. Prescribers directly involved in the care of these patients were also surveyed. Here, we report the results of the second wave of the GAPP2 survey, in which the primary variable of interest was self-treated hypoglycemia., Results: A total of 855 patients and 1003 prescribers, from 7 countries, completed the survey. Overall, 28% of patients had experienced self-treated hypoglycemia during the previous 30 days, with two-thirds of events occurring during the day and one-third of events occurring nocturnally. Prescribers reported discussing events with 55% of patients over this period. Patients worried about self-treated hypoglycemia in a range of situations, and prescribers under-estimated this worry. Many patients who had experienced self-treated hypoglycemia in the last 30 days reported missing (19%), mistiming (7%), or reducing (7%) their basal insulin dose as a result., Conclusion: Self-treated hypoglycemia was relatively common in patients using basal insulin analogs, with or without bolus insulin. Whilst the frequency of hypoglycemia was greater during the daytime than at night, patients worried more about nocturnal events and this level of worry was under-estimated by physicians. Additional advice and support may be needed for both patients and prescribers, to reduce the frequency and impact of self-treated hypoglycemia., Funding: Novo Nordisk.

Aims: Observational studies report inconsistent associations between moderate alcohol intake and blood pressure (BP). In a sub-study of a larger randomized controlled trial, we assessed the effect of initiating moderate red wine consumption on 24-h BP recordings and the effect of a common genetic variant of alcohol dehydrogenases (ADH) among patients with type 2 diabetes., Methods: Fifty-four type 2 diabetes, alcohol abstainers were randomized to consume 150 ml/dinner dry red wine or mineral water. Both groups were guided to adhere to a Mediterranean diet, without caloric restriction. We measured 24-h ambulatory BP monitoring (ABPM) at baseline and after 6 months., Results: Participants (age = 57 years; 85% men; mean 24-h BP = 129/77 mm Hg) had 92% 6-month retention. After 6 months of intervention, the average 24-h BP did not differ between the wine and water groups. A transient decrease in BP was observed in the red wine group at midnight (3-4 hours after wine intake: systolic BP: red wine = -10.6mm Hg vs. mineral water = +2.3 mm Hg; P = 0.031) and the following morning at 7-9 am (red wine: -6.2mm Hg vs. mineral water: +5.6mm Hg; P = 0.014). In a second post hoc sub-analysis among the red wine consumers, individuals who were homozygous for the gene encoding ADH1B*2 variant (Arg48His; rs1229984, TT, fast ethanol metabolizers), exhibited a reduction in mean 24-h systolic BP (-8.0mm Hg vs. +3.7 mm Hg; P = 0.002) and pulse pressure (-3.8 mm Hg vs. +1.2 mm Hg; P = 0.032) compared to heterozygotes and those homozygous for the ADH1B*1 variant (CC, slow metabolizers)., Conclusions: Initiating moderate red wine consumption at dinner among type 2 diabetes patients does not have a discernable effect on mean 24-h BP. Yet, a modest temporal BP reduction could be documented, and a more pronounced BP-lowering effect is suggested among fast ethanol metabolizers., Clinical Trials Registration: ClinicalTrials.gov Identifier: NCT00784433., (© American Journal of Hypertension, Ltd 2015. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Autophagy genes' expression is upregulated in visceral fat in human obesity, associating with obesity-related cardio-metabolic risk. E2F1 (E2F transcription factor 1) was shown in cancer cells to transcriptionally regulate autophagy. We hypothesize that E2F1 regulates adipocyte autophagy in obesity, associating with endocrine/metabolic dysfunction, thereby, representing non-cell-cycle function of this transcription factor. E2F1 protein (N=69) and mRNA (N=437) were elevated in visceral fat of obese humans, correlating with increased expression of ATG5 (autophagy-related 5), MAP1LC3B/LC3B (microtubule-associated protein 1 light chain 3 β), but not with proliferation/cell-cycle markers. Elevated E2F1 mainly characterized the adipocyte fraction, whereas MKI67 (marker of proliferation Ki-67) was elevated in the stromal-vascular fraction of adipose tissue. In human visceral fat explants, chromatin-immunoprecipitation revealed body mass index (BMI)-correlated increase in E2F1 binding to the promoter of MAP1LC3B, but not to the classical cell cycle E2F1 target, CCND1 (cyclin D1). Clinically, omental fat E2F1 expression correlated with insulin resistance, circulating free-fatty-acids (FFA), and with decreased circulating ADIPOQ/adiponectin, associations attenuated by adjustment for autophagy genes. Overexpression of E2F1 in HEK293 cells enhanced promoter activity of several autophagy genes and autophagic flux, and sensitized to further activation of autophagy by TNF. Conversely, mouse embryonic fibroblast (MEF)-derived adipocytes from e2f1 knockout mice (e2f1 -/- ) exhibited lower autophagy gene expression and flux, were more insulin sensitive, and secreted more ADIPOQ. Furthermore, e2f1 -/- MEF-derived adipocytes, and autophagy-deficient (by Atg7 siRNA) adipocytes were resistant to cytokines-induced decrease in ADIPOQ secretion. Jointly, upregulated E2F1 sensitizes adipose tissue autophagy to inflammatory stimuli, linking visceral obesity to adipose and systemic metabolic-endocrine dysfunction.

Background: Recommendations for moderate alcohol consumption remain controversial, particularly in type 2 diabetes mellitus (T2DM). Long-term randomized, controlled trials (RCTs) are lacking., Objective: To assess cardiometabolic effects of initiating moderate alcohol intake in persons with T2DM and whether the type of wine matters., Design: 2-year RCT (CASCADE [CArdiovaSCulAr Diabetes & Ethanol] trial). (ClinicalTrials.gov: NCT00784433)., Setting: Ben-Gurion University of the Negev-Soroka Medical Center and Nuclear Research Center Negev, Israel., Patients: Alcohol-abstaining adults with well-controlled T2DM., Intervention: Patients were randomly assigned to 150 mL of mineral water, white wine, or red wine with dinner for 2 years. Wines and mineral water were provided. All groups followed a Mediterranean diet without caloric restriction., Measurements: Primary outcomes were lipid and glycemic control profiles. Genetic measurements were done, and patients were followed for blood pressure, liver biomarkers, medication use, symptoms, and quality of life., Results: Of the 224 patients who were randomly assigned, 94% had follow-up data at 1 year and 87% at 2 years. In addition to the changes in the water group (Mediterranean diet only), red wine significantly increased high-density lipoprotein cholesterol (HDL-C) level by 0.05 mmol/L (2.0 mg/dL) (95% CI, 0.04 to 0.06 mmol/L [1.6 to 2.2 mg/dL]; P < 0.001) and apolipoprotein(a)1 level by 0.03 g/L (CI, 0.01 to 0.06 g/L; P = 0.05) and decreased the total cholesterol-HDL-C ratio by 0.27 (CI, -0.52 to -0.01; P = 0.039). Only slow ethanol metabolizers (alcohol dehydrogenase alleles [ADH1B*1] carriers) significantly benefited from the effect of both wines on glycemic control (fasting plasma glucose, homeostatic model assessment of insulin resistance, and hemoglobin A1c) compared with fast ethanol metabolizers (persons homozygous for ADH1B*2). Across the 3 groups, no material differences were identified in blood pressure, adiposity, liver function, drug therapy, symptoms, or quality of life, except that sleep quality improved in both wine groups compared with the water group (P = 0.040). Overall, compared with the changes in the water group, red wine further reduced the number of components of the metabolic syndrome by 0.34 (CI, -0.68 to -0.001; P = 0.049)., Limitation: Participants were not blinded to treatment allocation., Conclusion: This long-term RCT suggests that initiating moderate wine intake, especially red wine, among well-controlled diabetics as part of a healthy diet is apparently safe and modestly decreases cardiometabolic risk. The genetic interactions suggest that ethanol plays an important role in glucose metabolism, and red wine's effects also involve nonalcoholic constituents., Primary Funding Source: European Foundation for the Study of Diabetes.

Importance: The risk for herpes zoster (HZ) in patients with psoriasis treated with biologic medications or other systemic treatments has been given little attention to date., Objective: To describe the risk for HZ in patients with psoriasis and its relation to treatment., Design, Setting, and Participants: A cohort study was performed using the administrative database of Clalit Health Services, the largest public health care provider organization in Israel, in the setting of general community clinics, primary care and referral centers, and ambulatory and hospitalized care. We extracted information for all patients who received a psoriasis diagnosis from January 2002 to June 2013. Follow-up was conducted until the end of July 2013. The study included 95,941 patients with psoriasis in the analysis, with 522,616 person-years of follow-up. Incidence of HZ events was calculated for each systemic antipsoriatic medication provided, during a follow-up period of 11 years and 7 months. We used a generalized estimating equation Poisson regression model to examine the effect of each systemic treatment for psoriasis on HZ incidence, adjusting for age, sex, psoriasis severity, Charlson comorbidity index, steroid treatment, and socioeconomic status., Main Outcomes and Measures: Incidence of HZ associated with systemic therapies., Results: In a multivariate analysis, it was observed that treatment with phototherapy (rate ratio [RR], 1.09 [95% CI, 0.62-1.93]; P = .99), methotrexate (RR, 0.98 [95% CI, 0.78-1.23]; P = .83), cyclosporine (RR, 1.16 [95% CI, 0.48-2.80]; P = .49), and biologic medications as a single agent (RR, 2.67 [95% CI, 0.69-10.3]; P = .14) was not associated with HZ. The use of combination treatment with biologic medications and methotrexate was significantly associated with an increased incidence of HZ (RR, 1.66 [95% CI, 1.08-2.57]; P = .02). The use of acitritin was associated with decreased incidence of HZ (RR, 0.69 [95% CI, 0.49-0.97]; P = .004)., Conclusions and Relevance: Physicians may need to consider offering an HZ preventive vaccine to patients receiving combination treatment with biologic medications and methotrexate, particularly if they have additional risk factors for HZ.

The morbidity and mortality caused by diabetic foot ulcer (DFU) are still significant. Conservative treatment of DFU is often ineffective. Treatment modalities using stem cells directly into the DFU or systematically have been introduced recently. Ischemic preconditioning (IPC) has been proved to be a cheap, simple, and safe method which can augment stem cells number in the peripheral blood circulation. This study's purpose was to test whether IPC can improve DFU healing. Forty diabetic patients were enrolled and divided into study and control groups. All patients received their regular treatment. The study group patients received in addition brief, transient cycles of IPC while the control group patients received a sham procedure only. The procedure was repeated every 2 weeks to complete a follow-up period of 6 weeks. The ulcers were photographed to measure wound area, and the degree of granulation tissue was assessed. No serious adverse events were noted. Twenty-two patients from the study group and 12 from the control group completed the entire follow-up. The ratio of patients who reached complete healing of their ulcer was 9/22 (41%) in the study group compared with 0/12 (0%) in the control group, p = 0.01. Furthermore, the mean remaining ulcer area at the end of the follow-up was significantly smaller in the study group, 25 ± 6% of the initial area vs. 61 ± 10% in the control group, p = 0.007. The degree of granulation increased after one cycle of treatment in 8/24 (33%) study patients compared to 3/16 (19%) in the control group, p = 0.47. Remote, repeated IPC significantly improves the healing of DFU. This simple, safe, inexpensive treatment method should be considered to be routinely applied to diabetic patients with DFU in addition to other regular treatment modalities., (© 2015 by the Wound Healing Society.)

Background: As new members of a drug class are developed, head-to-head trials are an important strategy to guide personalised treatment decisions. We assessed two glucagon-like peptide-1 receptor agonists, once-weekly albiglutide and once-daily liraglutide, in patients with type 2 diabetes inadequately controlled on oral antidiabetic drugs., Methods: We undertook this 32-week, open-label, phase 3 non-inferiority study at 162 sites in eight countries: USA (121 sites), Australia (9 sites), Peru (7 sites), Philippines (7 sites), South Korea (5 sites), UK (5 sites), Israel (4 sites), and Spain (4 sites). 841 adult participants (aged ≥18 years) with inadequately controlled type 2 diabetes and a BMI between 20 and 45 kg/m(2) were enrolled and randomised in a 1:1 ratio to receive albiglutide 30 mg once weekly titrated to 50 mg at week 6, or liraglutide 0·6 mg once daily titrated to 1·2 mg at week 1 and 1·8 mg at week 2. The randomisation schedule was generated by an independent randomisation team by the permuted block method with a fixed block size of 16. Participants and investigators were unmasked to treatment. The primary endpoint was change from baseline in HbA1c for albiglutide versus liraglutide, with a 95% CI non-inferiority upper margin of 0·3%. The primary analysis was by modified intention to treat. The study is registered with ClinicalTrials.gov, number NCT01128894., Findings: 422 patients were randomly allocated to the albigultide group and 419 to the liraglutide group; 404 patients in the abliglutide group and 408 in the liraglutide group received the study drugs. The primary endpoint analysis was done on the modified intention-to-treat population, which included 402 participants in the albiglutide group and 403 in the liraglutide group. Model-adjusted change in HbA1c from baseline to week 32 was -0·78% (95% CI -0·87 to -0·69) in the albigludite group and -0·99% (-1·08 to -0·90) in the liraglutide group; treatment difference was 0·21% (0·08-0·34; non-inferiority p value=0·0846). Injection-site reactions occurred in more patients given albiglutide than in those given liraglutide (12·9% vs 5·4%; treatment difference 7·5% [95% CI 3·6-11·4]; p=0·0002), whereas the opposite was the case for gastrointestinal events, which occurred in 49·0% of patients in the liraglutide group versus 35·9% in the albiglutide group (treatment difference -13·1% [95% CI -19·9 to -6·4]; p=0·00013)., Interpretation: Patients who received once-daily liraglutide had greater reductions in HbA1c than did those who received once-weekly albiglutide. Participants in the albiglutide group had more injection-site reactions and fewer gastrointestinal events than did those in the liraglutide group., Funding: GlaxoSmithKline., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Objective: This study addressed the long-term effect of various diets, particularly low-carbohydrate high-protein, on renal function on participants with or without type 2 diabetes., Research Design and Methods: In the 2-year Dietary Intervention Randomized Controlled Trial (DIRECT), 318 participants (age, 51 years; 86% men; BMI, 31 kg/m(2); mean estimated glomerular filtration rate [eGFR], 70.5 mL/min/1.73 m(2); mean urine microalbumin-to-creatinine ratio, 12:12) with serum creatinine <176 μmol/L (eGFR ≥ 30 mL/min/1.73 m(2)) were randomized to low-fat, Mediterranean, or low-carbohydrate diets. The 2-year compliance was 85%, and the proportion of protein intake significantly increased to 22% of energy only in the low-carbohydrate diet (P < 0.05 vs. low-fat and Mediterranean). We examined changes in urinary microalbumin and eGFR, estimated by Modification of Diet in Renal Disease and Chronic Kidney Disease Epidemiology Collaboration formulas., Results: Significant (P < 0.05 within groups) improvements in eGFR were achieved in low-carbohydrate (+5.3% [95% CI 2.1-8.5]), Mediterranean (+5.2% [3.0-7.4]), and low-fat diets (+4.0% [0.9-7.1]) with similar magnitude (P > 0.05) across diet groups. The increased eGFR was at least as prominent in participants with (+6.7%) or without (+4.5%) type 2 diabetes or those with lower baseline renal function of eGFR <60 mL/min/1.73 m(2) (+7.1%) versus eGFR ≥ 60 mL/min/1.73 m(2) (+3.7%). In a multivariable model adjusted for age, sex, diet group, type 2 diabetes, use of ACE inhibitors, 2-year weight loss, and change in protein intake (confounders and univariate predictors), only a decrease in fasting insulin (β = -0.211; P = 0.004) and systolic blood pressure (β = -0.25; P < 0.001) were independently associated with increased eGFR. The urine microalbumin-to-creatinine ratio improved similarly across the diets, particularly among participants with baseline sex-adjusted microalbuminuria, with a mean change of -24.8 (P < 0.05)., Conclusions: A low-carbohydrate diet is as safe as Mediterranean or low-fat diets in preserving/improving renal function among moderately obese participants with or without type 2 diabetes, with baseline serum creatinine <176 μmol/L. Potential improvement is likely to be mediated by weight loss-induced improvements in insulin sensitivity and blood pressure.

Background: Diabetic ketoacidosis (DKA) occurs most often in patients with type 1 diabetes, however patients with type 2 diabetes are also susceptible to DKA under stressful conditions. The aims of our study were to evaluate and compare the clinical and biochemical characteristics and outcomes of type 1 versus type 2 diabetes mellitus (DM) patients with DKA., Methods: A retrospective cohort study of adult patients hospitalized with DKA between January 1, 2003, and January 1, 2010. The clinical and biochemical characteristics of DKA patients with type-1 DM were compared with those of patients with type-2 DM. The primary outcome was in-hospital all-cause mortality., Results: The study cohort included 201 consecutive patients for whom the admission diagnosis was DKA: 166 patients (82.6%) with type-1 DM and 35 patients (17.4%) with type-2 DM. The patients with DKA and type-2 DM were significantly older than patients with type-1 DM (64.3 versus 37.3, P < 0.001). Significantly more patients with severe forms of DKA were seen in the group with type-2 DM (25.7% versus 9.0%, P = 0.018). The total in-hospital mortality rate of patients with DKA was 4.5%. The primary outcome was significantly worse in the group of patients with type-2 DM., Conclusions: DKA in patients with type-2 DM is a more severe disease with worse outcomes compared with type-1 DM. Advanced age, mechanical ventilation and bed-ridden state were independent predictors of 30-day mortality.

Context: Adipose tissue macrophages (ATMs) are thought to engulf the remains of dead adipocytes in obesity, potentially resulting in increased intracellular neutral lipid content. Lipid-laden macrophages (foam cells [FCs]) have been described in atherosclerotic lesions and have been proposed to contribute to vascular pathophysiology, which is enhanced in obesity., Objective: The objective of this study was to determine whether a subclass of lipid-laden ATMs (adipose FCs) develop in obesity and to assess whether they may uniquely contribute to obesity-associated morbidity., Setting and Patients: Patients undergoing elective abdominal surgery from the Beer-Sheva (N = 94) and the Leipzig (N = 40) complementary cohorts were recruited. Paired abdominal subcutaneous (SC) and omental (Om) fat biopsy samples were collected and analyzed by histological and flow cytometry-based methods. Functional studies in mice included coculture of ATMs or FCs with adipose tissue., Results: ATM lipid content was increased 3-fold in Om compared with SC fat, particularly in obese persons. FCs could be identified in some patients and were most abundant in Om fat of obese persons, particularly those with intra-abdominal fat distribution. Stepwise multivariate models demonstrated depot differential associations: fasting glucose with SC FCs (β = 0.667, P < .001) and fasting insulin (β = 0.413, P = .006) and total ATM count (β = 0.310, P = .034) with Om FCs in models including age, body mass index, high-density lipoprotein cholesterol, and high-sensitivity C-reactive protein. When cocultured with adipose explants from lean mice, FCs induced attenuated insulin responsiveness compared with adipose explants cocultured with control ATMs with low lipid content., Conclusions: FCs can be identified as an ATM subclass in human SC and Om adipose tissues in 2 independent cohorts, with distinct depot-related associations with clinical parameters. Once formed, they may engage in local cross-talk with adipocytes, contributing to adipose insulin resistance.

Background: Diabetic ketoacidosis (DKA) is a common and serious complication of diabetes mellitus (DM)., Objectives: To evaluate the clinical characteristics, hospital management and outcomes of patients with DKA., Methods: We performed a retrospective cohort study of patients hospitalized with DKA during the period 1 January 2003 to 1 January 2010. Three groups were compared: patients with mild DKA, with moderate DKA, and with severe DKA. The primary outcome was in-hospital all-cause mortality. The secondary outcomes were 30 days all-cause mortality, length of hospital stay, and complication rate., Results: The study population comprised 220 patients with DKA. In the mild (78 patients) and moderate (116 patients) groups there was a higher proportion of patients with type 1 DM (75.6%, 79.3%) compared with 57.7% in the severe group (26 patients, P = 0.08). HbA1c levels prior to admission were high in all three groups, without significant difference (10.9 +/- 2.2, 10.7 +/- 1.9, and 10.6 +/- 2.4 respectively, P = 0.9). In all groups the most frequent precipitating factors were related to insulin therapy and infections. The patients with severe DKA had more electrolyte abnormalities (hypokalemia, hypomagnesemia, hypophosphatemia) compared with the mild and moderate forms of the disease. While 72.7% of the entire cohort was hospitalized in the general medical ward, 80.8% of those with severe DKA were admitted to the intensive care unit. The in-hospital mortality rate for the entire cohort was 4.1%, comparable with previous data from experienced centers. Advanced age, mechanical ventilation and bedridden state were independent predictors associated with 30 day mortality: hazard ratio (HR) 1.1, 95% confidence interval (CI) 1.02-1.11; HR 6.8, 95% CI 2.03-23.1; and HR 3.8, 95% CI 1.13-12.7, respectively., Conclusions: Patients with DKA in our study were generally poorly controlled prior to their admission, as reflected by high HbA1c levels. Type 2 DM is frequently associated with DKA including the severe form of the disease. The most common precipitating factors for the development of DKA were related to insulin therapy and infections. Advanced age, mechanical ventilation and bedridden state wer independent predictors of 30 day mortality.

Kidneys play an important role in retinol turnover. We postulated that retinol homeostasis is disturbed in diabetic nephropathy. The aim of this research was to study the effect of kidney impairment on urinary excretion and on serum concentrations of retinol in type 2 diabetes mellitus patients. For this purpose, 41 type 2 diabetes patients and 9 sex -and age-matched healthy subjects were enrolled. Serum and urinary retinol and retinol-binding protein (RBP) were assessed by high-pressure liquid chromatography and enzyme-linked immunosorbent assay, respectively. The study showed that 17 out of 41 diabetic patients (41.5%) and none of the controls excreted retinol in urine (P < 0.02). Retinol excretion in the urine in these patients was 1.5-fold more prevalent than hypercreatininemia. Urinary retinol significantly correlated with clinically diagnosed nephropathy (P = 0.02). All but one of the patients with hypercreatininemia excreted retinol in the urine. Serum retinol and RBP in patients with hypercreatininemia were higher than in controls (P < 0.002). Values of urinary retinol, unlike urinary RBP, albumin and total protein, did not overlap between patients and controls. Our results indicate that (i) urinary retinol is a specific sign of tubular damage in type 2 diabetic patients and (ii) urinary retinol enables a more clear-cut identification of proximal tubule dysfunction in type 2 diabetes patients than urinary RBP or albumin.

Aim: Epidemiological and mechanistic studies raised the possibility that cognitive function may be affected by brain responses to insulin. We systematically reviewed and analyzed existing clinical trials that assessed the potential beneficial effects of intranasal insulin administration on cognitive functions., Methods: Interventional studies measuring changes in cognitive functions in response to intranasal insulin were retrieved and included if they were in English and assessed cognitive functions before and after treatment. Cohen's effect size was calculated to allow comparison between studies., Results: Eight studies (328 participants) were analyzed. No significant side effects of intranasal insulin administration were reported. Seven studies included healthy subjects' response to intranasal insulin, and three evaluated the cognitive effect among patients with minimal cognitive impairment or overt Alzheimer's disease. In healthy people, Cohen's effect size calculations suggest that only 160 IU/d intranasal insulin induced potential beneficial effects. Although females, when compared head-to-head, exhibited greater improvements in cognitive tests than men, the composite analysis of all included studies did not support this trend. Among cognitively impaired patients, only lower doses of insulin were assessed, and 20 IU revealed potential beneficial effects on cognitive functions. This was significant in a single study assessing long-term intranasal insulin administration, whereas acute administration of 20 IU intranasal insulin tended to show a beneficial effect on immediate recall in Apo ε4(-), but not Apo ε4(+), patients., Conclusions: The current limited clinical experience suggests potential beneficial cognitive effects of intranasal insulin. Analyses provide clinical considerations for future research aimed at elucidating whether intranasal insulin may be used to improve cognitive functions.