Ethnicity Affects A1C Levels in Patients With Diagnosed Type 2 Diabetes in Southern Israel.

Purpose: To assess whether ethnicity affects the association between A1C and fasting glucose in people with type 2 diabetes. Methods: This investigation was an epidemiological, cross-sectional study based on computerized medical records of the Southern District of Clalit Health Services. The study population comprised patients ≥40 years of age with type 2 diabetes who underwent blood tests between 8 August 2015 and 20 July 2020. A normal-error multiple linear regression model was used to assess differences in associations among ethnic groups (i.e., Arabs, Ethiopian Jews, and non-Ethiopian Jews) and A1C. Results: A total of 59,432 patients with type 2 diabetes were included in the study. Of these, 1,804 were Jews of Ethiopian origin, 49,296 were non-Ethiopian Jews, and 8,332 were Arabs. Compared with non-Ethiopian Jews, A1C levels were increased by 0.1% (1 mmol/mol) among Ethiopian Jews and by 0.3% (3 mmol/mol) among Arabs. Ethnicity was a strong predictor of A1C, explaining 0.6% of its variance. An A1C level of 7% (53 mmol/mol) correlated with fasting glucose levels of 141, 136, and 126 mg/dL in non-Ethiopian Jews, Ethiopian Jews, and Arabs, respectively. Conclusion: Ethnic differences in A1C should be considered by clinicians, researchers, and policymakers.

Adherence to liraglutide among individuals with overweight and obesity: Patient characteristics and clinical measures.

AIM: To identify the sociodemographic, clinical and laboratory determinants relating to patient adherence to liraglutide treatment among individuals with overweight or obesity. METHODS: We retrospectively analysed patients with overweight or obesity who were treated with liraglutide between 2019 and 2022. Over a 6-month follow-up period, measurements of body mass index, sociodemographic characteristics, clinical and laboratory data, and prescription records for liraglutide were collected. Treatment adherence was assessed using the proportion of days covered (PDC) measure, with a PDC ≥80% indicating high adherence. RESULTS: The study population included 1890 participants (78.1% female, mean age 46 ± 12 years). At the end of the follow-up period, 84.9% of the participants exhibited low adherence to liraglutide treatment. Adherence to treatment improved with age (p = 0.04, odds ratio [OR] 1.013, confidence interval [CI] 1.001-1.025). Significant weight loss during treatment increased the likelihood of high adherence (p < 0.001, OR 1.251, CI 1.167-1.341). Individuals with a higher socioeconomic status displayed greater adherence (p = 0.023, OR 1.906, CI 1.091-3.328). Greater adherence was also seen in non-smokers (p = 0.047, OR 0.725, CI 0.528-0.996). CONCLUSIONS: Only 15.1% of study participants exhibited high adherence to treatment (PDC ≥80%) after 6 months of follow-up. Further research is needed to explore approaches to enhance adherence to liraglutide, including strategies to educate and support patients in their efforts to achieve and maintain weight loss with the use of this drug.

Circulating isomiRs May Be Superior Biomarkers Compared to Their Corresponding miRNAs: A Pilot Biomarker Study of Using isomiR-Ome to Detect Coronary Calcium-Based Cardiovascular Risk in Patients with NAFLD.

Circulating miRNAs are increasingly being considered as biomarkers in various medical contexts, but the value of analyzing isomiRs (isoforms of canonical miRNA sequences) has not frequently been assessed. Here we hypothesize that an in-depth analysis of the full circulating miRNA landscape could identify specific isomiRs that are stronger biomarkers, compared to their corresponding miRNA, for identifying increased CV risk in patients with non-alcoholic fatty liver disease (NAFLD)-a clinical unmet need. Plasma miRNAs were sequenced with next-generation sequencing (NGS). Liver fat content was measured with magnetic-resonance spectrometry (MRS); CV risk was determined, beyond using traditional biomarkers, by a CT-based measurement of coronary artery calcium (CAC) score and the calculation of a CAC score-based CV-risk percentile (CAC-CV%). This pilot study included n = 13 patients, age > 45 years, with an MRS-measured liver fat content of ≥5% (wt/wt), and free of overt CVD. NGS identified 1103 miRNAs and 404,022 different isomiRs, of which 280 (25%) and 1418 (0.35%), respectively, passed an abundance threshold. Eighteen (sixteen/two) circulating miRNAs correlated positively/negatively, respectively, with CAC-CV%, nine of which also significantly discriminated between high/low CV risk through ROC-AUC analysis. IsomiR-ome analyses uncovered 67 isomiRs highly correlated (R ≥ 0.55) with CAC-CV%. Specific isomiRs of miRNAs 101-3p, 144-3p, 421, and 484 exhibited stronger associations with CAC-CV% compared to their corresponding miRNA. Additionally, while miRNAs 140-3p, 223-3p, 30e-5p, and 342-3p did not correlate with CAC-CV%, specific isomiRs with altered seed sequences exhibited a strong correlation with coronary atherosclerosis burden. Their predicted isomiRs-specific targets were uniquely enriched (compared to their canonical miRNA sequence) in CV Disease (CVD)-related pathways. Two of the isomiRs exhibited discriminative ROC-AUC, and another two showed a correlation with reverse cholesterol transport from cholesterol-loaded macrophages to ApoB-depleted plasma. In summary, we propose a pipeline for exploring circulating isomiR-ome as an approach to uncover novel and strong CVD biomarkers.

Circulating miRNAs Detect High vs Low Visceral Adipose Tissue Inflammation in Patients Living With Obesity.

CONTEXT: The severity of visceral adipose tissue (VAT) inflammation in individuals with obesity is thought to signify obesity subphenotype(s) associated with higher cardiometabolic risk. Yet, this tissue is not accessible for direct sampling in the nonsurgical patient. OBJECTIVE: We hypothesized that circulating miRNAs (circ-miRs) could serve as biomarkers to distinguish human obesity subgroups with high or low extent of VAT inflammation. METHODS: Discovery and validation cohorts of patients living with obesity undergoing bariatric surgery (n = 35 and 51, respectively) were included. VAT inflammation was classified into low/high based on an expression score derived from the messenger RNA levels of TNFA, IL6, and CCL2 (determined by reverse transcription polymerase chain reaction). Differentially expressed circ-miRs were identified, and their discriminative power to detect low/high VAT inflammation was assessed by receiver operating characteristic-area under the curve (ROC-AUC) analysis. RESULTS: Fifty three out of 263 circ-miRs (20%) were associated with high-VAT inflammation according to Mann-Whitney analysis in the discovery cohort. Of those, 12 (12/53 = 23%) were differentially expressed according to Deseq2, and 6 significantly discriminated between high- and low-VAT inflammation with ROC-AUC greater than 0.8. Of the resulting 5 circ-miRs that were differentially abundant in all 3 statistical approaches, 3 were unaffected by hemolysis and validated in an independent cohort. Circ-miRs 181b-5p, 1306-3p, and 3138 combined with homeostatic model assessment of insulin resistance (HOMA-IR) exhibited ROC-AUC of 0.951 (95% CI, 0.865-1) and 0.808 (95% CI, 0.654-0.963) in the discovery and validation cohorts, respectively, providing strong discriminative power between participants with low- vs high-VAT inflammation. Predicted target genes of these miRNAs are enriched in pathways of insulin and inflammatory signaling, circadian entrainment, and cellular senescence. CONCLUSION: Circ-miRs that identify patients with low- vs high-VAT inflammation constitute a putative tool to improve personalized care of patients with obesity.

Visceral adipocyte size links obesity with dysmetabolism more than fibrosis, and both can be estimated by circulating miRNAs.

OBJECTIVE: In obesity, adipocyte hypertrophy is detrimental to health, but its' interrelation with fibrosis in the visceral adipose tissue (VAT) depot remains unclear. Because VAT is less accessible via biopsy, biomarkers for VAT quality are needed. The authors hypothesized that VAT adipocyte size and fibrosis are interrelated and can be estimated by circulating microRNAs (circ-miRNAs), contributing to subphenotyping obesity. METHODS: Adipocyte size and AT fibrosis were estimated in n = 43 participants (BMI ≥ 30 kg/m2 ). Circ-miRNAs were sequenced (Next Generation Sequencing). RESULTS: Participants with above- versus below-median VAT adipocyte area exhibited metabolic dysfunction but lower total and pericellular fibrosis. VAT adipocyte size remained associated with metabolic dysfunction even when controlling for BMI or VAT fibrosis in the entire cohort, as in matched-pairs subanalyses. Next Generation Sequencing uncovered 22 and 6 circ-miRNAs associated with VAT adipocyte size and fibrosis, respectively, with miRNA-130b-3p common to both analyses. The combination of miRNA-130b-3p + miR-150-5p + high-density lipoprotein cholesterol discriminated among those with large versus small VAT adipocytes (receiver operating characteristic-area under the curve: 0.872 [95% CI: 0.747-0.996]), whereas miRNA-130b-3p + miRNA-15a-5p + high-density lipoprotein cholesterol discriminated among those with low and high fibrosis (receiver operating characteristic-area under the curve: 0.823 [95% CI: 0.676-0.97]). CONCLUSIONS: These findings suggest that VAT adipocyte size and fibrosis are inversely correlated in obesity and can be estimated by distinct circ-miRNAs, providing a potential tool to subphenotype obesity via a liquid biopsy-like approach to assess VAT health in nonsurgical patients.

Simplifying carb counting: A randomized controlled study - Feasibility and efficacy of an individualized, simple, patient-centred carb counting tool.

INTRODUCTION: The purpose of this study was to introduce and test a simple, individualized carbohydrate counting tool designed for persons with Type 1 Diabetes Mellitus (T1DM) in order to determine whether the tool improved A1C levels for participants with age, education or language barriers. METHODS: In a randomized controlled trial, 85 participants were offered six diabetes instructional sessions free of charge over a six-month period. Forty-one received guidance using the regular carbohydrate counting (RCC) method. Forty-four received guidance using an individualized 'Simple Carb Counting' (SCC), involving two customized tables prepared for participants. RESULTS: The simple, individualized SCC tool for carbohydrate counting was non-inferior to the standard method of RCC. The SCC tool was more effective among participants aged 40 and older, while no differences were found when comparing participants by education level. Irrespective of intervention group, all participants improved their A1C level (9.9% = 13.2 mmol/L vs 8.6% = 11.1 mmol/L, p = .001). A greater improvement in A1C level was seen in newly diagnosed participants (-6.1 vs -0.7, p = .005, -3.4 vs 0.9, p = .032) in both the RCC and SCC groups. All participants expressed improved emotional level per their PAID5 questionnaires (Problem Areas in Diabetes Scale-PAID), (10.6 (±5.7) vs 9.5 (±5.7), p = .023), with women reporting greater improvement than men. CONCLUSIONS: SCC is a simple, individualized, feasible, low-tech tool for carbohydrate counting, which promotes and enables accurate insulin dosing in people with T1DM. It was found more effective among participants aged 40 and older. Additional studies are needed to corroborate these findings.

Glycemic control and macular edema in patients undergoing cataract surgery.

AIMS: Cataract, the most common cause of blindness, has higher prevalence among patients with diabetes mellitus. About 20% of cataract surgeries are performed on patients with diabetes. One of the complications of cataract surgery is pseudophakic cystoid macular edema (CME). This study examined whether patients' glycemic control (as indicated by HbA1c level before cataract surgery) is associated with CME incidence within one year post-surgery. METHODS: We conducted a retrospective cohort study of 1285 diabetes patients over age 18 who underwent cataract surgery between January 2015 and January 2020. Data were obtained from medical records reporting glycated hemoglobin (HbA1c) level prior to surgery and post-operative CME with intraocular anti-vascular endothelial growth factor injections. RESULTS: The patients with CME complications were younger, with longer duration diabetes, and higher percentages of type 1 diabetes and diabetic retinopathy. The main variables influencing risk of post-operative CME were found to be diabetic retinopathy and HbA1c level. Multivariate analysis revealed that HbA1c is an independent risk for post-operative CME with a relative risk of 2.01 when HBa1c is above 7 c (95% CI, 1.10-3.67). CONCLUSION: The study demonstrates that pre-cataract surgery diabetes control, measured by HbA1c level, is an independent risk factor for developing post-surgery CME.

Visceral Adipose Tissue E2F1-miRNA206/210 Pathway Associates with Type 2 Diabetes in Humans with Extreme Obesity.

Objective: Up-regulated expression of transcription-factor E2F1 in human visceral adipose tissue (VAT) characterizes a dysmetabolic obesity sub-phenotype. An E2F1-miRNA network has been described in multiple cancers. Here we investigated whether elevated VAT-E2F1 in obesity is associated with VAT-miRNA alterations similar to, or distinct from, those described in cancer. Furthermore, we assessed if E2F1-associated miRNA changes may contribute to the link between high- VAT-E2F1 and a dysmetabolic obesity phenotype. Methods: We assembled a cohort of patients with obesity and high-VAT-E2F1, matched by age, sex, ±BMI to patients with low-VAT-E2F1, with and without obesity (8 patients/groupX3 groups). We performed Nanostring©-based miRNA profiling of VAT samples from all 24 patients. Candidate E2F1-related miRNAs were validated by qPCR in an independent cohort of patients with extreme obesity, with or without type-2-diabetes (T2DM) (n = 20). Bioinformatic tools and manipulation of E2F1 expression in cells were used to establish the plausibility of the functional VAT-E2F1-miRNA network in obesity. Results: Among n = 798 identified miRNAs, 17 were differentially expressed in relation to E2F1 and not to obesity itself. No evidence for the cancer-related E2F1-miRNA network was identified in human VAT in obesity. In HEK293-cells, overexpression/downregulation of E2F1 correspondingly altered the expression of miRNA-206 and miRNA-210-5p, two miRNAs with reported metabolic functions consistent with those of E2F1. In VAT from both cohorts, the expression of both miRNA-206 and 210-5p intercorrelated, and correlated with the expression of E2F1. In cohort 1 we did not detect significant associations with biochemical parameters. In cohort 2 of patients with extreme obesity, all those with high VAT-E2F1 showed a diabetes-complicated obesity phenotype and higher expression of miRNA-206 and miRNA-210-5p, which also correlated with fasting glucose levels (both miRNAs) and fasting insulin (miRNA-210-5p). Conclusions: Whilst the previously described cancer-related E2F1-miRNA network does not appear to operate in VAT in obesity, miRNAs-206 and 210-5p may link high-E2F1 expression in VAT with diabetes-complicated extreme obesity phenotype.

Personalized insulin dose manipulation attack and its detection using interval-based temporal patterns and machine learning algorithms.

Many patients with diabetes are currently being treated with insulin pumps and other diabetes devices which improve their quality of life and enable effective treatment of diabetes. These devices are connected wirelessly and thus, are vulnerable to cyber-attacks which have already been proven feasible. In this paper, we focus on two types of cyber-attacks on insulin pump systems: an overdose of insulin, which can cause hypoglycemia, and an underdose of insulin, which can cause hyperglycemia. Both of these attacks can result in a variety of complications and endanger a patient's life. Specifically, we propose a sophisticated and personalized insulin dose manipulation attack; this attack is based on a novel method of predicting the blood glucose (BG) level in response to insulin dose administration. To protect patients from the proposed sophisticated and malicious insulin dose manipulation attacks, we also present an automated machine learning based system for attack detection; the detection system is based on an advanced temporal pattern mining process, which is performed on the logs of real insulin pumps and continuous glucose monitors (CGMs). Our multivariate time-series data (MTSD) collection consists of 225,780 clinical logs, collected from real insulin pumps and CGMs of 47 patients with type I diabetes (13 adults and 34 children) from two different clinics at Soroka University Medical Center in Beer-Sheva, Israel over a four-year period. We enriched our data collection with additional relevant medical information related to the subjects. In the extensive experiments performed, we evaluated the proposed attack and detection system and examined whether: (1) it is possible to accurately predict BG levels in order to create malicious data that simulate a manipulation attack and the patient's body in response to it; (2) it is possible to automatically detect such attacks based on advanced machine learning (ML) methods that leverage temporal patterns; (3) the detection capabilities of the proposed detection system differ for insulin overdose and underdose attacks; and (4) the granularity of the learning model (general / adult vs. pediatric clinic / individual patient) affects the detection capabilities. Our results show that (a) it is possible to predict, with nearly 90% accuracy, BG levels using our proposed methods, and by doing so, enable malicious data creation for our detection system evaluation; (b) it is possible to accurately detect insulin manipulation attacks using temporal patterns mining using several ML methods, including Logistic Regression, Random Forest, TPF class model, TPF top k, and ANN algorithms; (c) it is easier to detect an overdose attack than an underdose attack in more than 25%, in terms of AUC scores; and (d) the adult vs. pediatric model outperformed models of other granularities in the detection of overdose attacks, while the general model outperformed the other models in the case of detecting underdose attacks; for both attacks, attack detection among children was found to be more challenging than among adults. In addition to its use in the evaluation of our detection system, the proposed BG prediction method has great importance in the medical domain where it can contribute to improved care of patients with diabetes.

The roles of personal interview and cognitive abilities at admission to medical school in predicting performance of medical students in their internal medicine sub-internship.

BACKGROUND: The medical school admission process is complicated, perhaps reflecting unresolved debates concerning the most important skills necessary to become an ideal physician. The Goldman Medical School at Ben-Gurion University in Israel is known for placing great emphasis on the personal attributes of candidates in addition to their academic excellence. To this end, 1-h consecutive interviews are embedded in the admission process. This study aims to determine whether there is an association between candidates' personal interview ratings and the ratings assigned to these students at the conclusion of their 6th year internal medicine sub-internship. METHODS: Our study sample included 136 students who were admitted to the medical school in 2015, and who completed their 6th year internal medicine sub-internship in 2019-2020. Our data were derived from the admissions information for each candidate and from structured interviews concerning medical competence and personal traits, which were completed by medical personnel who were in contact with these students during their clinical rounds. RESULTS: Higher interview ratings of candidates during the admission process were associated with a higher probability that students would be evaluated as top-rated internists 6 years later (Odds Ratio (OR) = 9.4, p-value = 0.049), independent of gender (OR for male vs female = 0.2, p-value = 0.025) and age (OR = 1.3 per each year, p-value = 0.115). Although significant, the numeric difference in interview rating was relatively small (median 9.5 and 9.4 for top-rated and not top-rated internists, respectively). CONCLUSIONS: Our study shows that high personal interview ratings assigned to candidates as part of the medical school admission process are predictive of high performance ratings of students after they complete their 6th year internal medicine sub-internships. These findings demonstrate the value and importance of using semi-structured personal interviews in the medical school admission process.

Comparison of Insulin Dose Adjustments Made by Artificial Intelligence-Based Decision Support Systems and by Physicians in People with Type 1 Diabetes Using Multiple Daily Injections Therapy.

Objective: Artificial intelligence-based decision support systems (DSS) need to provide decisions that are not inferior to those given by experts in the field. Recommended insulin dose adjustments on the same individual data set were compared among multinational physicians, and with recommendations made by automated Endo.Digital DSS (ED-DSS). Research Design and Methods: This was a noninterventional study surveying 20 physicians from multinational academic centers. The survey included 17 data cases of individuals with type 1 diabetes who are treated with multiple daily insulin injections. Participating physicians were asked to recommend insulin dose adjustments based on glucose and insulin data. Insulin dose adjustments recommendations were compared among physicians and with the automated ED-DSS. The primary endpoints were the percentage of comparison points for which there was agreement on the trend of insulin dose adjustments. Results: The proportion of agreement and disagreement in the direction of insulin dose adjustment among physicians was statistically noninferior to the proportion of agreement and disagreement observed between ED-DSS and physicians for basal rate, carbohydrate-to insulin ratio, and correction factor (P < 0.001 and P ≤ 0.004 for all three parameters for agreement and disagreement, respectively). The ED-DSS magnitude of insulin dose change was consistently lower than that proposed by the physicians. Conclusions: Recommendations for insulin dose adjustments made by automatization did not differ significantly from recommendations given by expert physicians regarding the direction of change. These results highlight the potential utilization of ED-DSS as a useful clinical tool to manage insulin titration and dose adjustments.

Heterogenicity of diabetes as a risk factor for all-cause mortality after acute myocardial infarction: Age and sex impact.

AIM: Type 2 diabetes mellitus (T2DM) is a risk factor for mortality after acute myocardial infarction (AMI). We studied the impact of T2DM related to sex and age on post-AMI long-term mortality. METHODS: A retrospective study included post-AMI patients. Data were obtained from electronic medical records. We defined the study groups by T2DM, stratified by age-sex. OUTCOME: up-to-10 years post-discharge all-cause mortality. RESULTS: 16,168 patients were analyzed, 40.3% had T2DM. Ten-year mortality rates were 50.3% with T2DM vs. 33.1% without T2DM, adjHR = 1.622 (p < 0.001). Females (adjHR = 1.085, p = 0.052) and increased age (adjHR = 1.056 for one-year increase, p < 0.001) were associated with a higher risk of mortality (borderline statistical significance for sex). The relationship between T2DM and mortality was stronger in females than in males at < 50 and 60-69 years (p-for-interaction 0.025 and 0.009 respectively), but not for other age groups. CONCLUSIONS: The study implies heterogeneity in the impact of T2DM on mortality of post-AMI patients, being greater among young patients, particularly females, and no significant impact in octogenarians. That implies that young women with T2DM should have advanced measures for early detection of coronary artery disease and tight control of cardiovascular risk factors to lower the propensity to develop AMI.

Human adipose tissue is a putative direct target of daytime orexin with favorable metabolic effects: A cross-sectional study.

OBJECTIVE: Orexin/hypocretin (Ox) and its receptors (OxR), a neuroendocrine system centrally regulating sleep/wakefulness, were implicated in the regulation of peripheral metabolism. It was hypothesized that human adipose tissue constitutes a direct target of the OxA/OxR system that associates with distinct metabolic profile(s). METHODS: Serum Ox levels and abdominal subcutaneous and visceral adipose tissue expression of Ox/HCRT, OxR1/HCRTR1, and OxR2/HCRTR2 were measured in n = 81 patients. RESULTS: Higher morning circulating Ox levels were associated with improved lipid profile and insulin sensitivity, independently of BMI (ß = -0.363, p = 0.018 for BMI-adjusted homeostatic model of insulin resistance). Adipose HCRT mRNA was detectable in <20% of patients. Visceral HCRT expressers were mostly (80%) males and, compared with nonexpressers, had lower total and LDL cholesterol. HCRTR1 was readily detectable, and HCRTR2 was undetectable. HCRTR1 mRNA and OxR1 protein expression were higher in subcutaneous than visceral adipose tissue, and among nonobese patients, patients with obesity, and patients with obesity and T2DM were 3.4 (1.0), 0.7 (0.1), 0.6 (0.1) (AU) (p < 0.001) and 1.0 (0.2), 0.5 (0.1), 0.4 (0.1) (AU) (p = NS), respectively. Higher visceral HCRTR1 expression was associated with lower fasting insulin and homeostatic model of insulin resistance, also after adjusting for BMI. In human adipocytes, HCRTR1 expression did not exhibit significant oscillation. CONCLUSIONS: Human adipose tissue is a putative direct target of the OxA-OxR1 system, with higher morning input being associated with improved metabolic profile.

A TRAIL-TL1A Paracrine Network Involving Adipocytes, Macrophages, and Lymphocytes Induces Adipose Tissue Dysfunction Downstream of E2F1 in Human Obesity.

Elevated expression of E2F1 in adipocyte fraction of human visceral adipose tissue (hVAT) associates with a poor cardiometabolic profile. We hypothesized that beyond directly activating autophagy and MAP3K5 (ASK)-MAP kinase signaling, E2F1 governs a distinct transcriptome that contributes to adipose tissue and metabolic dysfunction in obesity. We performed RNA sequencing of hVAT samples from age-, sex-, and BMI-matched patients, all obese, whose visceral E2F1 protein expression was either high (E2F1high) or low (E2F1low). Tumor necrosis factor superfamily (TNFSF) members, including TRAIL (TNFSF10), TL1A (TNFSF15), and their receptors, were enriched in E2F1high While TRAIL was equally expressed in adipocytes and stromal vascular fraction (SVF), TL1A was mainly expressed in SVF, and TRAIL-induced TL1A was attributed to CD4+ and CD8+ subclasses of hVAT T cells. In human adipocytes, TL1A enhanced basal and impaired insulin-inhibitable lipolysis and altered adipokine secretion, and in human macrophages it induced foam cell biogenesis and M1 polarization. Two independent human cohorts confirmed associations between TL1A and TRAIL expression in hVAT and higher leptin and IL6 serum concentrations, diabetes status, and hVAT-macrophage lipid content. Jointly, we propose an intra-adipose tissue E2F1-associated TNFSF paracrine loop engaging lymphocytes, macrophages, and adipocytes, ultimately contributing to adipose tissue dysfunction in obesity.

Higher Mast Cell Accumulation in Human Adipose Tissues Defines Clinically Favorable Obesity Sub-Phenotypes.

The identification of human obesity sub-types may improve the clinical management of patients with obesity and uncover previously unrecognized obesity mechanisms. Here, we hypothesized that adipose tissue (AT) mast cells (MC) estimation could be a mark for human obesity sub-phenotyping beyond current clinical-based stratifications, both cross-sectionally and prospectively. We estimated MC accumulation using immunohistochemistry and gene expression in abdominal visceral AT (VAT) and subcutaneous (SAT) in a human cohort of 65 persons with obesity who underwent elective abdominal (mainly bariatric) surgery, and we validated key results in two clinically similar, independent cohorts (n = 33, n = 56). AT-MC were readily detectable by immunostaining for either c-kit or tryptase and by assessing the gene expression of KIT (KIT Proto-Oncogene, Receptor Tyrosine Kinase), TPSB2 (tryptase beta 2), and CMA1 (chymase 1). Participants were characterized as VAT-MClow if the expression of both CMA1 and TPSB2 was below the median. Higher expressers of MC genes (MChigh) were metabolically healthier (lower fasting glucose and glycated hemoglobin, with higher pancreatic beta cell reserve (HOMA-ß), and lower triglycerides and alkaline-phosphatase) than people with low expression (MClow). Prospectively, higher MC accumulation in VAT or SAT obtained during surgery predicted greater postoperative weight-loss response to bariatric surgery. Jointly, high AT-MC accumulation may be used to clinically define obesity sub-phenotypes, which are associated with a "healthier" cardiometabolic risk profile and a better weight-loss response to bariatric surgery.

The association between an increase in glucose levels and armed conflict-related stress: A population-based study.

Studies have shown stress may lead to diabetes-related morbidities. In recent years during enhanced hostility periods, the population of Southern Israel experienced alert sirens and rocket fire on a daily basis. We investigated whether the exposure to these stressful circumstances, which peaked during three large military operations (MO), was associated with increased glucose levels among the civilian population. We included all fasting serum glucose tests taken between 2007-2014, of Clalit Health Services members in Southern Israel who had at least one fasting glucose test during an MO period and at least one test drawn at other times. We analyzed the association between MO periods and glucose using linear mixed-effects models. We included 408,706 glucose tests (10% during MO periods). Among subjects who reside in proximity to Gaza, glucose levels were 2.10% (95% CI 1.24%; 2.97%) higher in MO days compared to other times. A weaker effect was observed among subjects in more remote locations. In conclusion, we found stress to be associated with increased fasting glucose levels, especially among those who reside in locations in which the intensity of the threat is higher. Since glucose may be a marker of the population at cardiovascular risk, further studies are required.

Improvement of Blood Samples Preanalytic Management Alters the Clinical Results of Glucose Values: Population Study.

BACKGROUND: Prolonged time elapsing between the blood drawing and separation of the cell mass may result in decreased sample glucose levels due to continuous glycolysis. This can lead to underdiagnoses of hyperglycemic states and overdiagnosis of hypoglycemia. We aimed to evaluate the clinical impact of shortened transit time and earlier centrifugation of laboratory specimens on reported glucose results and diagnosis of clinically significant hypoglycemia (<50 mg/dL) or elevated glucose levels (>100 mg/dL). METHODS: We assessed all fasting-serum glucose tests from the adult population (190 767 subjects) without known diabetes residing in Southern Israel. Before and after intervention periods were compared: 268 359 blood tests were performed during 2009-2010, and 317 336 during 2012-2013. RESULTS: While glucose levels were 94.17 mg/dL ± 14.12 in 2012-2013 versus 83.53 mg/dL ± 14.50 in 2009-2010 (12.75% ± 0.88 increase, P < .001), the difference in glycated hemoglobin levels was statistically significant but clinically negligible: 5.84% ± 0.56 in 2012-2013 versus 5.88% ± 0.56 in 2009-2010 (0.53% ± 0.78 decrease, P < .01). There was an increased likelihood of a glucose result to be above 100 mg/dL following intervention: 9.80% versus 25.90%, P < .001. For clinics distanced over 40 km from the laboratory, age-adjusted odds ratio value was 1.26 (95% CI 1.13, 1.41). The proportion of samples with hypoglycemia values decreased from 0.33% to 0.03% (P < .001). CONCLUSIONS: We demonstrated an important change in glucose values over a two-year period following an improvement of the preanalytic processes. The intervention was related to an increase in the frequency of hyperglycemia results and a decrease in the number of hypoglycemia results. Future administrative projects should consider clinical consequences with involvement of all relevant stakeholders.

Effect of wine on carotid atherosclerosis in type 2 diabetes: a 2-year randomized controlled trial.

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) mm3, CI (-2.7, 5.5), white-wine, -1.2 (16.9) mm3, CI (-3.8, 6.2), red wine, -1.3 (17.6) mm3, 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 (ß = 0.4; p < 0.001). Two-year decreases in systolic blood pressure were independently associated with regression in carotid-VWV (ß = 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.

Effects of initiating moderate wine intake on abdominal adipose tissue in adults with type 2 diabetes: a 2-year randomized controlled trial.

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 (ß=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.