Gram scale synthesis of A (type 2) and B (type 2) tetrasaccharides in the form of 3-aminopropyl glycosides is proposed starting from 3-O-benzoyl-1,6-anhydro-N-acetylglucosamine. Its galactosylation followed by re-protection gave lactosamine derivative with single free 2′-OH group in total yield 75%. Standard fucosylation and next run of re-protection in total yield 88% gave a trisaccharide Fuc-Gal-anhydroGlcNAc with single free 3′-OH group. Its standard α-galactosylation gave protected B (type 2) tetrasaccharide. For synthesis of correspondent A tetrasaccharide seven different 2-azido-2-deoxygalactosyl (GalN3) donors were tested: 6-O-acetyl-3,4-O-isopropylidene-GalN3 thioglycoside was shown to provide the best yield (89%) and stereoselectivity (α/β = 24:1). Further 1,6-anhydro cycle opening, spacer-arming and complete deprotection resulted in the target 3-aminopropyl glycosides of A (type 2) and B (type 2) tetrasaccharides, yields 87 and 85% correspondingly. [Display omitted] •Gram scale synthesis of spacer-armed A and B (type 2) tetrasaccharides.•1,6-Anhydro-GlcNAc is convenient synthon for synthesis of glycans with LacNAc core.•6-OAc-3,4-O-isopropylidene-GalN3SEt is a superior reagent for α-galactosaminylation.
Aims/Introduction To investigate the effect of endurance training on hippocampus DJ‐1 and cannabinoid receptor type 2 (CB2) protein and blood glucose concentration in diabetic rats. Materials and Methods A total of 32 rats were randomly divided into diabetic (D), diabetic and exercise (DE), exercise (E) and control (C) groups. The endurance training was carried out five times per week for 6 weeks. The hippocampus DJ‐1 and CB2 were measured using an enzyme‐linked immunosorbent assay method. Results The level of DJ‐1 in the D group was significantly higher than the other groups (P ≤ 0.01). However, the level of DJ‐1 was not significantly different between the C, E and DE groups. In addition, the level of CB2 was significantly lower in the D group compared with the other groups (P ≤ 0.01). Blood glucose was significantly higher in the D group compared with the DE group (P ≤ 0.05). Furthermore, a significant positive correlation between the level of DJ‐1 and blood glucose was observed (r = 0.67, P ≤ 0.001). There was also a significant inverse correlation between the level of CB2 and blood glucose (r = −0.77, P ≤ 0.001). Conclusions The results of this study suggest that the level of DJ‐1 and CB2 might change in response to diabetes, and regular aerobic exercise could mediate the effect of DJ‐1 and CB2 on diabetes‐induced neurodegenerative diseases. Diabetes may change the levels of DJ‐1 and CB2. These two proteins may play an important role in neural health in diabetic patients. Regular physical activity may reduce the negative effect of high blood glucose on the level of DJ‐1 and CB2.
Plasma metabolite concentrations reflect the activity of tissue metabolic pathways and their quantitative determination may be informative about pathogenic conditions. We searched for plasma lipid species whose concentrations correlate with various parameters of glucose homeostasis and susceptibility to type 2 diabetes (T2D). Shotgun lipidomic analysis of the plasma of mice from different genetic backgrounds, which develop a pre-diabetic state at different rates when metabolically stressed, led to the identification of a group of sphingolipids correlated with glucose tolerance and insulin secretion. Quantitative analysis of these and closely related lipids in the plasma of individuals from two population-based prospective cohorts revealed that specific long-chain fatty-acid-containing dihydroceramides were significantly elevated in the plasma of individuals who will progress to diabetes up to 9 years before disease onset. These lipids may serve as early biomarkers of, and help identify, metabolic deregulation in the pathogenesis of T2D. [Display omitted] •Shotgun lipidomics was performed on plasma samples from mice and humans•In mice, several sphingolipids correlate with diabetes-like traits•In human cohorts progressing to diabetes, dihydroceramide levels are elevated•A significant increase was found in two cohorts, up to 9 years before disease onset Wigger et al. find that several sphingolipids in mouse plasma correlate with glucose tolerance and insulin secretion. Quantitative analysis of these and closely related lipids in human plasma from two cohorts reveal that dihydroceramides are significantly elevated in individuals progressing to diabetes, up to 9 years before disease onset.
To evaluate the efficacy of azelnidipine and amlodipine on diabetic nephropathy and atherosclerosis, we designed a prospective and randomized controlled clinical study in type 2 diabetic patients with stable glycemic control with fixed dose of anti-diabetic medication. Although there was no difference in blood pressure between both groups, urinary albumin excretion and maximum carotid intima-media thickness were reduced in azelnidipine group, but not in amlodipine group. In addition, inflammatory cytokine levels were decreased only in azelnidipine group which possibly explains such beneficial effects of azelnidipine on urinary albumin excretion and carotid atherosclerosis.
Background: Diabetes mellitus (DM) is considered a global epidemic, and patient self-management education and support are critical in preventing and reducing the risk of complications. Self-monitoring of blood glucose (SMBG) is essential for care of individuals with DM, helping patients to achieve and maintain target blood glucose levels. The purpose of this study is to compare the satisfaction of insulinized DM patients on SMBG with use of investigational blood glucose meter (BGM) versus their routine device. Methods: A national, multicenter, open-label, phase 4 study was conducted on patients with type 1 or 2 DM under insulin therapy regimen, who were asked to use investigational BGM instead of their usual BGM device. The study was performed in 12 centers in Brazil for 12 weeks, with an extension period of 12 weeks. The primary endpoint was to measure the variation on the patients' level of satisfaction with investigational versus routine BGM, between visits, using a Visual Analogue Scale (VAS). Secondary endpoints addressed handling aspects, satisfaction, adherence and level of functionality and safety of investigational BGM. Results: The study included 292 patients (36.6 % DM1 and 63.4 % DM2), mean age 50.9 years old (+/- 17.3 years), 57.5 % females. There was statistically significant improvement in global satisfaction with investigational BGM compared with routine BGM according to VAS [mean VAS score raised from 78.8 mm (SD = 18.0) to 90.8 mm (SD = 12.2) between visits]. After 12 weeks, level of satisfaction with investigational BGM according to questionnaires was superior to routine BGM regardless of age group (p < 0.001), type of DM (p < 0.001) or insulin regimen (p < 0.001). Investigational BGM was also regarded as safe, with 10 patients (3.4 %) reporting a total of 13 adverse events during the study. Conclusions: Levels of satisfaction during SMBG were higher with use of investigational BGM and the device was deemed safe and easy to handle.
The expression of LeY, H2, H3, and H4 on a broad variety of human leukemia cell lines and native lymphocytes as well as on CD34(+) hematopoietic progenitor cells was examined by flow cytometry and immunocytochemistry. CD34(+) leukemia cell lines (KG1, KG1a, and TF1) and native CD34+ hematopoietic progenitor cells expressed H2 (CD173) and LeY (CD174). In contrast, CD34(-) cell lines (HL-60, U937, JOK-1, Raji, Molt-3, Jurkat, and CEM-C7) and mature lymphocytes from peripheral blood and tonsils lacked CD173 and CD174. All cell lines and native lymphocytes as well as CD34+ precursor cells were negative for H3 and H4. Immunoprecipitation and consecutive Western blotting revealed a 170-kDa glycoprotein as the carrier molecule for the CD173 and CD174 oligosaccharide sequences on CD34(+) hematopoietic precursors. The key enzyme for generating CD173 is the P-D-galactoside 2-alpha -L-fucosyltransferase (FUT1). As shown by RT-PCR, FUT1 was expressed in immature hematopoietic cells but absent in mature lymphocytes, which indicates that expression of CD173 within the hematopoietic system is regulated at the transcriptional level by FUT1. Due to their exclusive presence on CD34(+) hematopoietic progenitor cells, CD173 and CD174 represent novel markers of early hematopoiesis. The expression of the fucosylated histo-blood group antigens CD173 and CD174 in CD34(+) hematopoietic progenitor cells and down-regulation of FUT1 in mature lymphocytes may be important factors influencing the homing process of hematopoietic stem cells to the bone marrow.
Given the importance of glycemic control in the development of diabetes complications, the plethora of tools now available to monitor the day-to-day trends in glycemia is remarkable. In this regard, self-monitoring of blood glucose (SMBG) has been considered a key component of patient management. Arguably, there remains almost universal agreement that SMBG should be available to all diabetic patients regardless of current treatment strategy. However, recently there have been reports that have challenged the current paradigm that all patients should use SMBG and concluded that SMBG for type 2 diabetic patients not on insulin may not be beneficial on glycemic control and must be weighed against the expense and inconvenience. In the counterpoint narrative following the contribution by Malanda et al., Drs. Polonsky and Fisher provide a compelling argument suggesting that while it is evident that implementing SMBG in unstructured ways without training patients and clinicians is likely to be a waste of resources, there are effective and powerful ways to use structured SMBG in insulin-naïve type 2 diabetic patients. -William T. Cefalu, MD Editor in Chief, Diabetes Care.
OBJECTIVE - Because of blood lipid concerns, diabetes associations discourage fructose at high intakes. To quantify the effect of fructose on blood lipids in diabetes, we conducted a systematic review and meta-analysis of experimental clinical trials investigating the effect Of isocaloric fructose exchange for carbohydrate on triglycerides, total cholesterol, LDL cholesterol, and HDL cholesterol in type I and 2 diabetes. RESEARCH DESIGN AND METHODS - We searched MEDLINE, EMBASE, CINAHL, and the Cochrane Library for relevant trials of >= 7 days. Data were pooled by the generic inverse variance method and expressed as standardized mean differences with 95% Cl. Heterogeneity was assessed by chi(2) tests and quantified by I-2. Meta-regression models identified dose threshold and independent predictors of effects. RESULTS - Sixteen trials (236 subjects) met the eligibility criteria. Isocaloric fructose exchange for carbohydrate raised triglycerides and lowered total cholesterol under specific conditions Without affecting LDL cholesterol or HDL cholesterol. A triglyceride-raising effect without heterogeneity was seen only in type 2 diabetes when the reference carbohydrate was starch (mean difference 0.24 [95% CI 0.05-0.44]), dose was >60 g/day (0.18 [0.00-0.37]), or follow-up was 30% energy (-0.33 [-0.52 to -0. 151), or crystalline fructose (-0.28 [-0.47 to -0.091). Multivariate meta-regression analyses were largely in agreement. CONCLUSIONS - Pooled analyses demonstrated conditional triglyceride-raising and total cholesterol-lowering effects of isocaloric fructose exchange for carbohydrate in type 2 diabetes, Recommendations and large-scale future trials need to address the heterogeneity in the data.
INTRODUCTION: The prevalence of chronic kidney disease and diabetes is rising in Europe. These patients are at high cardiovascular and renal risk and need a challenging multifactorial therapeutic approach. METHOD: The goal of this cross-sectional study was to examine the treatment and attainments of goals related to cardiovascular risk factors within chronic kidney disease stages in type 2 diabetic patients followed up by primary care physicians in Switzerland. Each participating physician entered into a web database the anonymised data of up to 15 consecutive diabetic patients attending her/his office between December 2013 and June 2014. Diabetes, hypertension and lipid lowering therapies were analysed, as well as glycated haemoglobin (HbA1c), blood pressure and low-density lipoprotein-cholesterol (LDL-c) levels and goal attainments by KDIGO chronic kidney disease stage 1 to 4. RESULTS: A total of 1359 patients (mean age 66.5 +/- 12.4 years) were included by 109 primary care physicians. Chronic kidney disease stages 0-2, 3a, 3 b and 4 were present in 77.6%, 13.9%, 6.1%, and 2.4%, respectively. Average HbA1c was independent of chronic kidney disease stage and close to 7%; more than half of the patients reached the HbA1c goal. Eighty-four percent of patients were hypertensive and only 18.2% reached the then current Swiss or American Diabetes Association 2013 blood pressure goals. Despite loosening of blood pressure goals in 2015, only half of the patients reached them and most needed multiple therapies. Increased body mass index and advanced chronic kidney disease stage decreased the chance of reaching blood pressure goals. Lipid lowering therapy was prescribed in 62.1% of cases, with average LDL-c levels similar across chronic kidney disease stages. Only 42% of patients reached the LDL-c goal of = 68 years, median age) for HbA1c, LDL-c and diastolic blood pressure control. CONCLUSION: This cross-sectional study demonstrates that blood pressure and lipid goals are less often achieved than blood glucose control in type 2 diabetic patients followed up by primary care physicians in Switzerland. Goal attainments for HbA1c and LDL-c were not influenced by chronic kidney disease stages, in contrast to blood pressure. Reaching all three goals was rare (2.2%). There is a need for improvement in blood pressure control in advanced chronic kidney disease, whereas HbA1c goals may be loosened in the elderly and in advanced chronic kidney disease.
Background: Globally, Africans and African Americans experience a disproportionate burden of type 2 diabetes, compared to other race and ethnic groups. The aim of the study was to examine the association of plasma glucose with indices of glucose metabolism in young adults of African origin from 5 different countries. Methods: We identified participants from the Modeling the Epidemiologic Transition Study, an international study of weight change and cardiovascular disease (CVD) risk in five populations of African origin: USA (US), Jamaica, Ghana, South Africa, and Seychelles. For the current study, we included 667 participants (34.8 +/- 6.3 years), with measures of plasma glucose, insulin, leptin, and adiponectin, as well as moderate and vigorous physical activity (MVPA, minutes/day [min/day]), daily sedentary time (min/day), anthropometrics, and body composition. Results: Among the 282 men, body mass index (BMI) ranged from 22.1 to 29.6 kg/m(2) in men and from 25.8 to 34.8 kg/m(2) in 385 women. MVPA ranged from 26.2 to 47.1 min/day in men, and from 14.3 to 27.3 min/day in women and correlated with adiposity (BMI, waist size, and % body fat) only among US males after controlling for age. Plasma glucose ranged from 4.6 +/- 0.8 mmol/L in the South African men to 5.8 mmol/L US men, while the overall prevalence for diabetes was very low, except in the US men and women (6.7 and 12 %, respectively). Using multivariate linear regression, glucose was associated with BMI, age, sex, smoking hypertension, daily sedentary time but not daily MVPA. Conclusion: Obesity, metabolic risk, and other potential determinants vary significantly between populations at differing stages of the epidemiologic transition, requiring tailored public health policies to address local population characteristics.