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The trend of fasting until noon (omission or delayed breakfast) is increasingly prevalent in modern society. This eating pattern triggers discordance between endogenous circadian clock rhythms and the feeding/fasting cycle and is associated with an increased incidence of obesity and T2D. Although the underlying mechanism of this association is not well understood, growing evidence suggests that fasting until noon, also known as an “extended postabsorptive state”, has the potential to cause a deleterious effect on clock gene expression and to disrupt regulation of body weight, postprandial and overall glycemia, skeletal muscle protein synthesis, and appetite, and may also lead to lower energy expenditure. This manuscript overviews the clock gene-controlled glucose metabolism during the active and resting phases and the consequences of postponing until noon the transition from postabsorptive to fed state on glucose metabolism, weight control, and energy expenditure. Finally, we will discuss the metabolic advantages of shifting more energy, carbohydrates (CH), and proteins to the early hours of the day.

Painful diabetic peripheral neuropathy (PDPN) affects up to 26% of patients with diabetes mellitus, with major impacts on their general health and well-being. Most available drugs fail to deliver acceptable pain reduction in the majority of patients and are often poorly tolerated. NRD.E1 is a novel product that has shown anti-nociceptive preclinical effects and good tolerability in healthy volunteer studies.This phase 2a, randomized, dose-finding, Proof of Concept study enrolled patients with PDPN of ≥3 months duration. After at least one treatment-free week (WO week), 88 patients entered a 1-week single-blind (SB)-placebo run-in period, followed by 3 weeks' double-blind (DB) treatment, during which they received NRD.E1 at 10, 40 or 150 mg/day or placebo.The primary endpoint (change from SB-placebo run-in week to week 3 in weekly mean of daily average numerical rating scale [NRS] pain intensity) showed clinically relevant placebo-corrected treatment effect pain reductions at 40 mg and 150 mg/day of 0.82 (95% CI: 0.07, 1.58, p = 0.034) and 0.66 (95% CI: -0.03, 1.35; p = 0.061) NRS points, respectively, though did not meet the pre-specified value of p = 0.016 required due to multiplicity. An additional post hoc endpoint looking at the change from WO baseline to week 3 in weekly mean of daily average NRS showed the placebo-corrected treatment effect was 1.46 (95% CI: 0.26, 2.66), and 1.20 (95% CI: 0.10, 2.29) NRS points, respectively. Secondary and post hoc analyses of NRS pain data (including 3050% responder rate and NNT), sleep interference, Short-form McGill pain questionnaire (especially pain intensity assessed on Visual Analogue Scale), Patient's and Clinician's Global Impression of Change showed effects consistent with the primary findings. NRD.E1 was well tolerated, with only headache reported in more than two patients and more frequently on NRD.E1 than placebo.The data suggest that NRD.E1 potentially represents a novel non-opioid therapeutic option for patients with PDPN, with at least similar efficacy and better tolerability than available therapies, justifying its further evaluation in larger-scale confirmatory studies.NRD.E1 is a novel non-opioid therapeutic which is being developed for the treatment of PDPN. In this randomized, controlled, dose-finding, Proof of Concept study, NRD.E1 induced a clinically relevant pain reduction and it was well tolerated. Available data suggest that NRD.E1 has at least similar efficacy and better tolerability than the currently available therapies, potentially offering a promising new therapeutic option to patients with PDPN and possibly other neuropathic pain indications.

Our study looked at the association between changes in serum albumin (SA) levels during hospitalization and incidence of hypoglycaemia among non-critically ill patients.Included were patients discharged from internal medicine units with hospital stays ≤ 14 days. Patients were allocated to three groups: (1) admission SA 3.5 g/dL with no decrease during hospitalization; (2) admission SA 3.5 g/dL with no decrease during hospitalization; and (3) decrease in SA regardless of admission SA level. Incident hypoglycaemia (glucose ≤ 70 mg/dL) was predicted by applying regression analysis, using hypoglycaemia as a dependent variable. Mortality studies were performed using Cox regression.Included were 7718 patients (mean age 71.8 ± 17.4 years, 49.9% males, 27.1% with diabetes). Of these patients, 12.7% had at least one documented hypoglycaemia episode during hospitalization. Patients with decreases in SA levels during hospitalization (group 3) had higher rates of incident hypoglycaemia compared with patients in groups 1 and 2 (21.0% vs. 6.0% and 16.3%, respectively; P 0.001 for both). Results remained significant after controlling for admission SA. Strong negative correlations were observed between SA and serum osmolarity (r = -0.204, P 0.0001) and, separately, between changes in SA with changes in serum osmolarity (r = -0.157, P 0.001), indicating that SA changes were not due to haemodilution. Overall 1-year mortality was 16.7%, and Cox regression analysis showed an increased 1-year mortality in patients in group 3 (27.9%) compared with those in groups 1 and 2 (15.2% and 13.8%, respectively).Changes in SA during hospitalization are associated with an increased risk of hypoglycaemia during hospitalization of non-critically ill patients.

Objective: Finerenone significantly improved cardiorenal outcomes in patients with chronic kidney disease (CKD) and type 2 diabetes (T2D) in FIDELIO-DKD. We explored whether baseline HbA1c and insulin treatment influenced outcomes. Research design and methods: Patients with T2D, urine albumin-to-creatinine ratio (UACR) 30–5,000 mg/g, estimated glomerular filtration rate (eGFR) 25–2, and treated with optimized renin–angiotensin system blockade were randomized to finerenone or placebo. Efficacy outcomes included kidney (kidney failure, sustained decrease ≥40% in eGFR from baseline, or renal death) and cardiovascular (cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure) composite endpoints. Patients were analyzed by baseline insulin use and by baseline HbA1c Results: Of 5,674 patients, 3,637 (64.1%) received insulin at baseline. Overall, 5,663 patients were included in the analysis for HbA1c; 2,794 (49.3%) had baseline HbA1c 1c and insulin use (Pinteraction 0.41 and 0.56, respectively). Cardiovascular composite outcome incidence was reduced with finerenone irrespective of baseline HbA1c and insulin use (Pinteraction 0.70 and 0.33, respectively). Although baseline HbA1c did not affect kidney event risk, cardiovascular risk increased with higher HbA1c. UACR reduction was consistent across subgroups. Adverse events were similar between groups regardless of baseline HbA1c level and insulin use; few finerenone-treated patients discontinued treatment due to hyperkalemia. Conclusion: Finerenone reduces kidney and cardiovascular outcome risk in patients with CKD and T2D and risks appear consistent irrespective of HbA1c levels or insulin use.

The prevalence of diabetes increases with age. Diabetes is a risk factor for many complications such as cardiovascular disease, kidney failure, stroke, neuropathy, and retinopathy. Data from recent years indicate that it is also a risk factor for cognitive impairment, dementia, functional disability and frailty. Diabetes is a disease that requires complex self-care capabilities; the individuals with diabetes are required to take medications on time, examine their feet, exercise, maintain a balance diet, preform daily glucose monitoring, cope with hypoglycemia and understand how differing life situations may effect glucose levels. All of these require intact cognitive and functional abilities. Thus, treatment plans should take into consideration the person's cognitive/functional state. Indeed, in the last several years many professional organizations such as the American Diabetes Association, the International Diabetes Federation, and the American Endocrinology Society have published guidelines for treating older people with diabetes. The Israeli National Diabetes Council, headed by Prof. Itamar Raz, in collaboration with other physician unions and other national councils, have recently authorized the Israeli guidelines for treating older people with diabetes. The Israeli guidelines include categorization of older adults with diabetes in relation to their functional status in order to reach determined treatment targets. According to the Israeli guidelines and in accordance with international guidelines, the treatment targets of the elderly person with diabetes should not be determined by the chronological age of the individuals but rather by their risk for functional deterioration. Older people with diabetes are categorized into three groups according to their risk for functional deterioration. Each category has unique glucose, blood pressure and lipid targets. The guidelines offer valid and reliable tools that, in addition to personal acquaintance with the patient, can help determine the level of risk of functional decline.

In the present study we demonstrated that there are no clinically significant differences in the recommendations of the various factors that were examined as for the determination of a desirable HbA1c goal for diabetes patients who are discharged from an internal ward.To examine and compare the desirable HbA1c value recommended by internal ward physicians for diabetics who are discharged from hospitalization, to the target set by diabetes physicians, and compare them to the application "A1c target".The approach to diabetes treatment requires the setting of a desirable individual HbA1c balancing goal for each patient. This goal is usually set by diabetes physicians and it would be advisable that both internal and family physicians will set a desirable balancing goal as well. An online accessible application which assists in setting a desirable HbA1c goal for each patient according to his own data does exist. This application has not yet been validated.The study was conducted in Internal ward B of the Wolfson Medical Center, and included 100 diabetes patients prior to their discharge after hospitalization for whatever reason. In the discharge letter, internal physicians recommended a desirable HbA1c value at their discretion. The patient information was forwarded to two diabetes physicians, A and B, without the HbA1c data written by the ward physicians who determined the desirable value of the HbA1c on which they had decided. Later, an HbA1c value was also determined by the application. All the data was processed statistically and compared.The desirable average HbA1c values by internal physicians were: 7.4%; by diabetes physician A: 7.5%; by diabetes physician B : 7.7%; the HbA1c value obtained from the application was 7.4%. There was no significant difference between the internal physicians' recommendations and those of the diabetes physician A and the application. A statistically significant difference (P0.0001) was found between diabetes physician B and the rest. However, from a clinical point of view - that difference has no significance.Based on the present study data it can be concluded that the recommendation of the internal physicians regarding the choice of a desirable HbA1c goal, is not significantly different from that of the specialists. Furthermore, it can also be concluded, that using an application may assist in choosing a desirable goal, which is also not significantly different from the goal that was recommended by both the specialists and the internal physicians.Based on the data of our study we recommend to routinely introduce written balancing goals in all the internal ward discharge letters for diabetes patients who have been hospitalized in that ward, for whatever reason.

Background: Once-weekly exenatide (EQW) had a neutral effect on hospitalization for heart failure (HHF) in the EXSCEL study (Exenatide Study of Cardiovascular Event Lowering), with no differential treatment effect on major adverse cardiac events by baseline heart failure (HF) status. EQW’s effects on secondary end points based on HHF status have not been reported. The objective was to explore the effects of EQW on secondary end points in patients with and without baseline HF and test the effects of EQW on recurrent HHF events. Methods: The prespecified analysis of the randomized controlled EXSCEL trial, which enrolled patients with type 2 diabetes mellitus with and without additional cardiovascular disease, analyzed EQW effects on all-cause death, each major adverse cardiac event component, first HHF, and repeat HHF, by baseline HF status (regardless of ejection fraction). A subgroup analysis of the population stratified by preserved or reduced baseline ejection fraction was performed. Results: Of 14 752 EXSCEL participants, 2389 (16.2%) had HF at baseline. Compared with those without HF at baseline, patients with preexisting HF were older, and more likely to be male and white, with a higher burden of other cardiovascular diseases. Overall, those assigned to EQW had a lower incidence of all-cause death (hazard ratio [HR], 0.86 [95% CI, 0.77–0.97]) and the composite outcome of all-cause death or HHF (HR, 0.89 [95% CI, 0.80–0.99]). When stratified by presence or absence of baseline HF, there was no observed reduction in all-cause death with EQW with baseline HF (HR, 1.05 [95% CI, 0.85–1.29]), while the risk of mortality was reduced with EQW in the no-HF group (HR, 0.79 [95% CI, 0.68–0.92]) with an interaction P value of 0.031. The reduction in all-cause death or HHF seen with EQW in patients without baseline HF (HR, 0.81 [95% CI, 0.71–0.93]) was not seen in patients with baseline HF (HR, 1.07 [95% CI, 0.89–1.29]; interaction P =0.015). First, plus recurrent, HHF was reduced in the exenatide group versus placebo (HR, 0.82 [95% CI, 0.68–0.99]; P =0.038). Conclusions: In EXSCEL, the use of EQW in patients with or without HF was well tolerated, but benefits of EQW on reduction in all-cause death and first hospitalization for HF were attenuated in patients with baseline HF. Clinical Trial Registration: https://www.clinicaltrials.gov . Unique identifier: NCT01144338.

Serum cholesterol is inversely associated with incident hypoglycemia among patients admitted to internal medicine wards. We examined the association between statin use and incidence of hypoglycemia among patients who were not critically ill.In this retrospective study, we included all patients discharged between January 1, 2010, to December 31, 2013 from internal medicine units at the Wolfson Medical Center. Excluded were patients with hepatocellular or cholestatic liver disease upon admission. Patients were allocated to 4 groups, according to diabetes mellitus status (yes or no) and serum albumin3.5 g/dL (yes or no) on admission. Regression analysis was used to examine the association of incident hypoglycemia during hospitalization and statin treatment (yes or no), and later, statin intensity.Included in this analysis were 31,094 patients (mean age 68.9±17.5 years, 48.4% males, 21.7% with diabetes mellitus). Logistic regression models showed that among patients with low admission serum albumin, administration of high-intensity statins was associated with increased incidence of hypoglycemic events compared to patients not treated with statins (odds ratio [OR] 1.303, 95% confidence interval [CI] 1.016-1.671, P = 0.037), whereas treatment with low-intensity statins was associated with less hypoglycemic events (odds ratio 0.590, 95% confidence interval 0.396-0.879, P = 0.010). Among patients with normal serum albumin, no association was found between incident hypoglycemia and statin intensity. These findings were significant regardless of diabetes mellitus status.Statin treatment in general is associated with reduced incidence of hypoglycemia. However, among patients with low serum albumin upon admission, use of high-intensity statins is associated with an increased risk of hypoglycemic events regardless of diabetes mellitus status.

OBJECTIVE In type 2 diabetes, insulin resistance and progressive β-cell failure require treatment with high insulin doses, leading to weight gain. Our aim was to study whether a three-meal diet (3Mdiet) with a carbohydrate-rich breakfast may upregulate clock gene expression and, as a result, allow dose reduction of insulin, leading to weight loss and better glycemic control compared with an isocaloric six-meal diet (6Mdiet). RESEARCH DESIGN AND METHODS Twenty-eight volunteers with diabetes (BMI 32.4 ± 5.2 kg/m2 and HbA1c 8.1 ± 1.1% [64.5 ± 11.9 mmol/mol]) were randomly assigned to 3Mdiet or 6Mdiet. Body weight, glycemic control, continuous glucose monitoring (CGM), appetite, and clock gene expression were assessed at baseline, after 2 weeks, and after 12 weeks. RESULTS 3Mdiet, but not 6Mdiet, led to a significant weight loss (−5.4 ± 0.9 kg) (P < 0.01) and decreased HbA1c (−12 mmol/mol [−1.2%]) (P < 0.0001) after 12 weeks. Fasting glucose and daily and nocturnal glucose levels were significantly lower on the 3Mdiet. CGM showed a significant decrease in the time spent in hyperglycemia only on the 3Mdiet. Total daily insulin dose was significantly reduced by 26 ± 7 units only on the 3Mdiet. There was a significant decrease in the hunger and cravings only in the 3Mdiet group. Clock genes exhibited oscillation, increased expression, and higher amplitude on the 3Mdiet compared with the 6Mdiet. CONCLUSIONS A 3Mdiet, in contrast to an isocaloric 6Mdiet, leads to weight loss and significant reduction in HbA1c, appetite, and overall glycemia, with a decrease in daily insulin. Upregulation of clock genes seen in this diet intervention could contribute to the improved glucose metabolism.

To examine the association between hypoglycemic events and inpatient and outpatient mortality rates, and to characterize the profile of patients with diabetes who develop hypoglycemia during hospitalization in order to identify risk factors and potentially avoid it.This retrospective cohort study analyzed data of 3410 patients with diabetes hospitalized during 2012. The associations among biochemical measures, severity of hypoglycemia, inpatient length of stay, and mortality during hospitalization, one month and within one year after discharge were evaluated.Hypoglycemia was observed in 18.5% (633/3410) of patients with diabetes, 83% (529/633) with mild/moderate hypoglycemic values. Adjusted for age and sex, the 30-day mortality rate after discharge was higher in the group with mild/moderate hypoglycemia (HR = 1.749, CI 1.288-2.374, p 0.001) and in the group with severe hypoglycemia (HR = 3.390, CI 2.332-6.100, p 0.001). The mortality rate at the one-year follow-up was higher in the group with mild/moderate hypoglycemia (HR = 1.749, CI 1.288-2.374, p 0.001) and in the group with severe hypoglycemia (HR = 3.390, CI 2.332-6.100, p 0.001). In multivariate analysis, hemoglobin and albumin below normal values, and creatinine values above the upper limit were strongly associated with hypoglycemia (OR 1.35, 95%CI 1.1-1.6, p 0.03; OR 1.6, 95%CI 1.33-1.89, p 0.001; OR 1.3, 95%CI 1.08-1.55, p 0.04, respectively).Hospitalized patients with diabetes and low hemoglobin, low albumin or high creatinine levels are at increased risk of developing significant hypoglycemia. Identifying accurate high-risk factors in order to intervene early and efficiently can prevent life-threatening complications.

Background Diabetes mellitus (DM) is a prevalent metabolic disease characterized by chronic hyperglycemia. A primary burden of DM is related to its long-term complications, which have been shown to impact the course of hospitalization and to influence patients’ outcome. Aim To assess the role of in-hospital glucose control on length of stay, 30-days and 1-year mortality. Methods This is a retrospective study that included patients admitted to the cardiac intensive care unit (CICU) of the Edith Wolfson Medical Centre between 01 January, 2010 and 31 December 2013. Blood glucose was measured by glucometer and fed into an interactive database. Glucose status was referred to as controlled when more than 50% of a given patients glucose values were between 71 and 200 mg/dL. Chisquared tests were used to assess the distribution of categorical variables, while the ttest was applied for continuous variables. A multivariate logistic regression model was used to analyze the association between glucose control and mortality. Cox regression was conducted to assess survival and 1-year mortality. Results 2466 patients were admitted to the CICU over the study period, of which 370 had concomitant diabetes mellitus. Controlled glucose status was associated with shorter length of hospital stay (1.6 ± 1.7 versus 2.6 ± 3.0, p

Introduction: Finerenone is a novel, selective, nonsteroidal mineralocorticoid receptor antagonist that significantly reduced the risk of kidney and CV outcomes in patients with CKD and T2D in the FIDELIO-DKD trial, with no effect on blood glucose. In advanced T2D, insulin is often used to control glycemia. This analysis will report outcomes from the FIDELIO-DKD trial by baseline insulin treatment. Methods: In FIDELIO-DKD (NCT02540993), 5734 patients with T2D, UACR 30-5000 mg/g, eGFR 25- Results: Of the 5674 patients analyzed, 3637 (64.1%) were treated with insulin or insulin analogues at baseline. Patients treated with insulin at baseline had a higher A1C and a longer duration of diabetes, with higher proportions of statin and GLP-1RA use, and lower use of other anti-hyperglycemic agents than those who were not. Finerenone did not affect A1C during the trial. The primary and key secondary CV outcome occurred in fewer patients treated with finerenone, with no between-group interaction (primary outcome: HR 0.85, 95% CI 0.73-0.98 with insulin; HR 0.79, 95% CI 0.64-0.96 without insulin; P-value for interaction 0.56; CV outcome: HR 0.82, 95% CI 0.69-0.97 with insulin; HR 0.95, 95% CI 0.74-1.23 without insulin; P-value for interaction 0.33). Hyperkalemia events were similar between groups (mean treatment difference between finerenone and placebo for treatment-emergent serum potassium >5.5 mmol/L, 11.1% with insulin and 13.4% without insulin), with a low incidence of hyperkalemia-related treatment discontinuation. Conclusion: Finerenone has a beneficial effect on kidney and CV outcomes in patients with CKD and T2D, irrespective of insulin use at baseline. Disclosure P. Rossing: Advisory Panel; Self; Astellas Pharma Inc., AstraZeneca, Bayer AG, Boehringer Ingelheim International GmbH, Gilead Sciences, Inc., Merck KGaA, Merck Sharp & Dohme Corp., Novo Nordisk A/S, Sanofi, Vifor Pharma Management Ltd. L. Roessig: Employee; Self; Bayer AG. C. Scott: Employee; Self; Bayer PLC. G. Bakris: Consultant; Self; Alnylam Pharmaceuticals, Inc., Bayer AG, Ionis Pharmaceuticals, Merck & Co., Inc., Vascular Dynamics Inc. R. Agarwal: Advisory Panel; Self; Akebia Therapeutics, Inc., Bayer Healthcare Pharmaceuticals Inc., Diamedica, Relypsa Inc., Sanofi US, Consultant; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Reata Pharmaceuticals, Inc., Other Relationship; Self; AstraZeneca, Chinook. S. Anker: Consultant; Self; Abbott, Bayer AG, Boehringer Ingelheim International GmbH, Cardiac Dimensions Pty. Ltd., Impulse Dynamics, Novartis AG, Servier Laboratories, Vifor Pharma Management Ltd., Other Relationship; Self; Abbott, Vifor Pharma Management Ltd. G. Filippatos: Other Relationship; Self; Bayer AG, Boehringer Ingelheim International GmbH, Servier Laboratories. B. Pitt: Advisory Panel; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Lilly Diabetes, Consultant; Self; AstraZeneca, Bayer Healthcare Pharmaceuticals Inc., Lexicon Pharmaceuticals, Inc., Lexicon Pharmaceuticals, Inc., Sanofi. L. M. Ruilope: None. R. Macisaac: Advisory Panel; Self; AstraZeneca, Bayer Healthcare Pharmaceuticals Inc., Novo Nordisk, Servier Laboratories, Speaker’s Bureau; Self; Boehringer Ingelheim International GmbH, Novo Nordisk. J. Wainstein: Board Member; Self; Novo Nordisk, Research Support; Self; Bayer Healthcare Pharmaceuticals Inc., Kowa Company, Ltd., Speaker’s Bureau; Self; Novo Nordisk. A. Joseph: Employee; Self; Bayer AG. Funding Bayer AG

Aims Feeding regimens alter circadian rhythms in peripheral tissues, but the mechanism is not understood. We aimed to study whether soluble factors, rather than neuronal-based communication, directly influence circadian rhythms in the liver, in response to a nutritional treatment in type 2 diabetes (T2D) patients. Methods Cultured hepatocytes were treated with serum of insulin-treated T2D patients following either a three-meal diet (3Mdiet) or six-meal diet (6Mdiet) and the circadian expression of clock and metabolic genes was measured. Results Serum of the 3Mdiet group led to increased amplitudes and daily mRNA levels of the positive limb of the circadian clock (Clock, Bmal1, Rorα). In parallel, serum of the 3Mdiet group led to the downregulation of the negative limb of the circadian clock (Cry1 and Per1), compared to both baseline and 6Mdiet. In contrast, serum of the 6Mdiet group led to a more distorted expression pattern. The catabolic genes Sirt1 and Ampk were significantly upregulated only by serum of the 3Mdiet group. Conclusions Our results show that serum of type 2 diabetes patients consuming the 3Mdiet contains soluble factors that reset circadian rhythms leading to an expression pattern similar to that of healthy people. This clock pattern contributes to improved glucose metabolism.

The original version of this chapter was inadvertently published with a subtitle which was a duplication of the chapter title.

Hypoglycemia is one of the most significant factors to affect prognosis, and is detrimental to patients regardless of diabetes mellitus (DM) status. The classical paradigms dictate that hypoglycemia is a result of overtreatment with glucose lowering agents (iatrogenic hypoglycemia), or, as among patients without DM, this condition is attributed to disease severity. New information shows that hypoglycemia occurs among patients that have a tendency for it. Incident hypoglycemia is very prevalent in the hospital setting, occurring in 1:6 patients with DM and in 1:17 patients without DM (Leibovitz E, Khanimov I, Wainstein J, Boaz M; Diabetes Metab Syndr Clin Res Rev. 13:222–226, 2019).

AIM To study the association between serum albumin and cholesterol levels at hospital admission and incident hypoglycaemia among people admitted to internal medicine units. METHODS In this cross-sectional analysis, we examined the electronic medical records of people hospitalized in internal medicine departments. Data extracted included all glucose measurements as well as serum albumin and cholesterol, which were measured upon admission. A hypoglycaemia event was recorded for a given person if at least one glucose measurement of ≤ 3.9 mmol/l was recorded during the hospital stay. Regression analysis was used to determine which clinical measures predict hypoglycaemia. RESULTS During the acquisition period, 45 224 people (mean age 68.9 ± 17.8 years, 49.4% male, 21.1% diabetes mellitus) were discharged from internal medicine units. Hypoglycaemia was documented in 7.5% of these individuals (15.4% of people with diabetes vs. 5.5% of those without; P < 0.001). Logistic regression showed that both serum albumin [odds ratio (OR) 0.908, 95% confidence interval (CI) 0.896-0.919; P < 0.001) and cholesterol (OR 0.938, 95% CI 0.896-0.981; P = 0.005] were significantly associated with incident hypoglycaemia. Results remained significant even after controlling for age, sex, average glucose during hospitalization, length of hospital stay, acute infection upon admission, diabetes status, haemoglobin, white blood cell count and C-reactive levels. A combination of hypoalbuminaemia (< 35 g/l) and hypocholesterolaemia (< 3.37 mmol/l) upon admission greatly increased the risk of incident hypoglycaemia (OR 2.544, 95% CI 2.096-3.088; P < 0.001). CONCLUSION Hypoalbuminaemia and hypocholesterolaemia predict incident hypoglycaemia in the hospital setting among people with and without diabetes mellitus.

Introduction It remains unclear whether diabetic patients with diabetic foot complications benefit from strict glycemic control during hospitalization The present study investigates the effect of short- and long-term diabetes control on hospital outcomes including: in-hospital and one year mortality rates, length of hospital stay and the rate of repeated admissions. Methods Type 2 diabetic patients (n = 341) were hospitalized for diabetic foot complications at Wolfson Medical Center over a 5 year period (2008–2012). The adequate short-term glycemic control was defined as average glucose levels between 110 and 180 mg/dL. HbA1c values below 7% were defined as adequate long–term glycemic control. Results The average glucose levels during hospitalization were 179 ± 45 mg/dL and 40% of the measurements were between 110 and 180 mg/dL. Mean admission HBA1c levels were 8.43% ± 2.26%, and 31% of the values were below 7%. The mean length of hospital stay was 24.3 ± 22.6 days, 15.0% of the patients needed surgical intervention during admission, the in-hospital mortality rate was 10.3%, and the rate of 1-year readmission was 25.1%. Adequate diabetes control during hospitalization was not significantly associated with reduced in-hospital mortality (hazard ratio, 0.454, 95% confidence interval 0.186–1.103, p = 0.081). However, adequate diabetes control during hospitalization lead to significantly decreased one year mortality (hazard ratio, 0.269, 95% confidence interval 0.707–0.101, p = 0.009). Adequate diabetes control during hospitalization did not affect the length of hospital stay or the rate of repeated admission. Conclusions Improved glucose control during hospital admission (levels between 110 and 180 mg/dL) was associated with reduction of one year mortality.

Summary Background Lifestyle weight loss interventions represent the mainstay of treating children with obesity. Long-term follow-up studies of intervention programs are scarce. This study assessed the long-term effects and identified factors associated with significant weight loss. Methods This prospective, observational study involved 165 children with body mass index (BMI) z-score ≥1.5 who participated in after-school intervention program. Main outcome measure: change in BMI z-scores; decreased BMI z-score ≥0.5 units was defined as clinically significant. Results At baseline, 55/165 (33.3%) had BMI z-score 1.5–2 and 98 (59.4%) had BMI z-score >2. At follow-up (mean 5.4 ± 1.4 years), 80 (48.5%) had a clinically significant reduction in BMI z-score, while 56 (33.9%) reported a mildly decrease in BMI z-score of 0–0.5 and 29 (17.6%) reported increased BMI z-score. Lower BMI z-score at baseline and participation in sport activity at follow-up were associated with long-term decrease in BMI z-score. Participation in additional post-intervention weight control programs was correlated with weight gain. Conclusions Intervention program was associated with long-term improvement in weight control, especially in children with mild obesity. Physical activity was related to long-term success. Participation in an additional intervention program was associated with failure of weight control.

Acute studies show that addition of whey protein at breakfast has a glucose-lowering effect through increased incretin and insulin secretion. However, whether this is a long-term effect in Type 2 diabetes is unknown. Fifty-six Type 2 diabetes participants aged 58.9±4.5 years, BMI 32.1±0.9 kg/m2 and HbA1C 7.8±0.1% (61.6±0.79 mmol/mol) were randomized to one of 3 isocaloric diets with similar lunch and dinner, but different breakfast: 1) 42 g total protein, 28 g whey (WBdiet, n=19); 2) 42 g various protein sources (PBdiet, n=19); or 3) high-carbohydrate breakfast, 17 g protein from various sources (CBdiet, n=18). Body weight and HbA1C were examined after 12 weeks. All participants underwent three all-day meal challenges for postprandial glycemia, insulin, C-peptide, intact glucagon-like peptide 1 (iGLP-1), ghrelin and hunger and satiety scores. Overall postprandial AUCglucose was reduced by 12% in PBdiet and by 19% in WBdiet, compared with CBdiet (P

Background Dapagliflozin is a sodium-glucose cotransporter-2 inhibitor approved for the treatment of type 2 diabetes. We aimed to assess the efficacy and safety of dapagliflozin as an add-on to adjustable insulin in patients with inadequately controlled type 1 diabetes. Methods DEPICT-1 was a double-blind, randomised, parallel-controlled, three-arm, phase 3, multicentre study done at 143 sites in 17 countries. Eligible patients were aged 18–75 years and had inadequately controlled type 1 diabetes (HbA1c between ≥7·7% and ≤11·0% [≥61·0 mmol/mol and ≤97·0 mmol/mol]) and had been prescribed insulin for at least 12 months before enrolment. After an 8 week lead-in period to optimise diabetes management, patients were randomly assigned (1:1:1) using an interactive voice response system to dapagliflozin 5 mg or 10 mg once daily, given orally, or matched placebo. Randomisation was stratified by current use of continuous glucose monitoring, method of insulin administration, and baseline HbA1c. The primary efficacy outcome was the change from baseline in HbA1c after 24 weeks of treatment in the full analysis set, which consisted of all randomly assigned patients who received at least one dose of study drug. An additional 55 patients who were incorrectly and non-randomly allocated to only dapagliflozin treatment groups were included in the safety analysis set. This study was registered with ClinicalTrials.gov, number NCT02268214; data collection for the present analysis was completed on Jan 4, 2017, and a 28 week extension phase is ongoing. Findings Between Nov 11, 2014, and April 16, 2016, 833 patients were assigned to treatment groups and included in safety analyses (dapagliflozin 5 mg [n=277] vs dapagliflozin 10 mg [n=296] vs placebo [n=260]; 778 of these patients were randomly assigned and included in the full analysis set for efficacy analyses (259 vs 259 vs 260; difference due to randomisation error affecting 55 patients). Mean baseline HbA1c was 8·53% (70 mmol/mol; SD 0·67% [7·3 mmol/mol]). At week 24, both doses of dapagliflozin significantly reduced HbA1c compared with placebo (mean difference from baseline to week 24 for dapagliflozin 5 mg vs placebo was −0·42% [95% CI −0·56 to −0·28; p

OBJECTIVE The circadian clock regulates glucose metabolism by mediating the activity of metabolic enzymes, hormones, and transport systems. Breakfast skipping and night eating have been associated with high HbA1c and postprandial hyperglycemia after lunch and dinner. Our aim was to explore the acute effect of breakfast consumption or omission on glucose homeostasis and clock gene expression in healthy individuals and individuals with type 2 diabetes. RESEARCH DESIGN AND METHODS In a crossover design, 18 healthy volunteers and 18 volunteers with 14.5 ± 1.5 years diabetes, BMI 30.7 ± 1.1 kg/m2, and HbA1c 7.6 ± 0.1% (59.6 ± 0.8 mmol/mol) were randomly assigned to a test day with breakfast and lunch (YesB) and a test day with only lunch (NoB). Postprandial clock and clock-controlled gene expression, plasma glucose, insulin, intact glucagon-like peptide 1 (iGLP-1), and dipeptidyl peptidase IV (DPP-IV) plasma activity were assessed after breakfast and lunch. RESULTS In healthy individuals, the expression level of Per1, Cry1, Rorα, and Sirt1 was lower (P < 0.05) but Clock was higher (P < 0.05) after breakfast. In contrast, in individuals with type 2 diabetes, Per1, Per2, and Sirt1 only slightly, but significantly, decreased and Rorα increased (P < 0.05) after breakfast. In healthy individuals, the expression level of Bmal1, Rorα, and Sirt1 was higher (P < 0.05) after lunch on YesB day, whereas the other clock genes remained unchanged. In individuals with type 2 diabetes, Bmal1, Per1, Per2, Rev-erbα, and Ampk increased (P < 0.05) after lunch on the YesB day. Omission of breakfast altered clock and metabolic gene expression in both healthy and individuals with type 2 diabetes. CONCLUSIONS Breakfast consumption acutely affects clock and clock-controlled gene expression leading to normal oscillation. Breakfast skipping adversely affects clock and clock-controlled gene expression and is correlated with increased postprandial glycemic response in both healthy individuals and individuals with diabetes.

Aims To characterize the incidence of diabetes-associated complications and assess the safety of sitagliptin in participants with chronic kidney disease (CKD) in the Trial Evaluating Cardiovascular Outcomes with Sitagliptin (TECOS). Materials and methods For participants with baseline eGFR measurements (n = 14 528), baseline characteristics and safety outcomes were compared for the CKD cohort (eGFR

Background: Among people with diabetes, those with kidney disease have exceptionally high rates of cardiovascular (CV) morbidity and mortality and progression of their underlying kidney disease. Finerenone is a novel, nonsteroidal, selective mineralocorticoid receptor antagonist that has shown to reduce albuminuria in type 2 diabetes (T2D) patients with chronic kidney disease (CKD) while revealing only a low risk of hyperkalemia. However, the effect of finerenone on CV and renal outcomes has not yet been investigated in long-term trials. Patients and Methods: The Finerenone in Reducing CV Mortality and Morbidity in Diabetic Kidney Disease (FIGARO-DKD) trial aims to assess the efficacy and safety of finerenone compared to placebo at reducing clinically important CV and renal outcomes in T2D patients with CKD. FIGARO-DKD is a randomized, double-blind, placebo-controlled, parallel-group, event-driven trial running in 47 countries with an expected duration of approximately 6 years. FIGARO-DKD randomized 7,437 patients with an estimated glomerular filtration rate ≥25 mL/min/1.73 m2 and albuminuria (urinary albumin-to-creatinine ratio ≥30 to ≤5,000 mg/g). The study has at least 90% power to detect a 20% reduction in the risk of the primary outcome (overall two-sided significance level α = 0.05), the composite of time to first occurrence of CV death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure. Conclusions: FIGARO-DKD will determine whether an optimally treated cohort of T2D patients with CKD at high risk of CV and renal events will experience cardiorenal benefits with the addition of finerenone to their treatment regimen. Trial Registration: EudraCT number: 2015-000950-39; ClinicalTrials.gov identifier: NCT02545049.

Background Short-term treatment for people with type 2 diabetes using a low dose of the selective endothelin A receptor antagonist atrasentan reduces albuminuria without causing significant sodium retention. We report the long-term effects of treatment with atrasentan on major renal outcomes.Methods We did this double-blind, randomised, placebo-controlled trial at 689 sites in 41 countries. We enrolled adults aged 18-85 years with type 2 diabetes, estimated glomerular filtration rate (eGFR) 25-75 mL/min per 1.73 m(2) of body surface area, and a urine albumin-to-creatinine ratio (UACR) of 300-5000 mg/g who had received maximum labelled or tolerated renin-angiotensin system inhibition for at least 4 weeks. Participants were given atrasentan 0.75 mg orally daily during an enrichment period before random group assignment. Those with a UACR decrease of at least 30% with no substantial fluid retention during the enrichment period (responders) were included in the double-blind treatment period. Responders were randomly assigned to receive either atrasentan 0.75 mg orally daily or placebo. All patients and investigators were masked to treatment assignment. The primary endpoint was a composite of doubling of serum creatinine (sustained for >= 30 days) or end-stage kidney disease (eGFR = 90 days, chronic dialysis for >= 90 days, kidney transplantation, or death from kidney failure) in the intention-to-treat population of all responders. Safety was assessed in all patients who received at least one dose of their assigned study treatment. The study is registered with ClinicalTrials. gov, number NCT01858532.Findings Between May 17, 2013, and July 13, 2017, 11 087 patients were screened; 5117 entered the enrichment period, and 4711 completed the enrichment period. Of these, 2648 patients were responders and were randomly assigned to the atrasentan group (n=1325) or placebo group (n=1323). Median follow-up was 2.2 years (IQR 1.4-2.9). 79 (6.0%) of 1325 patients in the atrasentan group and 105 (7.9%) of 1323 in the placebo group had a primary composite renal endpoint event (hazard ratio [HR] 0.65 [95% CI 0.49-0.88]; p=0.0047). Fluid retention and anaemia adverse events, which have been previously attributed to endothelin receptor antagonists, were more frequent in the atrasentan group than in the placebo group. Hospital admission for heart failure occurred in 47 (3.5%) of 1325 patients in the atrasentan group and 34 (2.6%) of 1323 patients in the placebo group (HR 1.33 [95% CI 0.85-2.07]; p=0.208). 58 (4.4%) patients in the atrasentan group and 52 (3.9%) in the placebo group died (HR 1.09 [95% CI 0.75-1.59]; p=0.65).Interpretation Atrasentan reduced the risk of renal events in patients with diabetes and chronic kidney disease who were selected to optimise efficacy and safety. These data support a potential role for selective endothelin receptor antagonists in protecting renal function in patients with type 2 diabetes at high risk of developing end-stage kidney disease. Copyright (C) 2019 Elsevier Ltd. All rights reserved.

Postprandial hyperglycemia (PPHG) is strongly linked with the future development of cardiovascular complications in type 2 diabetes (T2D). Hence, reducing postprandial glycemic excursions is essential in T2D treatment to slow progressive deficiency of β-cell function and prevent cardiovascular complications. Most of the metabolic processes involved in PPHG, i.e., β-cell secretory function, GLP-1 secretion, insulin sensitivity, muscular glucose uptake, and hepatic glucose production, are controlled by the circadian clock and display daily oscillation. Consequently, postprandial glycemia displays diurnal variation with a higher glycemic response after meals with the same carbohydrate content, consumed at dusk compared to the morning. T2D and meal timing schedule not synchronized with the circadian clock (i.e., skipping breakfast) are associated with disrupted clock gene expression and is linked to PPHG. In contrast, greater intake in the morning (i.e., high energy breakfast) than in the evening has a resetting effect on clock gene oscillations and beneficial effects on weight loss, appetite, and reduction of PPHG, independently of total energy intake. Therefore, resetting clock gene expression through a diet intervention consisting of meal timing aligned to the circadian clock, i.e., shifting most calories and carbohydrates to the early hours of the day, is a promising therapeutic approach to improve PPHG in T2D. This review will focus on recent studies, showing how a high-energy breakfast diet (Bdiet) has resetting and synchronizing actions on circadian clock genes expression, improving glucose metabolism, postprandial glycemic excursions along with weight loss in T2D.

Dysglycemia, diabetes and abnormal blood pressure screening can be conducted by trained volunteers and may identify unknown cases. The aim of the study was to examine the feasibility and effectiveness of operating a screening station in pubic setting supervised by diabetes unit.A cross-sectional analysis of a program offering free screening services to non-hospitalized subjects. From 1.1.2011 through 31.12.2013 trained volunteers measured height, weight, blood glucose and blood pressure at the main entrance of the hospital. Subjects were asked whether they had diabetes or hypertension. Dysglycemia was defined as blood glucose 141-199mg/dL and probable newly-identified diabetes as ≥200mg/dL.13,112 adults underwent screening. Among the screened individuals (age 55.3±14.9 years) 2215 (16.9%) reported diabetes and 3037 (23.2%) hypertension. Among subjects without known hypertension, 9.6% had blood pressure ≥140/90. Among the subjects without known diabetes, 5012 (46%) had glucose ≤110mg/dL, 2873 (26.4%) ≥126mg/dL, 1553 (14.3%)140mg/dL and 170 (1.6%) ≥200mg/dL. Compared to subjects with blood glucose ≤140mg/dL, those with dysglycemia or diabetes were older (58.9±13.4 vs. 52.7±15.2 years, P0.001), had elevated BMI (27.5±4.6kg/m(2) vs. 26.6±4.6kg/m(2), P0.001), higher systolic (137.5±22.2mmHg vs. 132.2±21.3mmHg, P0.001) and diastolic blood pressure (80.3±15.6mmHg vs. 78.6±13.7mmHg, P0.001). Compared to subjects with blood glucose200mg/dL, those with probable newly-identified diabetes were older (58.6±10.9 vs. 53.5±15.2, P0.001), had elevated BMI (28.4±4.8kg/m(2) vs. 26.7±4.6kg/m(2), P0.001), higher systolic (139.4±24.0mmHg vs. 132.8±21.4mmHg, P0.001) and diastolic blood pressure (85.4±20.7mmHg vs. 78.8±13.9mmHg, P0.001).Screening supervised by healthcare center can identify individuals at high-risk for dysglycemia and abnormal blood pressure, who are referred for further diagnosis and treatment and may serve as a complementary step in primary health care setting.

BACKGROUND Diabetes is considered a major epidemic of the 21st century. Usually, diabetes begins asymptomatically and the diagnosis takes place an average of 8-12 years after the onset of dysglycaemia. Blood check for glucose is taken at different medical setting, whether at the fasting condition or randomly. Previous studies had shown that abnormal blood glucose predicts future diabetes. Hence, medical staff should consider taking reasonable actions in patients with abnormal blood glucose. OBJECTIVE To assess the prevalence of hyperglycaemia in patients presenting to the Department of Emergency Medicine (DEM) with no known history of diabetes, and to evaluate how often were they recommended following this up as an outpatient by the medical staff. DESIGN A cross-sectional study examined the medical records of adult patients referred to the DEM during 1 November 2011-31 January 2012. PARTICIPANTS Patients with random blood glucose ≥140 mg/dL and no known history of diabetes were included in the study. The discharge letter was examined for the presence of instructions to conduct further follow up. KEY RESULTS A total of 16 784 patients presented to the DEM. Of these, 402 patients (2.4%) without known diabetes were hyperglycaemic, 346 patients had blood glucose levels ≥140 mg/dL and 56 patients had blood glucose levels above 200 mg/dL. Only 35 of the 402 included patient files (8.7%) contained instructions for further investigation. There was no statistically significant difference between those who received a letter for further follow up compared with those who did not receive it with respect to age, sex or blood glucose levels. CONCLUSION Over 2% of patients who presented to the DEM were hyperglycaemic, without a prior diagnosis of diabetes. A small per cent was recommended to have outpatient follow-up. This represents a missed opportunity for earlier diagnosis of diabetes and emphasised the need for raising medical staff awareness concerning abnormal blood glucose and its implication.

The purpose of this study was to examine whether the increased glycemic variability associated with systemic glucocorticoid treatment is also associated with increased incidence of hypoglycemia.All patients discharged from internal medicine units between 2010 and 2013 were included in this retrospective analysis. Patients were assigned to 3 groups: Group 1: no steroids were prescribed;. Group 2: topical or inhaled steroids were prescribed with no systemic treatment; and Group 3: systemic steroids were prescribed, with or without topical or inhaled treatment.A total of 45,272 patients were included in the study. Patients in Group 3 had significantly higher rates of hypoglycemia (10.9%) compared to patients in Group 2 (7.4%), and patients in Group 1 (7.3%). Patients with diabetes mellitus had higher rates of hypoglycemia compared to patients without diabetes mellitus (14.3% vs 4.9%) but exhibited similar trends in response to steroid treatment. Multivariate analysis showed that systemic steroids were associated with increased risk for hypoglycemia (odds ratio [OR] 1.513, 95% confidence interval [CI] 1.311-1.746, P0.001). Hypoglycemia associated with systemic steroid treatment was also associated with increased risk of death (hazard ratio [HR] 2.328, 95% CI 1.931-2.807, P0.001). Patients who were treated with systemic steroids but did not have hypoglycemia did not have higher mortality rates (HR 1.068, 95% CI 0.972-1.175, P = 0.171).Treatment with systemic steroids is associated with increased hypoglycemia incidence during hospitalization. Patients treated with steroids that had incident hypoglycemia had a higher 1-year mortality risk compared to patients without hypoglycemia treated with steroids.

To study the association of documented hypoglycemia with length of stay, 30-day mortality, and 1-year mortality, among patients with and without diabetes admitted to internal medicine units.The electronic medical records of all patients hospitalized in internal medicine departments at E. Wolfson Medical Center, Holon, Israel, between 1/1/2010 and 31/12/2013, were reviewed. Data extracted included all glucose measurements (performed using an institutional blood glucose monitoring system). Patients were considered hypoglycemic if at least one hypoglycemic event was recorded. Regression analysis was used to assess the association between documented hypoglycemia and length of stay, 30-day and one-year mortality. Age, sex, reason for admission, and the Charlson comorbidity index were entered as covariates, and the most conservative model was developed.The study population included 45,272 patients (mean age 68.9 ± 17.8 years, 49.4% males, 21.0% had diabetes mellitus). The rate of hypoglycemia in the total study population was 7.5% (16.8% among DM patients, 6.0% among patients without diabetes, p 0.001). Patients with documented hypoglycemia had a longer length of hospital stay (9.3 ± 18.7 vs. 3.1 ± 6.4 days, p 0.001), as well as higher risk for both 30-day (23.7% vs. 7.0%, p 0.001) and 1-year mortality (41.6% vs. 15.3%, p 0.001). Cox regression analysis showed that hypoglycemia significantly increased risk death at one year (HR 2.436, 95% CI 2.298-2.582, p 0.001) independent of age, sex, the Charlson comorbidity index, DM status and reason for admission.Documented hypoglycemia is associated with prolonged length of hospital stay and increased risk for both 30-day and 1-year mortality, regardless of diabetes mellitus status.

Objective: To determine the satisfaction from treatment and effectiveness of flash glucose monitoring system (FGM) in patients with type 2 diabetes. Design and Methods: 101 individuals with type 2 diabetes on multiple daily insulin injection (MDI) therapy for ≥1 year (mean duration 21.81±7.65 years) and HbA1c 7.4-10.2% (57-88 mmol/mol) were randomized to the intervention (n=53) or the standard care group (n=48). Those in the intervention group were instructed to use FGM and once a week 7-points BG assessment to confirm any a symptomatic hypoglycemia. The control group continued the routine BG measurement as before the study and add once a week 7-points BG measurement at constant day. For 12 weeks, both groups were instructed to adjust insulin dose in the frequent face-to-face and telephone visits. Satisfaction from treatment, quality of life, comfort using FGM, HbA1c and hypoglycemia events were evaluated. Results: The mean age was 66.75 ± 7.55; 64.35% were male. Total treatment satisfaction increased in the intervention group (p=0.053). At the 12 week of the study, subjects in the intervention group found treatment significantly more flexible (p=0.019), convenient (p=0.052), and would recommend it more to their counterparts (p=0.023). The mean HbA1c was 8.51 ± 0.81%. After 10 weeks, HbA1c changes were -0.82% in the intervention group and -0.29% in the control (p=0.0013). 67.9% subjects from the intervention study and 27.1% from the control group reduced HbA1c ≥0.5% HbA1c (p Conclusion: FGM potentially produces a modification of behavior/life style and improves treatment satisfaction. It improves glycemic control in subjects with type 2 diabetes treated by MDI without increased frequency of hypoglycemia. Disclosure M. Yaron: None. E. Roitman: Speaker's Bureau; Self; Merck Sharp & Dohme Corp., Novo Nordisk A/S, Sanofi. Advisory Panel; Self; Sanofi. Speaker's Bureau; Self; AstraZeneca. Advisory Panel; Self; AstraZeneca. Speaker's Bureau; Self; Boehringer Ingelheim Pharmaceuticals, Inc.. Advisory Panel; Self; Boehringer Ingelheim Pharmaceuticals, Inc.. Consultant; Self; GlucoMe. Stock/Shareholder; Self; GlucoMe. G. Aharon-Hananel: None. Z. Landau: None. T. Ganz: None. M. Karp: None. M. Ish-Shalom: None. J. Singer: None. J. Wainstein: None. I. Raz: Advisory Panel; Self; AstraZeneca. Consultant; Self; AstraZeneca. Speaker's Bureau; Self; AstraZeneca. Advisory Panel; Self; Boehringer Ingelheim GmbH. Speaker's Bureau; Self; Boehringer Ingelheim GmbH. Advisory Panel; Self; Eli Lilly and Company. Speaker's Bureau; Self; Eli Lilly and Company. Stock/Shareholder; Self; DarioHealth. Advisory Panel; Self; Merck Sharp & Dohme Corp., Novo Nordisk Inc.. Speaker's Bureau; Self; Novo Nordisk Inc.. Advisory Panel; Self; Orgenesis Inc., Pfizer Inc., Sanofi R&D, SmartZyme Biopharma. Consultant; Self; Bristol-Myers Squibb Company. Speaker's Bureau; Self; Bristol-Myers Squibb Company, Johnson & Johnson Diabetes Institute, LLC., Merck Sharp & Dohme Corp., Novartis Pharma K.K., Sanofi-Aventis. Consultant; Self; FuturRx Ltd, Insuline Medical,Camereyes Ltd, Exscopia, Medial EarlySign Ltd. Stock/Shareholder; Self; Glucome Ltd, InsuLine Medical Ltd.. Consultant; Self; Dermal Biomics Inc. Stock/Shareholder; Self; Orgenesis Inc.. Speaker's Bureau; Self; Teva Pharmaceutical Industries Ltd.. Advisory Panel; Self; Concenter BioPharma/Silkim Ltd, Camereyes Ltd. Stock/Shareholder; Self; CameraEyes Ltd. Advisory Panel; Self; Breath of Life PharmaLtd, Panaxia.

OBJECTIVE To assess treatment satisfaction and the effectiveness of a flash glucose monitoring (FGM) system in patients with type 2 diabetes using insulin. RESEARCH DESIGN AND METHODS A total of 101 patients with type 2 diabetes on multiple daily insulin injections (MDI) for at least 1 year were assigned randomly to the FGM intervention (n = 53) or the standard care (control) group (n = 48) and followed for 10 weeks. Both groups were instructed to adjust their insulin doses in face-to-face and telephone visits. Satisfaction with treatment, quality of life, comfort using FGM, HbA1c, and frequency of hypoglycemic events were evaluated. RESULTS The intervention group found treatment significantly more flexible (P = 0.019) and would recommend it to their counterparts (P = 0.023). Satisfaction using the FGM system was high. The changes in HbA1c were –0.82% (9 mmol/mol) vs. –0.33% (3.6 mmol/mol) in the intervention and control group, respectively (P = 0.005); in nonprespecified post hoc analysis, 68.6% of the patients in the intervention group had their HbA1c reduced by ≥0.5% (5.5 mmol/mol) compared with 30.2% in the control group (P < 0.001), and 39.2% had their HbA1c reduced by ≥1.0% (10.9 mmol/mol) vs. 18.6% in the control group (P = 0.0023) without an increased frequency of hypoglycemia. CONCLUSIONS FGM tends to improve treatment satisfaction and may lead to amelioration of glycemic control in patients with type 2 diabetes on MDI without increasing the frequency of hypoglycemia.

OBJECTIVE Skipping breakfast has been consistently associated with high HbA1c and postprandial hyperglycemia (PPHG) in patients with type 2 diabetes. Our aim was to explore the effect of skipping breakfast on glycemia after a subsequent isocaloric (700 kcal) lunch and dinner. RESEARCH DESIGN AND METHODS In a crossover design, 22 patients with diabetes with a mean diabetes duration of 8.4 ± 0.7 years, age 56.9 ± 1.0 years, BMI 28.2 ± 0.6 kg/m2, and HbA1c 7.7 ± 0.1% (61 ± 0.8 mmol/mol) were randomly assigned to two test days: one day with breakfast, lunch, and dinner (YesB) and another with lunch and dinner but no breakfast (NoB). Postprandial plasma glucose, insulin, C-peptide, free fatty acids (FFA), glucagon, and intact glucagon-like peptide-1 (iGLP-1) were assessed. RESULTS Compared with YesB, lunch area under the curves for 0–180 min (AUC0–180) for plasma glucose, FFA, and glucagon were 36.8, 41.1, and 14.8% higher, respectively, whereas the AUC0-180 for insulin and iGLP-1 were 17% and 19% lower, respectively, on the NoB day (P < 0.0001). Similarly, dinner AUC0-180 for glucose, FFA, and glucagon were 26.6, 29.6, and 11.5% higher, respectively, and AUC0-180 for insulin and iGLP-1 were 7.9% and 16.5% lower on the NoB day compared with the YesB day (P < 0.0001). Furthermore, insulin peak was delayed 30 min after lunch and dinner on the NoB day compared with the YesB day. CONCLUSIONS Skipping breakfast increases PPHG after lunch and dinner in association with lower iGLP-1 and impaired insulin response. This study shows a long-term influence of breakfast on glucose regulation that persists throughout the day. Breakfast consumption could be a successful strategy for reduction of PPHG in type 2 diabetes.

High-energy breakfast and reduced-energy dinner (Bdiet) significantly reduces postprandial glycaemia in obese non-diabetic individuals. Our objective was to test whether this meal schedule reduces postprandial hyperglycaemia (PPHG) in patients with type 2 diabetes by enhancing incretin and insulin levels when compared with high-energy dinner and reduced-energy breakfast (Ddiet).In a randomised, open label, crossover design performed in a clinic setting, 18 individuals (aged 30-70 years with BMI 22-35 kg/m(2)) with type 2 diabetes (10 years duration) treated with metformin and/or diet were given either Bdiet or Ddiet for 7 days. Participants were randomised by a person not involved in the study using a coin flip. Postprandial levels of plasma glucose, insulin, C-peptide and intact and total glucagon-like peptide-1 (iGLP-1 and tGLP-1) were assessed. The Bdiet included 2,946 kJ breakfast, 2,523 kJ lunch and 858 kJ dinner. The Ddiet comprised 858 kJ breakfast, 2,523 kJ lunch and 2,946 kJ dinner.Twenty-two individuals were randomised and 18 analysed. The AUC for glucose (AUCglucose) throughout the day was 20% lower, whereas AUCinsulin, AUCC-peptide and AUCtGLP-1 were 20% higher for the Bdiet than the Ddiet. Glucose AUC0-180min and its peak were both lower by 24%, whereas insulin AUC0-180min was 11% higher after the Bdiet than the Ddiet. This was accompanied by 30% higher tGLP-1 and 16% higher iGLP-1 levels. Despite the diets being isoenergetic, lunch resulted in lower glucose (by 21-25%) and higher insulin (by 23%) with the Bdiet vs Ddiet.High energy intake at breakfast is associated with significant reduction in overall PPHG in diabetic patients over the entire day. This dietary adjustment may have a therapeutic advantage for the achievement of optimal metabolic control and may have the potential for being preventive for cardiovascular and other complications of type 2 diabetes. Trial registration ClinicalTrials.gov NCT01977833 Funding No specific funding was received for the study.

The cost effectiveness of generic drugs has promoted their use worldwide. However, the large variety of bioequivalent generic and brand-name drugs found in the marketplace increases the complexity and frequency of mistakes in drug consumption. This clinical study investigated the prevalence of various mistakes in drug consumption by patients using a hospital setting. This prospective clinical trial used a hospital setting to identify errors in drug consumption. Six hundred patients who were hospitalized for a minimum of 48 hours in the Internal Medicine Departments were checked at various time points. The medications prescribed by their physician was determined and compared to the medications each patient carried on their person for de facto consumption. Drug consumption errors were found in 13 cases (2.17%), most of which involved duplicate drugs. In 6 of these (46.1%), patients consumed different drugs from the same therapeutic family. In 5 cases (38.5%), patients used chemically similar medications with different names, and in 2 cases (15.4%), patients consumed different drugs from various therapeutic families to treat the same medical condition. Ten of the thirteen cases (76.9%) had the potential to cause serious adverse drug events. More errors were found in female patients (53.8%), elderly patients, and those consuming a large variety of drugs. Variations in names, colors, shapes, and sizes of various drugs cause confusion and errors in drug consumption among patients. Some of these errors have the potential to cause severe, adverse drug effects and can increase morbidity and mortality worldwide.

Summary Background Glucagon-like peptide-1 (GLP-1) receptor agonists and sodium-glucose co-transporter-2 (SGLT2) inhibitors improve glycaemic control and reduce bodyweight in patients with type 2 diabetes through different mechanisms. We assessed the safety and efficacy of the addition of the once-weekly GLP-1 receptor agonist dulaglutide to the ongoing treatment regimen in patients whose diabetes is inadequately controlled with SGLT2 inhibitors, with or without metformin. Methods AWARD-10 was a phase 3b, double-blind, parallel-arm, placebo-controlled, 24-week study done at 40 clinical sites in Austria, Czech Republic, Germany, Hungary, Israel, Mexico, Spain, and the USA. Eligible adult patients (≥18 years) with inadequately controlled type 2 diabetes (HbA 1c concentration ≥7·0% [53 mmol/mol] and ≤9·5% [80 mmol/mol]), a BMI of 45 kg/m 2 or less, and taking stable doses (>3 months) of an SGLT2 inhibitor (with or without metformin) were randomly assigned (1:1:1) via an interactive web-response system to subcutaneous injections of either dulaglutide 1·5 mg, dulaglutide 0·75 mg, or placebo once per week for 24 weeks. Patients and investigators were masked to dulaglutide and placebo assignment, and those assessing outcomes were masked to study drug assignment. The primary objective was to test for the superiority of dulaglutide (1·5 mg or 0·75 mg) versus placebo for change in HbA 1c concentration from baseline at 24 weeks. All analyses were done in the intention-to-treat population, defined as all randomly assigned patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, number NCT02597049. Findings Between Dec 7, 2015, and Feb 3, 2017, 424 patients were randomly assigned to dulaglutide 1·5 mg (n=142), dulaglutide 0·75 mg (n=142), and placebo (n=140). One patient in the dulaglutide 0·75 mg group was excluded from the analysis because they did not receive any dose of the study drug. The reduction in HbA 1c concentration at 24 weeks was larger in patients receiving dulaglutide (least squares mean [LSM] for dulaglutide 1·5 mg −1·34% [SE 0·06] or −14·7 mmol/mol [0·6]; dulaglutide 0·75 mg −1·21% [0·06] or −13·2 mmol/mol [0·6]) than in patients receiving placebo (−0·54% [0·06] or −5·9 mmol/mol [0·6]; p vs placebo). The LSM differences were −0·79% (95% CI −0·97 to −0·61) or −8·6 mmol/mol (−10·6 to −6·7) for dulaglutide 1·5 mg and −0·66% (−0·84 to −0·49) or −7·2 mmol/mol (−9·2 to −5·4) for dulaglutide 0·75 mg (p vs seven [5%] in the dulaglutide 0·75 mg group vs five [4%] in the placebo group), diarrhoea (eight [6%] vs 14 [10%] vs four [3%]), and vomiting (five [4%] vs four [3%] vs one [1%]) were more common with dulaglutide than with placebo. One episode of severe hypoglycaemia was reported in the dulaglutide 0·75 mg group. Two (1%) patients receiving dulaglutide 1·5 mg died, but these deaths were not considered to be related to study drug; no deaths occurred in the other groups. Interpretation Dulaglutide as add-on treatment to SGLT2 inhibitors (with or without metformin) resulted in significant and clinically relevant improvements in glycaemic control, with acceptable tolerability that is consistent with the established safety profile of dulaglutide. Funding Eli Lilly and Company.

Helicobacter pylori (HP) infection of the gastric mucosa may be involved in the development of insulin resistance (IR).To investigate the association between HP status in stomach biopsies and weight reduction in patients who underwent laparoscopic sleeve gastrectomy (LSG).In this retrospective analysis of medical charts, all patients who underwent LSG for weight reduction and had at least 1 year of follow-up were included. HP status was ascertained by two to four biopsies of the removed stomach.The study group comprised 70 patients; their mean age was 45.9 ± 11.9 years and 31.9% were males. Fourteen patients (20%) tested positive for HP colonization in gastric mucosa. HP status was not associated with age or smoking status. No difference was noted in the rate of diabetes mellitus (DM) or hypertension, but patients with HP had lower rates of hyperlipidemia (0 vs. 29 patients, 52%, P0.001). Patients lost an average of 10.5 kg/m2 after 12 months of follow-up, and no difference was noted between HP-positive and HP-negative patients. The rate of DM control was also similar between HP-positive and HP-negative patients at baseline (33.3 vs. 29.4, P = NS) and at 12 months of follow-up (70% vs. 50%, P = NS).HP status was not associated with changes in metabolic profiles and co-morbidity status, or in the efficacy of LSG.

Background Screening and early diagnosis of prediabetes and diabetes can prevent or delay disease onset and complications. To that end, a free public health station was established in a large, government medical centre. This study evaluated the long-term outcomes of abnormal random blood glucose results among patients with no history of diabetes or prediabetes. Methods The Diabetes Unit supervised a public dysglycaemia and hypertension screening station. Participants with blood glucose >140 mg/dL and no history of diabetes or prediabetes were contacted by telephone for follow-up. Results Among screened subjects, 868 (average age 57.5±12 years) had a random blood glucose level >140 mg/dL and 341 (39.3%) responded to the telephone survey. Of these, 313 (91.8%) subsequently had fasting blood glucose measured at their health maintenance organisation (HMO), of which 101 (32.3%) were abnormal. A total of 173 (51%) respondents initiated interventions: 59 (17.3%) antidiabetic treatment; 145 (42.5%) sugar-restricted diet; and 96 (28.2%) a physical activity programme. Of patients with abnormal fasting blood glucose, 17 (14.5%) reported having had this result previously compared with 9 (4.2%) with normal fasting glucose (P=.001). Among respondents, 216 (63.3%) stated the screening was effective and 273 (80.1%) would recommend it. Conclusion The station was effective in promoting additional screening among high-risk age groups and encourages subjects to make lifestyle changes. Operating the screening station is simple and effective; therefore it may serve as a complementary step in promoting community healthcare.

Background Previous studies have shown that heating the insulin injection site may accelerate insulin absorption. We investigated the pharmacological profile of insulin administered with InsuPatch, a local skin-heating device. Methods In this randomized, crossover study carried out in 56 subjects with type 1 diabetes treated with insulin pump [mean age 32 ± 13.5 years; 23 women; HbA1c:7.8 ± 0.9% (62 ± 10 mmol/mol) (mean+/−standard deviation)]. Euglycemic glucose clamps were performed after administration of 0.15 units/kg of short-acting insulin analogues. Each subject underwent three clamp procedures: two with the InsuPatch device (day 1 and day 3) and one without the device (day 1 control). The primary endpoints were the following: (1) the change in the area under the curve (AUC) of insulin during the first 60 min post-insulin bolus on day 1 with the InsuPatch device versus day 1 control and (2) parameters to assess the safety of using the device. Results The area under the curve of insulin during the initial 60 min (insulin AUC0–60) after insulin bolus was increased by 29.7 ± 7% on day 1 InsuPatch versus day 1 control (p

Prevalence of atopic dermatitis (AD) has been studied mainly in infants and young children. Surveys on AD in adolescents and adults are based largely on self-reported questionnaires and cohorts of different ages, precluding meaningful comparisons and conclusions. We aimed to provide data on the prevalence of AD and its relation to demographic factors in adolescents. A large database of youths eligible for military service was searched for subjects one year before service at the age of 18. Parameters included country of origin, age of immigration to Israel, education, and presence and severity of AD. AD rose 3-fold for both genders over the study period 1998-2008 (0.4-1%). The increase was higher in females (0.5-1.2%) than males (0.3-0.9%). Mild and moderate disease was higher in females than males. Severe AD was rarely noted. Russian (OR = 1.47), Asian (OR = 1.15) and Euro-American (OR = 1.26) origins had highest association with AD. Immigrants after age 7 had higher association with AD than Israeli-born subjects and immigrants before age 7 (1.88 vs. 1.33). More years of education was significantly associated with high prevalence of AD. The increased prevalence of AD during the 11-year period underscores the need for awareness of the condition in this population, in which AD affects health and quality of life.

To compare sleep quality and sleep-wake pat- terns in parents of children with type 1 diabetes before routine use of the continuous glucose monitoring system (CGMS) and while using it. Thirteen parents completed the Pittsburg Sleep Quality Index (PSQI), a 7-day sleep diary, and wore an actigraph (a wristwatch-size motion detector) during the night for 1 week before pediatric use of CGMS and 4-8 weeks after initiating routine use of the CGMS. Mean age of parents (ten mothers, three fathers) was 39 (range 32-47) years; mean age of children was 9.3 years (range 5.5-16.5 years); mean disease duration was 3.4 (range 0.6-11.2) years. PSQI total score demonstrated similar quality of sleep with and without use of the CGMS (4.6 and 4.9, respectively, p = 0.45). Six of the 13 parents reported severe sleep problems (PSQI C 5) with and without the CGMS. The sleep diary indicated a greater number of awakening episodes during CGMS use than without the CGMS (1.6 and 1, respectively, p = 0.03), and actigraphy documented an increase in the number of wake bouts (22.9 and 19.7, p = 0.03) as well as in total wake time (48.3 and 42.2 min, p = 0.03) during CGMS use as compared with the period prior to CGMS use. Although self-perception of sleep quality remained unchanged, CGMS use appeared to affect actual parental sleep conti- nuity somewhat negatively. This should be made clear to parents who may hold expectations of improvement in sleep quality following initiation of CGMS use.

Objective Our goal was to evaluate the effect of breakfast size and composition on body weight, glycemic control, and metabolic markers in adults with type 2 diabetes mellitus (T2DM). Methods 59 overweight/obese adults with T2DM were randomized to one of two isocaloric diabetic diets for 3 months; big breakfast (BB), breakfast was rich in fat and protein and provided 33% of total daily energy or small breakfast (SB), breakfast was rich in carbohydrates and provided 12.5% of total daily energy. Results Although body weight was reduced similarly in both groups, the BB group showed greater HbA1c and systolic blood pressure reductions (HbA1c: −4.62% vs. −1.46%, p = 0.047; SBP −9.58 vs. −2.43 mmHg; p = 0.04). T2DM medication dose was reduced in a greater proportion of the BB participants (31% vs. 0%; p = 0.002) while in the SB, a greater proportion of participants had a dose increases (16.7% vs. 3.4%; p = 0.002). Hunger scores were lower in the BB group and greater improvements in fasting glucose were observed in the BB group. Conclusions A simple dietary manipulation enriching breakfast with energy as protein and fat appears to confer metabolic benefits and might be a useful alternative for the management of T2DM.

Patients with type 1 diabetes and a significant portion of patients with type 2 diabetes must use subcutaneous insulin injections, in order to maintain normoglycemia and to prevent immediate and long-term complications. For these patients, testing blood glucose levels more frequently is necessary to safely achieve glycated hemoglobin targets. In the current study, the effects of a CoolSense™ device (CoolSense Medical Ltd., Tel Aviv, Israel) were examined in relieving pain caused by needle-pricking for glucose measurements in adult patients with diabetes.One hundred seventy-seven patients assessed the severity of pain they experienced during needle-pricking. The patients were randomly divided into an experimental group or a control group that used either a cooled CoolSense instrument or a non-cooled device, respectively. Participants were asked to rank the severity of their pain by a questionnaire developed for this study. Blood glucose levels were monitored as a control.The majority of participants (58.3-71.7%; P0.001) reported significant ache during measurements, the desire for an instrument that relieves pain, and its negative influence on their quality of life. Significant differences were indicated in pain perception between the experimental group and the control group that served as placebo, with no differences in blood glucose measurements in the groups.The CoolSense instrument significantly reduces subjective pain felt by patients and can therefore serve as an additional tool for clinicians to help ease the needle-pricking pain. Future study is needed in order to provide information regarding the practical use of the instrument and its effect on hyper- and hypoglycemia.