Expert Opinion on Current Trends in the Use of Insulin in the Management of People with Type 2 Diabetes from the South-Eastern European Region and Israel.

Despite the availability of various antihyperglycaemic therapies and comprehensive guidelines, glycaemic control in diabetes management has not improved significantly during the last decade in the real-world clinical setting. Treatment inertia arising from a complex interplay among patient-, clinician- and healthcare-system-related factors is the prime reason for this suboptimal glycaemic control. Also, the key factor leading to inadequate glycaemic levels remains limited communication between healthcare professionals (HCPs) and people with type 2 diabetes (PwT2D). Early insulin administration has several advantages including reduced glucotoxicity, high efficacy and preserved ß-cell mass/function, leading to lowering the risk of diabetes complications. The current publication is based on consensus of experts from the South-Eastern European region and Israel who reviewed the existing evidence and guidelines for the treatment of PwT2D. Herein, the experts emphasised the timely use of insulin, preferably second-generation basal insulin (BI) analogues and intensification using basal-plus therapy, as the most-potent glucose-lowering treatment choice in the real-world clinical setting. Despite an increase in the use of glucagon-like peptide-1 receptor agonists (GLP-1 RAs), the experts urged timely insulin initiation for inadequate glycaemic control in PwT2D. Furthermore, the combination of BI and GLP-1 RA addressing both fasting plasma glucose and post-prandial excursions as a free- or fixed-ratio combination was identified to reduce treatment complexity and burden. To minimise discontinuation and improve adherence, the experts reiterated quality, regular interactions and discussions between HCPs and PwT2D/carers for their involvement in the diabetes management decision-making process. Clinicians and HCPs should consider the opinions of the experts in accordance with the most recent recommendations for diabetes management.

Clinical characteristics and healthcare utilisation associated with undiagnosed cognitive impairment in elderly patients with diabetes in a primary care setting: a population-based cohort study.

OBJECTIVES: The objective of this study is to report the prevalence, clinical characteristics and healthcare utilisation of patients with type 2 diabetes (T2DM) and previously undiagnosed cognitive impairment who were identified as having a low Montreal Cognitive Assessment (MoCA) score. DESIGN: A population-based cohort study comparing clinical characteristics, medications, outpatient and inpatient care of patients with a MoCA score <19 to MoCA >26 using descriptive statistics, linear regression and multivariate logistic regression. SETTING: Electronic medical records of a large health maintenance organisation in Israel. PARTICIPANTS: 350 patients, age >65 with T2DM who participated in a cognitive function screening initiative using MoCA, and had a follow-up visit during the 12 months after screening. RESULTS: 130 (37.1%) had a MoCA score >26 and 68 (19.4%) <19. Patients with MoCA<19 had more diabetes-related complications, poorer glycaemic and lipid control, fewer visits to their main primary care physician (PCP; 3.9±3.2 vs 7.3±4.2 visits/year p=0.008), shorter duration of PCP visits (8.3±4.5 vs 4.0±3.5 min, p=0.007), fewer nutritionist and endocrinologist visits, and lower participation in diabetes or smoking cessation workshops. They were less likely to be treated with glucagon-like peptide-1 (GLP-1) agonists, dipeptidyl peptidase-4 inhibitor (DPP-4), or sodium-glucose transport protein 2 (SGLT-2) inhibitors and more likely to receive insulin or sulfonylurea. Moreover, they had more emergency room visits (ER; 15 (11.5%) vs 16 (23.5%), p=0.019), hospitalisations (8 (6.2%) vs 22 (32.4%), p=0.001), and longer hospital stays (4.3±3.2 vs 14.5±9.8, p=0.001). Using statistical models, MoCA<19 was identified as a risk factor for fewer and shorter PCP visits and more ER visits and hospitalisations. CONCLUSIONS: This study highlights the high prevalence of undiagnosed severe cognitive impairment in elderly patients with T2DM and its association with poor outpatient care. Appropriate interventions are needed to improve outcomes and prevent hospitalisation in this high-risk population.

Identifying Diabetes Related-Complications in a Real-World Free-Text Electronic Medical Records in Hebrew Using Natural Language Processing Techniques.

BACKGROUND: Studies have demonstrated that 50% to 80% of patients do not receive an International Classification of Diseases (ICD) code assigned to their medical encounter or condition. For these patients, their clinical information is mostly recorded as unstructured free-text narrative data in the medical record without standardized coding or extraction of structured data elements. Leumit Health Services (LHS) in collaboration with the Israeli Ministry of Health (MoH) conducted this study using electronic medical records (EMRs) to systematically extract meaningful clinical information about people with diabetes from the unstructured free-text notes. OBJECTIVES: To develop and validate natural language processing (NLP) algorithms to identify diabetes-related complications in the free-text medical records of patients who have LHS membership. METHODS: The study data included 2.3 million records of 41 469 patients with diabetes aged 35 or older between the years 2012 and 2017. The diabetes related complications included cardiovascular disease, diabetic neuropathy, nephropathy, retinopathy, diabetic foot, cognitive impairments, mood disorders and hypoglycemia. A vocabulary list of terms was determined and adjudicated by two physicians who are experienced in diabetes care board certified diabetes specialist in endocrinology or family medicine. Two independent registered nurses with PhDs reviewed the free-text medical records. Both rule-based and machine learning techniques were used for the NLP algorithm development. Precision, recall, and F-score were calculated to compare the performance of (1) the NLP algorithm with the reviewers' comments and (2) the ICD codes with the reviewers' comments for each complication. RESULTS: The NLP algorithm versus the reviewers (gold standard) achieved an overall good performance with a mean F-score of 86%. This was better than the ICD codes which achieved a mean F-score of only 51%. CONCLUSION: NLP algorithms and machine learning processes may enable more accurate identification of diabetes complications in EMR data.

Subcutaneous Semaglutide Use for Weight Management: Practice and Attitudes of Physicians in Israel.

BACKGROUND: In 2019, 1 mg subcutaneous semaglutide was registered for the treatment of diabetes in Israel. Recognition of its effect on weight has led to its use as a treatment for obesity. OBJECTIVES: To explore physicians' pre-therapy considerations, therapy practices, and attitudes regarding subcutaneous semaglutide for weight loss. METHODS: A 22-item questionnaire was disseminated to physicians who prescribed semaglutide 1-mg for weight loss using an authorized off-label path. RESULTS: In total, 127 physicians completed the questionnaire. As for pretreatment requirements, in the absence of diabetes, 30% requested a minimal body mass index of 30 kg/m2. Additional requirements were documented lifestyle-change effort (67%) and prior weight loss medication use (13%). Half of the physicians regarded calorie restriction, and 23% considered physical activity as necessary for weight loss while on therapy. As for dose, most physicians (78%) started with a 0.25-mg weekly injection, 57% doubled the dose monthly, and all others recommended doubling when side effects subsided. Regarding weight loss goal, 43% of the physicians set a personal goal with each patient while 26% limited the goal to 10% of initial weight. Fewer than 50% of physicians discussed treatment duration with their patients, and 52% of patients discontinued therapy in the first 3 months. The main reasons for discontinuation were price, lack of effect, and fear of long-term side effects. CONCLUSIONS: The diverse approaches regarding off-label use of semaglutide for weight reduction highlight the necessity to guide physicians and standardize treatment regimen.

Transitioning from having no metabolic abnormality nor obesity to metabolic impairment in a cohort of apparently healthy adults.

INTRODUCTION: The global prevalence of metabolic syndrome and its association with increased morbidity and mortality has been rigorously studied. However, the true prevalence of "metabolic health", i.e. individuals without any metabolic abnormalities is not clear. Here, we sought to determine the prevalence of "metabolically healthy" individuals and characterize the "transition phase" from metabolic health to development of dysfunction over a follow-up period of 5 years. METHODS: We included 20,507 individuals from the Tel Aviv Sourasky Medical Center Inflammation Survey (TAMCIS) which comprises apparently healthy individuals attending their annual health survey. A second follow-up visit was documented after 4.8 (± 0.6) years. We defined a group of metabolically healthy participants without metabolic abnormalities nor obesity and compared their characteristics and change in biomarkers over time to participants who developed metabolic impairment on their follow-up visit. The intersections of all metabolic syndrome components and elevated high sensitivity C-reactive protein (hs-CRP) were also analyzed. RESULTS: A quarter of the cohort (5379 individuals, (26.2%) did not fulfill any metabolic syndrome criteria during their baseline visit. A total of 985 individuals (12.7% of returning participants) developed metabolic criteria over time with hypertension being the most prevalent component to develop among these participants. Individuals that became metabolically impaired over time demonstrated increased overlap between metabolic syndrome criteria and elevated hs-CRP levels. The group that became metabolically impaired over time also presented higher delta values of WBC, RBC, liver biomarkers, and uric acid compared with participants who were consistently metabolically impaired. LDL-C (low-density lipoprotein cholesterol) delta levels were similar. CONCLUSIONS: Roughly one-quarter of apparently healthy adults are defined as "metabolically healthy" according to current definitions. The transition from health to metabolic dysfunction is accompanied with active inflammation and several non-metabolic syndrome biomarkers. Aggressive screening for these biomarkers, blood pressure and hs-CRP might help identify apparently healthy individuals at increased risk of developing metabolic syndrome over time.

Hand Grip Strength Relative to Waist Circumference as a Means to Identify Men and Women Possessing Intact Mobility in a Cohort of Older Adults with Type 2 Diabetes.

Possessing intact mobility in older adults assures their continued independence. The early identification of reduced mobility in older adults with type 2 diabetes (T2DM) is paramount for preventing their future physical deterioration. Hand grip strength (HGS), relative to body size, is associated with mobility in older T2DM patients. This study aims to identify an HGS index that best identifies mobilityintact older T2DM patients, along with its optimal cut-off point. The baseline data are from a cohort of 122 older T2DM patients (59% women) (mean age of 70.2 ± 4.4 years). Three mobility tests encompassing three main mobility domains were measured, including usual gait speed (UGS), timed up and go (TUG), and a two-minute walk test (2MWT). Passing scores were defined as those either above the established cut-off points or above the 25th percentile of population norms. Passing all three tests was considered as possessing intact mobility. Receiver operating characteristic (ROC) curves of the most relevant HGS indices were constructed to determine the area under the curve (AUC) that best identifies patients with intact mobility. In a sample of 122 older adults with T2DM, 63.9% of women and 60% of men were found to possess intact mobility. HGS relative to waist circumference (WC) was found to have the strongest association with intact mobility, presenting the highest AUC in both men (0.78) and women (0.72) for discriminating mobility status, with an optimal cut-off of 0.355 (kg/cm) and 0.245 (kg/cm) in men and women, respectively. HGS relative to WC best differentiated between mobility-intact older adults with T2DM and those with mobility limitations, especially in men. Using HGS/WC as a simple and safe screening mode for mobility in a clinical setting could potentially identify older patients with T2DM that require therapeutic interventions.

Oral insulin (ORMD-0801) in type 2 diabetes mellitus: A dose-finding 12-week randomized placebo-controlled study.

AIMS: To assess the safety and efficacy of multiple daily doses of oral insulin (ORMD-0801) in subjects with type 2 diabetes (T2DM) over 12 weeks. MATERIALS AND METHODS: Participants with T2DM on metformin or combination oral therapy with glycated haemoglobin (HbA1c) levels ≥ 7.5% (58 mmol/mol) were randomized to receive ORMD-0801 8 mg or 16 mg once (QD) or twice (BID) daily, or 32 mg QD, BID or three times daily (TID) over a 12-week period. RESULTS: A total of 373 subjects were randomized to active treatment or placebo (~60% male, age ~ 56 years, HbA1c 9%-9.8%; 75-84 mmol/mol). Placebo-adjusted HbA1c changes from baseline to Week 12 were observed with ORMD-0801 8 mg BID (-7.15 ± 3.57 mmol/mol [-0.65% ± 0.33%]; P = 0.046). However, a significant site interaction was observed in two sites. After excluding these, HbA1c reduction was observed with 8 mg QD (-0.81 ± 0.37%; -8.89 ± 4.01 mmol/mol; P = 0.028, n = 15), 8 mg BID (-0.82 ± 0.37%; -8.95 ± 4.08 mmol/mol; P = 0.029, n = 17), 32 mg QD (-0.54 ± 0.26%; -5.89 ± 2.78 mmol/mol;P = 0.036, n = 69) and 32 mg BID (-0.53 ± 0.26%; -5.80 ± 2.83 mmol/mol; P = 0.042, n = 68). No effect was observed with 16 mg QD (0.25 ± 0.37%; 2.76 ± 3.99 mmol/mol; P = 0.48, n = 18), 16 mg BID (-0.36 ± 0.40%; -3.97 ± P = 0.36, n = 15) or 32 mg TID (-0.45 ± 0.27%, -4.89 ± 2.90 mmol/mol; P = 0.093, n = 69). Continuous glucose monitor and serum glucose measurements showed similar trends but were not significant. ORMD-0801 was safe, well tolerated and not associated with weight gain or hypoglycaemia. CONCLUSIONS: Oral insulin (ORMD-0801) induced greater reductions in HbA1c when compared to placebo, and was safe and well tolerated in individuals with uncontrolled T2DM. The efficacy and safety findings support continued development of the 8-mg dose at bedtime, which is currently being evaluated in two Phase 3 trials.

The Effects of Metabolism Tracker Device (Lumen) Usage on Metabolic Control in Adults with Prediabetes: Pilot Clinical Trial.

INTRODUCTION: Prediabetes is a risk factor for type 2 diabetes mellitus (T2DM). However, it may be reversed via lifestyle changes. Lumen is a novel handheld device that measures exhaled CO2 producing results in agreement with those of indirect calorimetry when assessing metabolic fuel usage. The aim of this study was to examine the effects of following Lumen's personalized, measurement-guided lifestyle intervention program on anthropometric and metabolic variables in adults with prediabetes. METHODS: A 12-week single-arm intervention study was conducted in 27 participants. Body composition and blood markers were measured at the start and end of the study. Each participant took a daily morning (fasted) measurement and received feedback on their metabolic state (i.e., their degree of fat vs. carbohydrate oxidation). Participants were then provided with personalized daily guidelines for their carbohydrate, fat, and protein consumption, along with recommended lifestyle changes. RESULTS: Intention-to-treat analysis revealed a significant decrease in body weight (5.99 kg, p < 0.001), comprising a significant reduction in percentage body fat (2.93%, p < 0.001) and waist circumference (6.23 cm, p < 0.001). Significant reductions were also observed in glycated hemoglobin A1c (0.27%, p < 0.001), triglycerides (0.45 mg/dL, p < 0.001), and systolic blood pressure (0.5 mm Hg, p < 0.05). CONCLUSION: In a 12-week pilot study of participants with prediabetes, Lumen usage significantly improved multiple metabolic parameters, demonstrating its potential to deliver better clinical outcomes for patients with T2DM and metabolic syndrome.

Validation of a multi-frequency bioelectrical impedance analysis device for the assessment of body composition in older adults with type 2 diabetes.

BACKGROUND: Aging and type 2 diabetes (T2DM) are associated with an increased risk of sarcopenia. Diagnosis of sarcopenia is commonly done using dual-energy X-ray absorptiometry (DXA) in specialized settings. Another available method for assessing body composition is direct segmental multi-frequency bioelectrical impedance analysis (DSMF-BIA). Here, we examine the accuracy of a DSMF-BIA (InBody-770) for assessing body composition in older adults with T2DM when compared to DXA. METHODS: Eighty-four obese/overweight older adults (49 women, 71 ± 5 years) with T2DM who were recruited for the CEV-65 study and had both DSMF-BIA and DXA assessments at baseline were included. The analysis included Bland-Altman plots and intra class correlation coefficients. Sub-analyses were performed according to gender and following 10 weeks of interventions (diet, circuit training, and Empagliflozin). RESULTS: The leg lean mass results according to DSMF-BIA and DXA were 14.76 ± 3.62 kg and 15.19 ± 3.52 kg, respectively, with no difference between devices according to Bland-Altman analyses (p = 0.353). Assessment of appendicular skeletal mass index did not differ between DSMF-BIA and DXA (7.43 vs. 7.47 kg/m2; p = 0.84; ICC = 0.965, p < 0.0001; mean difference -0.068, p = 0.595). Gender and treatment interventions did not modify the accuracy of the DSMF-BIA when compared to DXA. CONCLUSIONS: In older adults with T2DM the degree of agreement between DSMF-BIA and DXA, was high, supporting the use of DSMF-BIA to measure muscle mass.

Flash Glucose Monitoring in Israel: Understanding Real-World Associations between Self-Monitoring Frequency and Metrics of Glycemic Control.

OBJECTIVE: Flash glucose monitoring has been widely used in Israel for diabetes treatment and since 2018, the cost is reimbursed for all people with type 1 diabetes nationally. In the current study, we present the daily scanning behavior for FreeStyle Libre users in Israel and how this was associated with a range of metrics for glycemic assessment. METHODS: Deidentified data from FreeStyle Libre readers were collected between September 2014 and October 2020. Scan-rate data from Israel was extracted and sorted into 10 equal-sized groups based on scan frequency. The glucose parameters derived for each group were: estimated HbA1c (eA1c), time in range (TIR) between 70 and 180 mg/dL, and time with glucose levels of <70 mg/dL, <54 mg/dL, and >180 mg/dL. RESULTS: The data set for Israel included 12 370 readers, with data from 131 639 separate glucose sensors representing 152 million automatically recorded individual glucose readings. Users performed an average of 15 daily glucose scans, ranging from a mean of 4.1 scans per day (lowest, 10%), rising to a mean of 38.7 scans/day (highest, 10%) (median, 12; IQR, 8-18 for all readers). As the scan rates increased, the eA1c decreased from 7.6% to 6.7% (P < .001). Mean TIR increased from 56.9% to 70.0% with increasing scan rates (P < .001). Concordantly, time with glucose levels of >180 mg/dL and <54 mg/dL decreased from 37.2% to 23.6% (P < .001) and from 2.23% to 1.99%, respectively, as scan frequency increased. CONCLUSION: In Israel, people with diabetes under real-world conditions record higher rates of FreeStyle Libre scanning. These are associated with improvements in TIR, eA1c, and reduced time with glucose levels of >180 mg/dL or <54 mg/dL.

Should knee extension strength testing be implemented as a screening test for identifying probable and confirmed sarcopenia in older T2DM patients?

BACKGROUND: The accelerated loss of muscle strength and mass observed in older type 2 diabetes mellitus (T2DM) patients due to the combined effects of diabetes and obesity, greatly increases their risk for sarcopenia. Early detection and treatment of probable and confirmed sarcopenia is paramount to delay mobility disability. Using low handgrip strength cut-off points for the initial identification of sarcopenia according to the new European Working Group on Sarcopenia in Older People (EWGSOP2) guidelines may mask the presence of sarcopenia. Relative knee extension strength cut-off points using a simple hand-held dynamometer can assist clinicians in the diagnosis of probable and confirmed sarcopenia by possibly reducing false negative results. METHODS: A cohort of one hundred T2DM older patients (60% women) (mean age 74.5 years) mostly obese community dwelling older adults were evaluated for body composition by Bioelectrical impedance analysis (BIA), yielding appendicular skeletal mass index (ASMI) results. Patients underwent handgrip strength (HGS) and knee extension strength (KES) tests as well as functional ability tests. Prevalence of probable and confirmed sarcopenia using HGS and KES cut-off points were calculated. Pearson correlations were performed to evaluate the relationship between ASMI and limbs strength. A regression analysis was conducted to examine which variables best predict ASMI values. A multivariate analysis of covariance was performed to assess the effect of independent variables on KES and HGS. RESULTS: Using cutoff points for low KES identified 24 patients with probable sarcopenia and two with confirmed sarcopenia. Conversely, using the EWGSOP2 cut off points for low HGS, identified only one patient with probable sarcopenia and none of the patients with confirmed sarcopenia. CONCLUSION: KES cut-off points using a simple hand-held dynamometer can assist in the identification of probable and confirmed sarcopenia using EWGSOP2 cut off points for low muscle mass in a population of older T2DM patients for further analysis and early treatment. This is notably true in patients possessing high body mass index (BMI) alongside normal ASMI and HGS, potentially reducing false positive sarcopenia screening results. TRIAL REGISTRATION: ClinicalTrials.gov PRS: NCT03560375 . Last registration date (last update): 06/06/2018. The trial was a-priori registered before actual recruitment of subjects.

Glycemic Control and Diabetes Related Complications in Adults with Type 1 Diabetes Mellitus and ADHD.

OBJECTIVE: To assess the correlation of co-morbid ADHD and diabetes-related complications in patients with type-1-diabetes-mellitus (T1DM). METHODS: A retrospective cross-sectional study was conducted during 2018 using the Leumit-Health-Services(LHS) database. Diabetes-related complications were assessed in patients with T1DM and ADHD (T1DM-ADHD+) and compared with patients with T1DM alone (T1DM-ADHD-). RESULTS: Out of 789 adult-patients with T1DM, 75 (9.5%) were T1DM-ADHD+, matched to 225 T1DM-ADHD-. HbA1C levels were higher in T1DM-ADHD+ patients (8.1% ± 1.6 vs. 7.4% ± 1.2, p < .01), as well as diabetes-related complications: neuropathy (22.7% vs. 5.8%, p < .01), ulcers (8% vs. 0.9%, p < .05), limb amputation (5.3% vs. 0.9%, p < .05), albuminuria (15.5% vs. 2.8%, p < .01), chronic renal failure (10.6% vs. 2.5%, p = .01), and emergency room admissions rate (26.7% vs. 15.1%, p < .05). In sub-analysis, lower average HbA1C levels and diabetic ulcer rates were found among ADHD patients treated with stimulants, all p < .05. CONCLUSION: Co-morbidity of ADHD and T1DM is associated with poor glycemic control and higher complication rates.

[HEMOGLOBIN A1C AND MORTALITY FROM COVID-19].

INTRODUCTION: People with diabetes mellitus are at increased risk of developing a more severe disease or death when contracting coronavirus disease 2019 (COVID-19 ) but the effect of pre-COVID-19 infection glycemic control on disease outcomes is still unclear. In a previous study that we published from Leumit Health Services (LHS) including 183 patients with diabetes, pre-COVID-19 infection HbA1c>9% was associated with the need for hospitalization during the disease. In the current study we present the clinical characteristics of patients who died from COVID-19 in LHS and demonstrate a significant link to pre-infection HbA1c. METHODS: We collected demographic, clinical and laboratory information regarding all patients insured in LHS who contracted COVID-19 between 1st February and 31st May 2020 and had diabetes or pre-diabetes. To better understand the contribution of pre-infection glycemic control on COVID-19 mortality we conducted a case control study at a 1:5 ratio between patients who had died and survivors, adjusting for age, sex and socioeconomic status. RESULTS: We identified 888 patients of whom 24 (2.7%) died from COVID-19 . Patients who died were older, had more chronic disease, higher HbA1c and creatinine and lower hemoglobin, iron and vitamins B12 and D. In the case control study, patients who died had more obesity, dementia, cerebrovascular disease, congestive heart failure, use of SGLT-2 inhibitors and fewer smokers. In a multivariate logistic regression analysis we found that HbA1c and prior cerebrovascular disease significantly increased the risk of death and normal levels of vitamin D, iron and an estimated glomerular filtration rate >60ml/min were associated with a protective effect. CONCLUSIONS: Pre- COVID-19 HbA1c levels and prior cerebrovascular disease are associated with an increased risk of mortality. Identifying pre-infection clinical parameters which predict COVID-19 mortality may improve risk stratification and vaccine prioritization for at-risk populations. Further study is needed to understand the potential mechanism and causality of poor glycemic control on COVID-19 death.

Efficacy and safety of 28-day treatment with oral insulin (ORMD-0801) in patients with type 2 diabetes: A randomized, placebo-controlled trial.

AIM: To assess the safety and efficacy of oral insulin (ORMD-0801) in patients with type 2 diabetes (T2D). MATERIALS AND METHODS: After a 2-week washout of other medications, adult metformin-treated patients with T2D were randomized to receive placebo or 16 or 24 mg ORMD-0801, once daily, at bedtime, for 28 days. The mean change from baseline weighted mean night-time glucose levels was determined from 2 nights of continuous glucose monitoring (CGM) recordings during the placebo run-in and last week of treatment. RESULTS: In total, 188 patients (HbA1c: 7.82% ± 0.88% [placebo] and 8.08% ± 1.11% [pooled ORMD-0801 group]) were enrolled. In the placebo group, mean night-time CGM increased from baseline by 13.7 ± 26.1 mg/dL, whereas the increase was significantly smaller in the pooled ORMD-0801 group (1.7 ± 23.5 mg/dL, P = .0120). Glycaemic control variables (24-hour, fasting and daytime CGM glucose) also displayed smaller increases with ORMD-0801 versus placebo. Change from baseline HbA1c was -0.01% in the pooled ORMD-0801 group versus +0.20% in the placebo group (P = .0149). ORMD-0801 was well tolerated, with similar adverse event and hypoglycaemia rates as placebo. CONCLUSIONS: In patients with T2D, bedtime ORMD-0801 curbed increases in night-time glycaemia, 24-hour glycaemia and HbA1c, without increasing the risk of hypoglycaemia or safety events compared with the control arm.

Effect of a primary-care-team focused diabetes educational program project on diabetes care quality indicators in a large health maintenance organization.

AIMS: In 2011 the central district of Leumit Health Services (LHS) (a health maintenance organization in Israel) implemented a chronic care program to improve diabetes care in general practice: MESSAGE program (Motivation, Education, Skills and Supervision to Achieve better diabetes care in General practice Environment), included training phase and ongoing time allocation for diabetes care. METHODS: A population-based retrospective analysis of LHS Electronic Medical Records of all patients with diabetes in LHS between 1 June 2015 and 31 May 2018. Data was processed according to the definitions of the Israeli national program for quality indicators in community healthcare. ~442,000 adults were included, ~49,000 in MESSAGE engaged clinics. RESULTS: The prevalence of diabetes in LHS was ~9.7-9.31% during study period. Over 3 years follow up, the prevalence of patients with A1C ≥ 9% declined in all districts of LHS but to a significantly greater extent in MESSAGE clinics [2015: MESSAGE 12.4%, LHS-combined 13.09%; OR 0.92 (0.83-1.01) p = 0.075; 2018: MESSAGE 8.51%, LHS-combined 10.85%; 0.76 (0.69-0.85) p < 0.001]. Other indicators of diabetes care did not change. CONCLUSION: The MESSAGE intervention program resulted in improved glycemic control. It is currently being modified to address all aspects of diabetes care and is implemented across all districts of LHS in Israel.

The Interrelation Between Chronic Headache, Cognitive Scores, and MRI Markers Among Stroke Survivors.

BACKGROUND: Migraine is known to mildly increase the risk for ischemic stroke and is associated with vascular MRI markers. However, the potential effect of chronic headache (CH) on stroke outcomes has not been studied. OBJECTIVE: We aimed to assess the interrelation between CH and post-stroke cognitive impairment. METHODS: Data from 455 patients with a first ever stroke from the TABASCO study was available. All patients underwent 3T brain MRI, blood analysis, and a serial cognitive assessment at baseline and 6, 12, and 24 months after. RESULTS: Eighty-five (18.7%) patients reported suffering from CH, of whom 53 (62.4%) reported symptoms of photophobia or nausea, and 34 (40%) reported an aura. CH was associated with female sex, lower prevalence of T2DM (p < 0.001), and lower HbA1C levels (p < 0.001). Multiple regression analysis, controlling for age, sex, education, vascular risk factors, and the presence of acute lesions in MRI, revealed that CH was an independent predictor of better cognitive scores 6, 12, and 24 months post-stroke (p = 0.015, p = 0.01, and p = 0.012, respectively). Stroke patients suffering from CH had also higher normalized gray, white matter, and thalamus volumes, and better white matter microstructural integrity (p < 0.001, p = 0.037, p < 0.001, p = 0.008, respectively)Conclusion:In this study, CH was consistently associated with better long term cognitive scores among post stroke subjects. These surprising findings may partially arise from the higher prevalence of T2DM among subjects without CH, that may represent the existence of chronic cerebrovascular disease, and may reflect mechanisms involving glucose metabolism.

Comparison of Equations Estimating Resting Metabolic Rate in Older Adults with Type 2 Diabetes.

Measuring resting metabolic rate (RMR) is time-consuming and expensive, and thus various equations for estimating RMR have been developed. This study's objective was to compare five equations in elderly people with type 2 diabetes (T2DM). RMR was measured in 90 older adults (≥65 years) with T2DM (mean body mass index (BMI) of 31.5 kg/m2), using indirect calorimetry. Results were compared to four frequently used equations (those of Cunningham, Harris and Benedict, and Gougeon developed for young adults with T2DM, and that of Lührmann, which was developed for the elderly), in addition to a new equation developed recently at the Academic College at Wingate (Nachmani) for overweight individuals. Estimation accuracy was defined as the percentage of subjects with calculated RMR within ±10% of measured RMR. Measured RMR was significantly underestimated by all equations. The equations of Nachmani and Lührmann had the best estimation accuracy: 71.4% in males and 50.9% in females. Skeletal muscle mass, fat mass, hemoglobin A1c (HbA1c), and the use of insulin explained 70.6% of the variability in measured RMR. RMR in elderly participants with T2DM was higher than that calculated using existing equations. The most accurate equations for this specific population were those developed for obesity or the elderly. Unbalanced T2DM may increase caloric demands in the elderly. It is recommended to adjust the RMR equations used for the target population.

NF-κB activity during pancreas development regulates adult ß-cell mass by modulating neonatal ß-cell proliferation and apoptosis.

NF-κB is a well-characterized transcription factor, widely known for its roles in inflammation and immune responses, as well as in control of cell division and apoptosis. However, its function in ß-cells is still being debated, as it appears to depend on the timing and kinetics of its activation. To elucidate the temporal role of NF-κB in vivo, we have generated two transgenic mouse models, the ToIß and NOD/ToIß mice, in which NF-κB activation is specifically and conditionally inhibited in ß-cells. In this study, we present a novel function of the canonical NF-κB pathway during murine islet ß-cell development. Interestingly, inhibiting the NF-κB pathway in ß-cells during embryogenesis, but not after birth, in both ToIß and NOD/ToIß mice, increased ß-cell turnover, ultimately resulting in a reduced ß-cell mass. On the NOD background, this was associated with a marked increase in insulitis and diabetes incidence. While a robust nuclear immunoreactivity of the NF-κB p65-subunit was found in neonatal ß-cells, significant activation was not detected in ß-cells of either adult NOD/ToIß mice or in the pancreata of recently diagnosed adult T1D patients. Moreover, in NOD/ToIß mice, inhibiting NF-κB post-weaning had no effect on the development of diabetes or ß-cell dysfunction. In conclusion, our data point to NF-κB as an important component of the physiological regulatory circuit that controls the balance of ß-cell proliferation and apoptosis in the early developmental stages of insulin-producing cells, thus modulating ß-cell mass and the development of diabetes in the mouse model of T1D.

Haemoglobin A1c is a predictor of COVID-19 severity in patients with diabetes.

AIM: Poor outcomes of coronavirus disease 2019 (COVID-19) have been linked to diabetes, but its relation to pre-infection glycaemic control is still unclear. MATERIALS AND METHODS: To address this question, we report here the association between pre-infection Haemoglobin A1c (HbA1c) levels and COVID-19 severity as assessed by need for hospitalization in a cohort of 2068 patients with diabetes tested for COVID-19 in Leumit Health Services (LHSs), Israel, between 1 February and 30 April 2020. Using the LHS-integrated electronic medical records system, we were able to collect a large amount of clinical information including age, sex, socio-economic status, weight, height, body mass index, HbA1c, prior diagnosis of ischaemic heart disease, depression/anxiety, schizophrenia, dementia, hypertension, cerebrovascular accident, congestive heart failure, smoking, and chronic lung disease. RESULTS: Of the patients included in the cohort, 183 (8.85%) were diagnosed with COVID-19 and 46 were admitted to hospital. More hospitalized patients were female, came from higher socio-economic background and had a higher baseline HbA1c. A prior diagnosis of cerebrovascular accident and chronic lung disease conferred an increased risk of hospitalization but not obesity or smoking status. In a multivariate analysis, controlling for multiple prior clinical conditions, the only parameter associated with a significantly increased risk for hospitalization was HbA1c ≥ 9%. CONCLUSION: Using pre-infection glycaemic control data, we identify HbA1c as a clear predictor of COVID-19 severity. Pre-infection risk stratification is crucial to successfully manage this disease, efficiently allocate resources, and minimize the economic and social burden associated with an undiscriminating approach.

Nutritional profiling of frail and obese, community dwelling older subjects: Results from a national survey.

INTRODUCTION: Less attention has been given to the detection and nutritional status and needs of obese frail/sarcopenic older subjects. The aim of this study was to characterize the nutritional composition in older (≥65 years), frail-prone, obese subjects (defined by either waist circumference [WC] or body mass index [BMI]). METHODS: A cross-sectional study with analysis of the national survey "Mabat Zahav". Random sample of 1751 community dwelling Israeli older adults (≥65 years). Eleven nutritional factors formerly linked to frailty were a-priori selected based on the current literature. Data was extracted from a 24-hour dietary recall. Adherence for each nutritional factor was defined using the Dietary Reference Intakes (DRI), and aggregated into a sum score of the overall adherence (ranging from "0" to "11", where "fair" adherence was defined as ≥6; inadequate adherence otherwise). Frailty likelihood was estimated using a validated non-direct model, and associations of nutritional factors with frailty-likelihood in obese vs non-obese individuals were examined. Additionally, a decision tree procedure based on machine learning was applied in order to capture nutritional factors related to frailty, stratified by gender, as well as by WC and/or BMI. RESULTS: Overall, the prevalence rates of frailty and pre-frailty were 7.1 and 57.6%, respectively. A "fair nutritional adherence" was less common among frail-prone compared to robust subjects (23.1% vs. 32.1%; p < 0.0001). The intake of most frailty-related nutritional factors did not co-segregate according to the presence of abdominal or BMI-defined obesity. Still, compared to robust normal/overweight subjects, frail-prone obese (by BMI) individuals had a higher rate of inadequate nutritional adherence (odds-ratio 1.842; p < 0.05). Of all 11 nutritional factors, folate in obese women and vitamin A (as retinol) and calcium in non-obese and obese men, respectively, were recognized as the most prominent predictors of frail-prone prevalence by the machine learning process. Although BMI was more closely associated with impaired intake of the 11 selected nutritional components than WC, this association was eliminated when frailty status, low income and education were considered. CONCLUSIONS: Frail-prone subjects differed from robust subjects in their nutritional intake. Nutritional inadequacies related to frailty-likelihood were mostly seen among obese women and non-obese men. In the prediction of inadequate adherence to the DRI of 11 nutritional components, obesity is a weaker predictor than frailty, lower education and low income in older Israeli adults.