Curalin supplement for patients with type 2 diabetes mellitus.

OBJECTIVE: To examine the efficacy and safety of Curalin supplement in patients with type 2 diabetes. RESEARCH DESIGN AND METHODS: Adult patients with type 2 diabetes were randomized 1:1 to receive Curalin supplement or placebo. The primary endpoint was HbA1c decrease at 1 month. The secondary endpoint was a decrease in HbA1c by more than 0.5% and 1% and a change in 7 daily blood glucose measurements. A satisfaction questionnaire was used as an exploratory endpoint. Safety variables and adverse events were assessed. RESULTS: After 1 month of intervention, HbA1c was reduced by 0.94% in the Curalin arm versus 0.4% in the placebo arm (P = 0.008). 72% of Curalin patients had decreased HbA1c levels >0.5% versus 35% in the placebo arm (P < 0.05). The Treatment Satisfaction Questionnaire indicated that Curalin arm patients reported higher overall satisfaction. CONCLUSIONS: Curalin treatment significantly reduced HbA1c over a 1-month period and was well-tolerated.

Influence of Fasting until Noon (Extended Postabsorptive State) on Clock Gene mRNA Expression and Regulation of Body Weight and Glucose Metabolism.

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.

Association between estimated GFR and incident hypoglycaemia during hospitalization.

BACKGROUND: Kidney function is a significant factor associated with increased incidence of hypoglycaemia, especially among patients with diabetes mellitus (DM). We here quantified the association between elevated creatinine and incident hypoglycaemia among patients admitted to internal medicine departments, with and without DM. METHODS: This is a retrospective cohort analysis study. Included were all patients discharged from internal medicine units between 2010 and 2013. Patients were excluded if creatinine levels rose or dropped more than 0.3 mg/dL during hospitalization. The CKD-EPI equation was used to calculate glomerular filtration rate (eGFR). Logistic regression analysis (backward LR method) was used to study the association between eGFR and hypoglycaemia incidence. RESULTS: Included were 39 316 patients (mean age 68.0 ± 18.0 years, 49.3% males, 25.9% with DM, eGFR 69.5 ± 24.9 mL/min/1.73 m2 ). Among study participants, 6.5% had at least one hypoglycaemic event. Logistic regression modelling showed that eGFR was inversely associated with incident hypoglycaemia (OR 0.988, 95% CI 0.986-0.990, p < .001). Results were similar for patients with and without DM. Estimated GFR was negatively correlated with admission CRP levels for patients with (r = -.143, p < .001) and without DM (r = -.166, p < .001). Estimated GFR was also positively correlated with admission serum albumin levels for both patients with (r = .304, p < .001) and without DM (r = .354, p < .001). CONCLUSION: Among non-critically-ill patients hospitalized in internal medicine departments, reduced eGFR is associated with increased risk of hypoglycaemia. Glucose monitoring for all inpatients with CKD is suggested, regardless of DM status.

[COMPARISON OF A RECOMMENDATION FOR A DESIRABLE HBA1C VALUE BY INTERNAL WARD PHYSICIANS, DIABETES PHYSICIANS AND AN APPLICATION, FOR DIABETES PATIENTS DISCHARGED FROM HOSPITALIZATION IN AN INTERNAL WARD].

INTRODUCTION: 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. AIMS: 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". BACKGROUND: 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. METHODS: 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. RESULTS: 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 (P> 0.0001) was found between diabetes physician B and the rest. However, from a clinical point of view - that difference has no significance. CONCLUSIONS: 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. DISCUSSION: 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.

[THE CHALLENGE OF HEALTHY AGING WITH DIABETES: THE ISRAELI NATIONAL DIABETES COUNCIL GUIDELINES FOR TREATING OLDER PEOPLE].

INTRODUCTION: 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.

Effect of Once-Weekly Exenatide in Patients With Type 2 Diabetes Mellitus With and Without Heart Failure and Heart Failure-Related Outcomes: Insights From the EXSCEL Trial.

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.

Improved outcome of patients with diabetes mellitus with good glycemic control in the cardiac intensive care unit: a retrospective study.

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 < 0.001), reduced 30-day mortality (0.7% versus 4.6%, p < 0.001), and improved 1-year mortality (2.2% versus 7.5%, p < 0.001). Moreover, attainment of glucose control was independently associated with a significant decrease in 1-year mortality (OR = 0.371, 95% CI 0.140-0.988, p = 0.047). CONCLUSION: In-hospital control of glucose parameters is associated with shorter length of hospital stay, and lowered 30-day and 1-year mortality. An effort to maintain glucose levels within reference ranges is warranted in critically ill patients to reduce mortality.

The role of insulin pump therapy for type 2 diabetes mellitus.

Many patients with type 2 diabetes fail to achieve adequate glucose control despite escalation of treatment and combinations of multiple therapies including insulin. Patients with long-standing type 2 diabetes often suffer from the combination of severe insulin deficiency in addition to insulin resistance, thereby requiring high doses of insulin delivered in multiple injections to attain adequate glycemic control. Insulin-pump therapy was first introduced in the 1970s as an approach to mimic physiological insulin delivery and attain normal glucose in patients with type 1 diabetes. The recent years have seen an increase in the use of this technology for patients with type 2 diabetes. This article summarizes the clinical studies evaluating insulin pump use in patients with type 2 diabetes and discusses the benefits and shortcomings of pump therapy in this population. Copyright © 2016 John Wiley & Sons, Ltd.

Serum asymmetric dimethylarginine and arginine levels predict microvascular and macrovascular complications in type 2 diabetes mellitus.

BACKGROUND: Increased oxidative stress in diabetes increases nitric oxide (NO) oxidation and low l-arginine (Arg) could further reduce NO and impair vascular function, thereby accelerating, in the long run, vascular complications. We therefore measured Arg and asymmetric dimethylarginine (ADMA) levels in patients with type 2 diabetes mellitus (T2DM) and healthy controls. Additionally, we observed the diabetic individuals over time to see if Arg and asymmetric dimethylarginine predicted T2DM complications. METHODS: We examined baseline serum Arg and ADMA levels in a cohort of 105 participants with type 2 diabetes and compared them with an age- and weight-matched nondiabetic group of 137 individuals who served as a reference population. Additionally, we assessed whether Arg and/or ADMA predicted macrovascular and microvascular complications over 6 years of follow-up. RESULTS: Serum Arg was lower in individuals with T2DM than in controls (64 ± 28 vs 75 ± 31 µmol/L; P = .009) and inversely related to hemoglobin A1c (r = -0.2; P = .002). Over follow-up, we observed that participants with T2DM in the lowest quartile of Arg had increased risk for the subsequent evolution of nephropathy, peripheral neuropathy, and composite microvascular complications (odds ratio [OR] = 5.5; 95% confidence interval [CI] -1.9 to 16; P = .002). The highest ADMA quartile was associated with increased risk for both microvascular (OR = 4.5; 95% CI -1.4 to 14.1; P = .009) and 6.5-year incident macrovascular complications (OR = 8.3; 95% CI 1.9-35.5; P = .004). CONCLUSION: l-Arginine levels are lower in individuals with T2DM than in matched controls. Both low Arg and high ADMA, independent of each other and adjusted for classical risk factors, predict the incidence of microvascular complications.

Safety of sitagliptin in patients with type 2 diabetes and chronic kidney disease: outcomes from TECOS.

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 < 60 mL/min per 1.73 m2 ) vs those without CKD. Within the CKD cohort, the same analyses were performed, comparing sitagliptin- and placebo-assigned participants. Baseline characteristics were summarized for all participants, and serious adverse events were analysed in those who received at least 1 dose of study medication. Adverse events of interest and diabetes complications were summarized for the intention-to-treat population. RESULTS: CKD was present in 3324 (23%) participants at entry into TECOS. The mean (SD) age for this CKD cohort was 68.8 (7.9) years, mean diabetes duration was 13.7 (9.0) years, and 62% were men. Incidences of serious adverse events, malignancy, bone fracture, severe hypoglycaemia and most categories of diabetes complications were higher in the CKD cohort compared with those without CKD. Over ~2.8 median years of follow-up, CKD participants assigned to sitagliptin had rates of diabetic eye disease, diabetic neuropathy, renal failure, malignancy, bone fracture, pancreatitis and severe hypoglycaemia similar to those of placebo-assigned participants. CONCLUSIONS: Participants in TECOS with CKD had higher incidences of serious adverse events and diabetes complications than those without CKD. Treatment with sitagliptin was generally well tolerated, with no meaningful differences in safety outcomes observed between those with CKD assigned to sitagliptin or placebo.

Error in Drugs Consumption Among Older Patients.

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.

Random blood glucose screening at a public health station encouraged high risk subjects to make lifestyle changes.

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.

Prevalence of undiagnosed hyperglycaemia in patients presenting to the Department of Emergency Medicine with no known history of diabetes.

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.

Effects of Helicobacter Pylori Colonization/Infection on the Metabolic Profile of Obese Persons Undergoing Sleeve Gastrectomy Surgery for Weight Reduction.

BACKGROUND: Helicobacter pylori (HP) infection of the gastric mucosa may be involved in the development of insulin resistance (IR). OBJECTIVES: To investigate the association between HP status in stomach biopsies and weight reduction in patients who underwent laparoscopic sleeve gastrectomy (LSG). METHODS: 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. RESULTS: 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%, P < 0.001). 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). CONCLUSIONS: HP status was not associated with changes in metabolic profiles and co-morbidity status, or in the efficacy of LSG.

High-energy breakfast with low-energy dinner decreases overall daily hyperglycaemia in type 2 diabetic patients: a randomised clinical trial.

AIMS/HYPOTHESIS: 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). METHODS: 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. RESULTS: 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. CONCLUSIONS/INTERPRETATION: 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.

Incretin, insulinotropic and glucose-lowering effects of whey protein pre-load in type 2 diabetes: a randomised clinical trial.

AIMS/HYPOTHESIS: Since protein ingestion is known to stimulate the secretion of glucagon-like peptide-1 (GLP-1), we hypothesised that enhancing GLP-1 secretion to harness its insulinotropic/beta cell-stimulating activity with whey protein pre-load may have beneficial glucose-lowering effects in type 2 diabetes. METHODS: In a randomised, open-label crossover clinical trial, we studied 15 individuals with well-controlled type 2 diabetes who were not taking any medications except for sulfonylurea or metformin. These participants consumed, on two separate days, 50 g whey in 250 ml water or placebo (250 ml water) followed by a standardised high-glycaemic-index breakfast in a hospital setting. Participants were randomised using a coin flip. The primary endpoints of the study were plasma concentrations of glucose, intact GLP-1 and insulin during the 30 min following meal ingestion. RESULTS: In each group, 15 patients were analysed. The results showed that over the whole 180 min post-meal period, glucose levels were reduced by 28% after whey pre-load with a uniform reduction during both early and late phases. Insulin and C-peptide responses were both significantly higher (by 105% and 43%, respectively) with whey pre-load. Notably, the early insulin response was 96% higher after whey. Similarly, both total GLP-1 (tGLP-1) and intact GLP-1 (iGLP-1) levels were significantly higher (by 141% and 298%, respectively) with whey pre-load. Dipeptidyl peptidase 4 plasma activity did not display any significant difference after breakfast between the groups. CONCLUSIONS/INTERPRETATION: In summary, consumption of whey protein shortly before a high-glycaemic-index breakfast increased the early prandial and late insulin secretion, augmented tGLP-1 and iGLP-1 responses and reduced postprandial glycaemia in type 2 diabetic patients. Whey protein may therefore represent a novel approach for enhancing glucose-lowering strategies in type 2 diabetes. Trial registration ClinicalTrials.gov NCT01571622 Funding The Israeli Ministry of Health and Milk Council funded the research.

Genome-wide survey reveals predisposing diabetes type 2-related DNA methylation variations in human peripheral blood.

Inter-individual DNA methylation variations were frequently hypothesized to alter individual susceptibility to Type 2 Diabetes Mellitus (T2DM). Sequence-influenced methylations were described in T2DM-associated genomic regions, but evidence for direct, sequence-independent association with disease risk is missing. Here, we explore disease-contributing DNA methylation through a stepwise study design: first, a pool-based, genome-scale screen among 1169 case and control individuals revealed an excess of differentially methylated sites in genomic regions that were previously associated with T2DM through genetic studies. Next, in-depth analyses were performed at selected top-ranking regions. A CpG site in the first intron of the FTO gene showed small (3.35%) but significant (P = 0.000021) hypomethylation of cases relative to controls. The effect was independent of the sequence polymorphism in the region and persists among individuals carrying the sequence-risk alleles. The odds of belonging to the T2DM group increased by 6.1% for every 1% decrease in methylation (OR = 1.061, 95% CI: 1.032-1.090), the odds ratio for decrease of 1 standard deviation of methylation (adjusted to gender) was 1.5856 (95% CI: 1.2824-1.9606) and the sensitivity (area under the curve = 0.638, 95% CI: 0.586-0.690; males = 0.675, females = 0.609) was better than that of the strongest known sequence variant. Furthermore, a prospective study in an independent population cohort revealed significant hypomethylation of young individuals that later progressed to T2DM, relative to the individuals who stayed healthy. Further genomic analysis revealed co-localization with gene enhancers and with binding sites for methylation-sensitive transcriptional regulators. The data showed that low methylation level at the analyzed sites is an early marker of T2DM and suggests a novel mechanism by which early-onset, inter-individual methylation variation at isolated non-promoter genomic sites predisposes to T2DM.

Improved pharmacokinetic and pharmacodynamic profiles of insulin analogues using InsuPatch, a local heating device.

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 AUC(0-60)) after insulin bolus was increased by 29.7 ± 7% on day 1 InsuPatch versus day 1 control (p < 0.01). Maximal post-insulin bolus concentration was 57 mU/L on day 1 InsuPatch versus 47.6 mU/L on day 1 control (p < 0.01). On day 3 InsuPatch, insulin AUC(0-60) was increased by 27.9 ± 72% versus day 1 InsuPatch (p < 0.01). Maximal insulin concentration was 70.4 mU/L versus 57 mU/L, respectively (p = 0.05). CONCLUSIONS: The use of the heating device upon administration of short-acting insulin analogues in pump-treated type 1 diabetic patients was found to enhance insulin absorption. This heating device may therefore serve to achieve better meal insulin coverage.

Gender aspects suggestive of gastroparesis in patients with diabetes mellitus: a cross-sectional survey.

BACKGROUND: It is suggested that symptoms related to gastroparesis are more common in female than in male patients with type 2 diabetes mellitus (T2DM). The association between sex and prevalence of symptoms suggestive of gastroparesis among patients with T2DM in Israel has not been reported. The aim of this study was to describe the associations between sex, clinical characteristics, type, severity and prevalence of dyspeptic symptoms in a large population of patients with T2DM in Israel. METHODS: All patients completed a demographic questionnaire and the Gastroparesis Cardinal Symptom Index (GCSI). Data regarding disease duration, medications, complications, recent blood glucose and HbA1c levels were also collected. In this nested case-control study, 173 female and 209 male patients were identified from within a cross-sectional survey of 382 patients with T2DM. Logistic and general linear modeling was used to assess associations between sex, clinical data, and the presence (type and number) of symptoms. RESULTS: Compared to males, female patients with T2DM had a higher body mass index (BMI) (31.9 vs. 29.2; P = 0.001) and HbA1c levels (7.9 vs. 7.5; P = 0.04). A larger proportion of males suffered from peripheral vascular disease (P = 0.02) and ischemic heart disease (P = 0.001). Other disease characteristics did not differ between the sexes. The prevalence of nausea (P = 0.001), early satiety (P = 0.005), loss of appetite (P = 0.002), or presence of any cardinal symptom (P = 0.001) was significantly higher among females. Severity of most cardinal symptoms was also higher in females. The presence of at least one cardinal symptom was more likely among obese females with longer disease duration and poor glycemic control. CONCLUSIONS: Prevalence and severity of symptoms suggestive of gastroparesis is particularly high among obese females with long standing and poorly controlled T2DM.

Atopic dermatitis in Israeli adolescents - a large retrospective cohort study.

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.