Search

Background: Increasing global diabetes incidence has profound implications for health systems and for people living with diabetes. Guidelines have established clinical targets but there may be variation in clinical outcomes including HbA1c, based on location and practice size. Investigating this variation may help identify factors amenable to systemic improvement interventions. The aims of this study were to identify centre-specific and patient-specific factors associated with variation in HbA1c levels and to determine how these associations contribute to variation in performance across diabetes centres., Methods: This cross-sectional study analysed data for 5,872 people with type 1 (n = 1,729) or type 2 (n = 4,143) diabetes mellitus collected through the Australian National Diabetes Audit (ANDA). A linear mixed-effects model examined centre-level and patient-level factors associated with variation in HbA1c levels., Results: Mean age was: 43±17 years (type 1), 64±13 (type 2); median disease duration: 18 years (10,29) (type 1), 12 years (6,20) (type 2); female: 52% (type 1), 45% (type 2). For people with type 1 diabetes, volume of patients was associated with increases in HbA1c (p = 0.019). For people with type 2 diabetes, type of centre was associated with reduction in HbA1c (p <0.001), but location and patient volume were not. Associated patient-level factors associated with increases in HbA1c included past hyperglycaemic emergencies (type 1 and type 2, p<0.001) and Aboriginal and Torres Strait Islander status (type 2, p<0.001). Being a non-smoker was associated with reductions in HbA1c (type 1 and type 2, p<0.001)., Conclusions: Centre-level and patient-level factors were associated with variation in HbA1c, but patient-level factors had greater impact. Interventions targeting patient-level factors conducted at a centre level including sick-day management, smoking cessation programs and culturally appropriate diabetes education for and Aboriginal and Torres Strait Islander peoples may be more important for improving glycaemic control than targeting factors related to the Centre itself., Competing Interests: Sally Green is employed by Monash University and receives funding from the National Health and Medical Research Council (NHMRC), the Medical Research Future Fund (MRFF) and the Victorian Department of Health and Human Services. She has no declaration of interest specific to the research reported in this paper. Sophia Zoungas reports financial activities outside the submitted work including: Eli Lilly Australia Ltd – Participation in Steering Committee (CVOT) 2019 & 2021 on behalf of Monash University – payment to institution; Boehringer-Ingelheim – Participation in Advisory Board, expert committees or educational meeting 2019 on behalf of Monash University – payment to institution; MSD Australia - Participation in Advisory Board, expert committees or educational meeting 2019 & 2020 on behalf of Monash University – payment to institution; AstraZeneca – Participation in Advisory Board, expert committees or educational meeting 2017, 2018, 2019, 2020 & 2021 on behalf of Monash University – payment to institution; Novo Nordisk - Participation in Advisory Board, expert committees or educational meeting 2016, 2018, 2019 & 2020 on behalf of Monash University – payment to institution; Sanofi – Participation in Advisory Board, expert committees or educational meeting 2018 on behalf of Monash University – payment to institution. This does not alter her adherence to PLOS ONE policies on sharing data and materials. The other authors declare no relevant declarations of interest with regards to this manuscript.

Fibroblast growth factor (FGF) 21 has various functions, including glucose and lipid metabolism. This cross-sectional study aimed to investigate specific conditions that might influence the functions of FGF21. 398 men who underwent a health examination were enrolled in this study. Physical and biochemical parameters and information on several lifestyle behaviors were obtained from all subjects. FGF21 levels correlated with age, body mass index (BMI), waist circumference (WC), systolic blood pressure (SBP), diastolic blood pressure (DBP), aspartate aminotransferase (AST), alanine aminotransferase (ALT), gamma-glutamyl transpeptidase (γ-GTP), uric acid, total cholesterol (TC), triglycerides (TG), high-density lipoprotein cholesterol (HDLC), fasting plasma glucose (FPG), and HbA1c. Moreover, FGF21 levels were significantly associated with lifestyle behaviors, including smoking status and breakfast and alcohol consumption frequency. Multivariable regression analysis showed that age, ALT, γ-GTP, smoking status, and breakfast and alcohol consumption frequency were independent variables for FGF21 levels. Assessment among the non-obese and obese groups showed that FGF21 levels correlated with WC, SBP, and TC only in the non-obese group. Thus, serum FGF21 levels were affected by several factors, including lifestyle behaviors, age, and liver function. To assess the functions of FGF21 in individuals, considering these factors would be essential., (© 2021. The Author(s).)

Introduction: It is common for patients to switch between several healthcare providers. In this context, the long-term follow-up of medical conditions based on laboratory test results obtained from different laboratories is a challenge. The measurement uncertainty in an inter-laboratory context should also be considered in data mining research based on routine results from randomly selected laboratories. As a proof-of-concept study, we aimed at estimating the inter-laboratory reference change value (IL-RCV) for exemplary analytes from publicly available data on external quality assessment (EQA) and biological variation., Materials and Methods: External quality assessment data of the Reference Institute for Bioanalytics (RfB, Bonn, Germany) for serum creatinine, calcium, aldosterone, PSA, and of whole blood HbA1c from campaigns sent out in 2019 were analysed. The median CVs of all EQA participants were calculated based on 8 samples from 4 EQA campaigns per analyte. Using intra-individual biological variation data from the EFLM database, positive and negative IL-RCV were estimated with a formula based on log transformation under the assumption that the analytes under examination have a skewed distribution., Results: We estimated IL-RCVs for all exemplary analytes, ranging from 13.3% to 203% for the positive IL-RCV and - 11.8% to - 67.0% for the negative IL-RCV (serum calcium - serum aldosterone), respectively., Conclusion: External quality assessment data together with data on the biological variation - both freely available - allow the estimation of inter-laboratory RCVs. These differ substantially between different analytes and can help to assess the boundaries of interoperability in laboratory medicine., Competing Interests: Potential conflict of interest None declared., (Croatian Society of Medical Biochemistry and Laboratory Medicine.)

Diabetes is one of the largest global health problems and exhibits a constantly increasing trend. A series of nationwide hospital-based cross-sectional surveys of clinical outcomes was performed annually from 2011 to 2015 and 2018 among patients with type 2 diabetes aged ≥ 20 years receiving medical care for at least 12 months. A two-stage stratified cluster that was proportional to the size sampling technique was used to select a nationally and provincially representative sample of patients with type 2 diabetes in Thailand. A total of 186,010 patients with type 2 diabetes were enrolled in the study from 2011 to 2018. The prevalence of adequate glycemic control (hemoglobinA1c level < 7.0%) among patients with type 2 diabetes were estimated to be 34.5% (95%CI 33.8-35.2%) in 2011, 33.0% (95%CI 32.4-33.6%) in 2012, 34.7% (95%CI 34.1-35.4%) in 2013, 35.5 (95%CI 34.9-36.1%) in 2014, 35.6 (95%CI 35.0-36.2%) in 2015, and 35.6% (95%CI 35.0-36.2%) in 2018, respectively (p for trend < 0.001). Independent factors related to poor glycemic control (hemoglobinA1c ≥ 7%) were being female, younger aged, living in the northeastern region, received care form hospitals lower than regional level, under universal health coverage scheme, greater duration of diabetes, higher body mass index level and absence of hypertension comorbidity., (© 2021. The Author(s).)

Despite the benefits of early and effective glycemic control in the management of type 2 diabetes (T2D), achieving glycated hemoglobin (HbA 1c ) targets is challenging in some patients. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) provide effective reductions in HbA 1c and body weight. Semaglutide is the only GLP-1RA that is available in both an injectable and oral formulation. The efficacy of once-weekly subcutaneous semaglutide and once-daily oral semaglutide has been investigated in the global SUSTAIN and PIONEER phase III clinical trial programs in a range of clinical settings, including early T2D managed with diet and exercise only, more established T2D uncontrolled on one to three oral antidiabetic drugs, and advanced disease treated with insulin. Across the SUSTAIN program, once-weekly subcutaneous semaglutide 1.0 mg reduced HbA 1c by 1.5-1.8% after 30-56 weeks, which was significantly more than sitagliptin, liraglutide, exenatide extended release, dulaglutide, canagliflozin, or insulin glargine. Across the PIONEER program, once-daily oral semaglutide 14 mg reduced HbA 1c by 1.0-1.4%, significantly more than sitagliptin or empagliflozin, and to a similar extent as liraglutide after 26 weeks. In addition, subcutaneous semaglutide reduced body weight significantly more than all active comparators tested, while oral semaglutide reduced body weight more than sitagliptin and liraglutide, and to a similar extent as empagliflozin. Neither formulation of semaglutide has been associated with an increased risk of hypoglycemia and both improve various measures of health-related quality of life. Semaglutide offers the benefits of a highly effective GLP-1RA in both injectable and oral formulations. Selection of the most appropriate formulation can be made on an individual basis to best suit the patient's preferences and needs., Competing Interests: JJM has received lecture honoraria and consulting fees from AstraZeneca, Berlin-Chemie, Boehringer Ingelheim, Eli Lilly, Merck Sharp & Dohme (MSD), Novartis, Novo Nordisk, and Sanofi; has received reimbursement of congress participation fees and travel expenses from MSD, Novo Nordisk, and Sanofi; and has initiated projects supported by Boehringer Ingelheim, MSD, Novo Nordisk, and Sanofi. The author declares that this article received funding from Novo Nordisk. The funder had the following involvement in the article: medical writing support., (Copyright © 2021 Meier.)

Reliable protein markers for pre-diabetes in humans are not clinically available. In order to identify novel and reliable protein markers for pre-diabetes in humans, healthy volunteers and patients diagnosed with pre-diabetes and stroke were recruited for blood collection. Blood samples were collected from healthy and pre-diabetic subjects 12 h after fasting. BMI was calculated from body weight and height. Fasting blood glucose (FBG), glycated hemoglobin (Hb A1C ), triglyceride (TG), total cholesterol, high-density lipoprotein, low-density lipoprotein (LDL), insulin and albumin were assayed by automated clinical laboratory methods. We used a quantitative proteomics approach to identify 1074 proteins from the sera of pre-diabetic and healthy subjects. Among them, 500 proteins were then selected using Mascot analysis scores. Further, 70 out of 500 proteins were selected via volcano plot analysis according to their statistical significance and average relative protein ratio. Eventually, 7 serum proteins were singled out as candidate markers for pre-diabetes due to their diabetic relevance and statistical significance. Immunoblotting data demonstrated that laminin subunit alpha 2 (LAMA2), mixed-lineage leukemia 4 (MLL4), and plexin domain containing 2 (PLXDC2) were expressed in pre-diabetic patients but not healthy volunteers. Receiver operating characteristic curve analysis indicated that the combination of the three proteins has greater diagnostic efficacy than any individual protein. Thus, LAMA2, MLL4 and PLXDC2 are novel and reliable serum protein markers for pre-diabetic diagnosis in humans., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Yang, Chang, Kuo, Shen, Yang, Tien, Lai, Chen, Chang and Yang.)

Objectives: To explore the glycemic control [represented by glycated hemoglobin (HbA1c) concentrations] in children with diabetes mellitus (DM) in east China and middle- and low-income countries, from 2010 to 2019., Methods: Retrospective data of children with DM from two hospital-based health records were reviewed. Data on HbA1c concentrations, hospitalization due to diabetic ketoacidosis, and patient demographics were collected and analyzed. A systematic review was subsequently performed to analyze publications that report HbA1c concentrations in patients aged <18 years. Patients' characteristics extracted from each publication were used to generate simulated individual data for pooled analysis. HbA1c estimates were derived from steady-state iterations., Results: Data of 843 diabetic children (aged 11.2 ± 3.9 years) with 2,658 HbA1c measures were retrieved from the two hospitals during the period 2010-2020. The duration of diabetes in the patients was 4.4 ± 2.8 years, and their HbA1c was 8.1 ± 2.2%. Patients who were internal migrants had significantly higher HbA1c concentration than resident patients (8.4 vs. 7.9%). The literature review yielded 1,164 publications, and the majority (74.1%) of patient data were published in high-income countries. The patient data extracted from these publications generated 486,416 HbA1c concentration estimates between 2005 and 2019. The average HbA1c concentration during the 15 years was 9.07 ± 2.15%. The mean HbA1c concentrations among children were 8.23, 8.73, 9.20, and 10.11% in high-income country (HIC), upper-middle income country (UMIC), lower-middle income country (LMIC), and low-income country (LIC) respectively. The mean rate of optimized glycemic control (HbA1c <7.5%) among children was 32.4, 27.5, 21.7, and 12.7% in HIC, UMIC, LMIC, and LIC, respectively., Conclusions: The current study indicated that there is substantial room for improvement in glycemic control in children with DM worldwide, especially in middle- and low-income countries., Competing Interests: The authors declare that the study was conducted in the absence of any commercial or financial relationships that could lead to potential conflict of interest., (Copyright © 2021 Chen, Pei, Zhang, Xu, Zhao, Lu, Chen, Luo, Chen and Sun.)

Objective: To comprehensively evaluate and compare the therapeutic effects of various hypoglycemic agents in NAFLD patients with or without diabetes., Methods: All literature from the Cochrane Central Register of Controlled Trials (CENTRAL), PubMed, and Clinical Trials was searched, and the language was limited to English. Two reviewers independently assessed study eligibility, continuous data extraction, and independent assessment of bias risk. Our primary outcomes were alanine aminotransferase (ALT), aspartate aminotransferase (AST) and triglyceride levels, while our secondary outcomes were high-density lipoprotein (HDL) and low-density lipoprotein (LDL) levels, body weight, BMI, and fasting glucose and glycosylated hemoglobin (HbA1c) levels., Results: The review identified 20 eligible trials that met the inclusion criteria. We found that, compared to other drugs, thiazolidinediones, especially pioglitazone, had a greater effect on the levels of ALT (-8.01 (95% CI -14.3 to 2.02)) and AST (-5.0 (95% CI -9.21 to -1,22)) and other biological indicators, but they were also associated with an increased risk of weight gain (3.62 (95% CI 2.25 to 4.99) and increased BMI (0.59 (95% Cl -0.13 to 1.29). GLP1 RAs and metformin also had better therapeutic effects than other drugs as measured by the levels of ALT (liraglutide: -9.36 (95% Cl -18 to -0.34), metformin: -2.84 (95% CI -11.09 to 5.28)) and AST (liraglutide: -5.14 (95% CI -10.69 to 0.37), metformin: -2.39 (95% CI -7.55, 2.49)) and other biological indicators., Conclusion: Despite the significant risk of weight gain, thiazolidinediones, especially pioglitazone, are beneficial in normalizing liver and glucose metabolism in NAFLD patients. In clinical practice, we believe that GLP1 RAs such as liraglutide and exenatide or metformin can be used in combination to offset the risk of weight gain associated with thiazolidinediones. However, long-term studies are still needed to verify the efficacy and safety of individual hypoglycemic agents., Systematic Review Registration: [PROSPERO], identifier [CRD42020212025]., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Lian and Fu.)

Objective: Circulating osteoglycin may facilitate the crosstalk between bone and pancreas to empower adaptation of bone mass to whole body energy balance. We aimed to examine whether osteoglycin is associated with bone and metabolic parameters and if osteoglycin levels differ between patients with type 1 and 2 diabetes (T1D and T2D)., Design and Methods: A cross-sectional study of 190 patients with diabetes mellitus and stable hemoglobin A1c (HbA1c) (97 T1D and 93 T2D) was conducted. S-osteoglycin was analyzed by ELISA. Unpaired t-tests were performed to test differences between patients with T1D and T2D and linear regression analyses were performed to investigate associations between osteoglycin, glycemic markers, bone turnover markers and characteristics., Results: S-osteoglycin did not differ between patients with T1D and T2D (p=0.10). No associations were present between osteoglycin and age, gender, microvascular complications, HbA1c, or plasma glucose in T1D or T2D patients (p>0.05 for all). S-osteoglycin was not associated with levels of bone turnover markers (C-terminal cross-linked telopeptide of type-I collagen (CTX), P-procollagen type 1 amino terminal propeptide (P1NP), P-osteocalcin (OC), P-sclerostin, S-osteoprotegerin (OPG) or S-Receptor Activator of Nuclear factor Kappa beta Ligand (RANKL)) in neither T1D or T2D patients (p>0.05 for all)., Conclusion: Osteoglycin levels were similar in T1D and T2D patients. Osteoglycin did not correlate with glucose, HbA1c or any other biochemical marker of bone turnover. Thus, we did not find evidence supporting the existence of an osteoglycin-bone-pancreas axis., Clinical Trial Registration: ClinicalTrials.gov, identifier NCT01870557., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Starup-Linde, Viggers, Langdahl, Gregersen, Lykkeboe, Handberg and Vestergaard.)

A multicenter randomized controlled pilot trial investigated whether motivational interviewing (MI) by diabetes physicians improves glycemic control and variability in the context of follow-up for adolescent patients with poorly controlled type 1 diabetes. Patients ( n = 47) aged 12 to 15.9 years who showed poor glycemic control (HbA1c >75 mmol/mol/9.0%) were randomized to standard education (SE) only or MI+SE, with study physicians randomized to employ MI+SE ( N = 24 patients) or SE only ( N = 23). For one year of follow-up, the main outcome measurements were obtained at three-month visits (HbA1c) or six-monthly: time in range (TIR) and glycemic variability (CV). Mean adjusted 12-month change in HbA1c was similar between the MI+SE and SE-only group (-3.6 vs. -1.0 mmol/mol), and no inter-group differences were visible in the mean adjusted 12-month change in TIR (-0.8 vs. 2.6%; P = 0.53) or CV (-0.5 vs. -6.2; P = 0.26). However, the order of entering the study correlated significantly with the 12-month change in HbA1c in the MI+SE group ( r  = -0.5; P = 0.006) and not in the SE-only group ( r = 0.2; P = 0.4). No link was evident between MI and changes in quality of life. The authors conclude that MI's short-term use by diabetes physicians managing adolescents with poorly controlled type 1 diabetes was not superior to SE alone; however, improved skills in applying the MI method at the outpatient clinic may produce greater benefits in glycemic control., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Tuomaala, Hero, Tuomisto, Lähteenmäki, Miettinen, Laine, Wehkalampi, Kiiveri, Ahonen, Ojaniemi, Kaunisto, Tossavainen, Lapatto, Sarkola and Pulkkinen.)

Introduction: The relationship between HbA1c and diabetic retinopathy is expected to differ between different races. This study was designed to verify whether HbA1c or fasting plasma glucose (FPG) is more effective in detecting diabetic retinopathy in a Japanese population., Materials and Methods: The study subjects underwent health examinations between 2008 and 2009 with fasting. Of these participants, we analyzed the data for 2,921 Japanese men who had undergone an ophthalmologic examination. Retinopathy was classified into 7 categories according to a simplified diabetic retinopathy scale. The odds ratios of retinopathy according to the eight groups of FPG and HbA1c were estimated using multiple logistic regression analysis adjusted for age. Receiver operator characteristic analysis was used to evaluate each value associated with the presence or absence of retinopathy. Results and Discussion . The odds ratios (95% CI) of retinopathy for HbA1c level categories, in ascending order, were 1.0 (ref.), 0.88 (0.28-2.75), 1.27 (0.44-3.69), 1.52 (0.48-4.79), 1.89 (0.52-6.85), 2.70 (0.66-11.10), 4.10 (0.80-21.00), and 6.34 (2.37-16.97) where the odds ratios significantly increased with HbA1c ≥ 6.8%. The area under the curve (SE) for FPG and HbA1c was almost the same, at 0.668 (0.043) and 0.680 (0.043), respectively., Conclusions: It was clarified that the higher the level of HbA1c, the higher the prevalence of retinopathy, and there was no clear threshold. The detection ability of retinopathy was almost the same, suggesting that it is possible to detect the risk of retinopathy by HbA1c only., Competing Interests: The authors declare that there are no conflicts of interest., (Copyright © 2020 Yumi Matsushita et al.)

Background: The long-term insulin therapy for type 1 diabetes mellitus (T1DM) fails to achieve optimal glycemic control and avoid adverse events simultaneously. Stem cells have unique immunomodulatory capacities and have been considered as a promising interventional strategy for T1DM. Stem cell therapy in T1DM has been tried in many studies. However, the results were controversial. We thus performed a meta-analysis to update the efficacy and safety of stem cell therapy in patients with T1DM., Methods: We systematically searched the Medline, EMBASE, Cochrane Central Register of Controlled Trials, ClinicalTrials.gov, Web of Science, Wan Fang Data, China National Knowledge Infrastructure, VIP database, and the Chinese Biomedical Literature Database (SinoMed) for relevant studies published before March 19, 2019. The outcomes included parameters for glycemic control (i.e., glycosylated hemoglobin (HbA1c) levels and insulin dosages), β cell function (i.e., fasting C-peptide levels and area-under-curve of C-peptide concentration (AUCC)), and relative risk of adverse events. Statistical analysis was conducted by using RevMan 5.3 and Stata 12.0., Results: Five randomized controlled trials (RCTs) and eight nonrandomized concurrent control trials (NRCCTs) with a total of 396 individuals were finally included into the meta-analysis. Among RCTs, stem cell therapy could significantly reduce HbA1c levels (MD = -1.20, 95% CI -1.91 to -0.49, P = 0.0009) and increase fasting C-peptide levels (MD = 0.25, 95% CI 0.04 to 0.45, P = 0.02) and AUCC (SMD = 0.66, 95% CI 0.13 to 1.18, P = 0.01). Stem cell therapy could also reduce insulin dosages (SMD = -2.65, 95% CI -4.86 to -0.45, P = 0.02) at 6 months after treatment. NRCCTs also had consistent results. Furthermore, RCTs showed stem cell therapy did not increase relative risk of gastrointestinal symptom (RR = 0.69, 95% CI 0.14 to 3.28, P = 0.64) and infection (RR = 0.97, 95% CI 0.40 to 2.34, P = 0.95). However, NRCCTs showed stem cell therapy increased relative risk of gastrointestinal symptom (RR = 44.49, 95% CI 9.20 to 215.18, P < 0.00001)., Conclusion: Stem cell therapy for T1DM may improve glycemic control and β cell function without increasing the risk of serious adverse events. Stem cell therapy may also have a short-term (3-6 months) effect on reducing insulin dosages., Competing Interests: The authors declare that there is no conflict of interest regarding the publication of this paper., (Copyright © 2020 Shi-Yi Sun et al.)

Clozapine (CLZ), an antipsychotic with a unique mechanism of action, is known to be superior to any other antipsychotic for schizophrenia. However, CLZ is also known to be associated with the development of lethal side effects, which include agranulocytosis and glucose intolerance (GI). Regular measurement and registration of blood test results have been mandatory for all CLZ users; however, these risks may still prevent therapists from prescribing CLZ. While CLZ-induced agranulocytosis has been well documented, CLZ-induced GI in the real world has not been fully investigated. Therefore, in this study, we used data registered in monitoring systems to investigate background factors associated with new-onset GI after CLZ administration and changes in HbA1c levels during CLZ treatment. Data of all patients with schizophrenia who were using CLZ from July 29, 2009 to January 20, 2016 were used for the analysis. Of the 3,746 patients enrolled in the study, 92 (2.5%) had GI at baseline; of the remaining 3,654 patients, 428 (11.7%) developed new-onset GI. Multivariate logistic regression analysis revealed that the development of new-onset GI was significantly associated with older age, higher baseline HbA1c levels, and longer treatment duration. In patients with GI at baseline, HbA1c levels were maintained or improved over 18 months, while in the other patients, CLZ administration gradually elevated HbA1c levels. The findings of this study suggest that, although adequate monitoring and intervention is required, CLZ induction and maintenance therapy may be safe, even for patients with impaired glucose tolerance.

Type 2 diabetes is a leading cause of morbidity and a common risk of several disorders. Identifying the microbial ecology changes is essential for disease prediction, therapy, and prevention. Thus, our study is aimed at investigating the intestinal microbiota among healthy and type 2 diabetes individuals and exploring the effect of antidiabetic agents on gut bacterial flora. 24 type 2 diabetes (metformin, glimepiride, and nontherapeutic subgroups; N = 8) and 24 healthy control subjects were enrolled in this study, and intestinal bacterial microbiota was investigated by analyzing V3-V4 regions of 16S rRNA gene sequence. Numerous alterations were observed in the gut microbial community of diabetic individuals. These changes were characterized by a significant lowered abundance of Faecalibacterium , Fusobacterium , Dialister , and Elusimicrobium in the nontherapeutic subgroup compared to the healthy control group. Likewise, correlation analysis showed a substantial decline in gut microbiota richness and diversity with the duration of illness. Furthermore, antidiabetic agents restored to some extent the richness and diversity of gut microbiota and improved the abundance of many beneficial bacteria with a significant increase of Methanobrevibacter in the metformin subcategory compared to the nontherapeutic subgroup. In return, they decreased the abundance of some opportunistic pathogens. The findings of this study have added a novel understanding about the pathogenesis of the disease and the mechanisms underlying antidiabetic therapy, which are of potential interest for therapeutic lines and further studies., Competing Interests: The authors declare that there are no conflicts of interest regarding the publication of this paper., (Copyright © 2020 Babiker Saad Almugadam et al.)

Meta-analyses of clinical trials typically focus on one outcome at a time. However, treatment decision-making depends on an overall assessment of outcomes balancing benefit in various domains and potential risks. This calls for meta-analysis methods for combined outcomes that encompass information from different domains. When individual patient data (IPD) are available from all studies, combined outcomes can be calculated for each individual and standard meta-analysis methods would apply. However, IPD are usually difficult to obtain. We propose a method to estimate the overall treatment effect for combined outcomes based on first reconstructing pseudo IPD from available summary statistics and then pooling estimates from multiple reconstructed datasets. We focus on combined outcomes constructed from two continuous original outcomes. The reconstruction step requires the specification of the joint distribution of these two original outcomes, including the correlation which is often unknown. For outcomes that are combined in a linear fashion, misspecifications of this correlation affect efficiency, but not consistency, of the resulting treatment effect estimator. For other combined outcomes, an accurate estimate of the correlation is necessary to ensure the consistency of treatment effect estimates. To this end, we propose several ways to estimate this correlation under different data availability scenarios. We evaluate the performance of the proposed methods through simulation studies and apply these to two examples: (a) a meta-analysis of dipeptidyl peptidase-4 inhibitors vs control on treating type 2 diabetes; and (b) a meta-analysis of positive airway pressure therapy vs control on lowering blood pressure among patients with obstructive sleep apnea., (© 2020 John Wiley & Sons, Ltd.)

The objective of the present study was to develop a population pharmacodynamic (PPD) model to describe the glycated hemoglobin (HbA1c)-lowering effects of metformin in type 2 diabetes mellitus patients with and without secondary failure and to characterize changes in HbA1c levels in the two subpopulations using a mixture model. Information on patients was collected retrospectively from electronic medical records. In this study, the mixture model was used to characterize the bimodal effects of metformin. A PPD analysis was performed using NONMEM 7.3.0. A physiological indirect response model, based on 829 HbA1c levels of 69 patients, described the time course for the HbA1c-lowering effects of metformin. Evidence for the different effectiveness of metformin subpopulations was provided using the mixture model. In the final PPD model, the inhibition effect was constant over a study duration in a patient subpopulation without secondary failure. In contrast, the inhibition effect decreased as a function of time after start of metformin treatment in a subpopulation with secondary failure. These results indicated that HbA1c improvements appeared to deteriorate over time in patients with secondary failure. In a PPD analysis of metformin, it was possible to assign patients with secondary failure using the mixture model., (Copyright © 2018 The Japanese Society for the Study of Xenobiotics. Published by Elsevier Ltd. All rights reserved.)

Abelmoschus esculentus (AE), a commonly consumed vegetable, is well-known for its anti-hyperglycemic effects. However, few scientific reports have identified its targets because mucilage increases the difficulty of manipulation. We recently reported extraction steps to obtain subfractions of AE, which were found to attenuate the adverse effects of high glucose and fatty acid in vitro. In this study, we used modified extraction steps and type 2 diabetic rats to explore whether AE subfractions can improve the metabolic disturbances caused by insulin resistance in vivo. AE subfractions (F1, F2, and FR) were prepared. The type 2 diabetes model was induced by feeding male Sprague-Dawley rats with a high-fat diet and injecting them with 35 mg/kgbw streptozotocin when their body weight reached 475 ± 15 g. After a hyperglycemic status had been confirmed, the rats were tube-fed with or without different doses of AE subfractions. Serum glucose, lipid markers, insulin, HbA1c and HOMA-IR were measured in the following 12 weeks. Serum glucose promptly increased and insulin resistance was noted in the diabetic rats (glucose: 360-500 mg/dl, HOMA-IR 9.8-13.8). F2, rich in polysaccharides and carbohydrates, was most effective in attenuating hyperglycemia and insulin resistance (glucose: 200 mg/dl; HOMA-IR: 5.3) and especially HbA1C (from 8.0% to 6.5%). All of the AE subfractions lowered the level of triglycerides and free fatty acid, but not the level of total cholesterol. FR significantly increased the high-density lipoprotein/low-density lipoprotein ratio, indicating its benefits for lipoprotein profiles. While F2 and FR were associated with weight gain, F1 possessed an anti-obese effect. In conclusion, whether it is consumed as a vegetable or as a nutraceutical, AE has the potential to be an adjuvant therapy for diabetes. AE subfractions could be developed individually and deserve further investigation.

Background: Although HbA1c is commonly used for assessing glycemic control before surgery, there is no consensus regarding its role and the appropriate threshold in predicting adverse outcomes. This study was designed to evaluate the potential link between HbA1c and subsequent periprosthetic joint infection (PJI), with the intention of determining the optimal threshold for HbA1c., Methods: This is a multicenter retrospective study, which identified 1645 diabetic patients who underwent primary total joint arthroplasty (1004 knees and 641 hips) between 2001 and 2015. All patients had an HbA1c measured within 3 months of surgery. The primary outcome of interest was a PJI at 1 year based on the Musculoskeletal Infection Society criteria. Secondary outcomes included orthopedic (wound and mechanical complications) and nonorthopedic complications (sepsis, thromboembolism, genitourinary, and cardiovascular complications). A regression analysis was performed to determine the independent influence of HbA1c for predicting PJI., Results: Overall 22 cases of PJI occurred at 1 year (1.3%). HbA1c at a threshold of 7.7 was distinct for predicting PJI (area under the curve, 0.65; 95% confidence interval, 0.51-0.78). Using this threshold, PJI rates increased from 0.8% (11 of 1441) to 5.4% (11 of 204). In the stepwise logistic regression analysis, PJI remained the only variable associated with higher HbA1c (odds ratio, 1.5; confidence interval, 1.2-2.0; P = .0001). There was no association between high HbA1c levels and other complications assessed., Conclusion: High HbA1c levels are associated with an increased risk for PJI. A threshold of 7.7% seems to be more indicative of infection than the commonly used 7% and should perhaps be the goal in preoperative patient optimization., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Context: A previous genome-wide association study showed that a genetic variant of sortilin was associated with the risk of coronary artery disease (CAD). However, the role of circulating sortilin is still unknown. We investigated the potential role of plasma sortilin as a biomarker for CAD and diabetes mellitus., Methods: We enrolled statin-naïve subjects with CAD (n = 31) who underwent coronary artery bypass surgery and control subjects (n = 116) who were free from CAD as evaluated by coronary CT angiography. The presence of diabetes mellitus was evaluated and plasma sortilin levels were measured with a commercial ELISA kit., Results: Plasma sortilin levels were higher in subjects with CAD and subjects with diabetes mellitus than in those without CAD or diabetes mellitus. Subjects in the highest sortilin tertile group were older and had higher glucose and HbA1c levels, but lipid profiles in the three tertile groups were comparable. Multivariable logistic regression analysis revealed that sortilin levels were independently associated with CAD. In addition, the receiver operating characteristic curve analysis showed that plasma sortilin levels could identify the presence of CAD or diabetes mellitus., Conclusions: Elevated circulating sortilin levels are associated with CAD and diabetes mellitus and can be used as a biomarker of both diseases in statin-naïve subjects.

Accumulating evidence has shown that epigenetic regulation is involved in hypertension and aging. L-type voltage-gated Ca 2+ channels (LTCCs), the dominant channels in vascular myocytes, greatly contribute to arteriole contraction and blood pressure (BP) control. We investigated the dynamic changes and epigenetic regulation of LTCC in the mesenteric arteries of aging hypertensive rats. LTCC function was evaluated by using microvascular rings and whole-cell patch-clamp in the mesenteric arteries of male Wistar-Kyoto rats and spontaneously hypertensive rats at established hypertension (3 month old) and an aging stage (16 month old), respectively. The expression of the LTCC α1C subunit was determined in the rat mesenteric microcirculation. The expression of miR-328, which targets α1C mRNA, and the DNA methylation status at the promoter region of the α1C gene (CACNA1C) were also determined. In vitro experiments were performed to assess α1C expression after transfection of the miR-328 mimic into cultured vascular smooth muscle cells (VSMCs). The results showed that hypertension superimposed with aging aggravated BP and vascular remodeling. Both LTCC function and expression were significantly increased in hypertensive arteries and downregulated with aging. miR-328 expression was inhibited in hypertension, but increased with aging. There was no significant difference in the mean DNA methylation of CACNA1C among groups, whereas methylation was enhanced in the hypertensive group at specific sites on a CpG island located upstream of the gene promoter. Overexpression of miR-328 inhibited the α1C level of cultured VSMCs within 48 h. The results of the present study indicate that the dysfunction of LTCCs may exert an epigenetic influence at both pre- and post-transcriptional levels during hypertension pathogenesis and aging progression. miR-328 negatively regulated LTCC expression in both aging and hypertension.

The therapeutic utility of exenatide (Ex-4) is limited due to short plasma half-life of 2.4h and thus numerous approaches have been used to obtain a longer action time. However, such strategies often attend to one thing and lose another. The study aimed to identify a candidate with balanced glucoregulatory activity and prolonged in vivo activity. A series of fatty chain conjugates of Ex-4 were designed and synthesized. First, thirteen cysteine modified peptides (1-13) were prepared. Peptides 1, 10, and 13 showed improved glucagon-like peptide-1 (GLP-1) receptor activate potency and were thus selected for second step modifications to yield conjugates I-1-I-9. All conjugates retained significant GLP-1 receptor activate potency and more importantly exerted enhanced albumin-binding properties and in vitro plasma stability. The protracted antidiabetic effects of the most stable I-3 were further confirmed by both multiple intraperitoneal glucose tolerance test and hypoglycemic efficacies test in vivo. Furthermore, once daily injection of I-3 to streptozotocin (STZ) induced diabetic mice achieved long-term beneficial effects on hemoglobin A1C (HbA1C) lowering and glucose tolerance. Once daily injection of I-3 to diet induced obesity (DIO) mice also achieved favorable effects on food intake, body weight, and blood chemistry. Our results suggested that I-3 was a promising agent deserving further investigation to treat obesity patients with diabetes., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Elderly patients with type 2 diabetes are at a greater risk for cognitive decline. The purpose of this study was to assess the relationship between the degree of hyperglycemia and cognitive status in nondemented, elderly diabetics. Between Jan 2013 and Dec 2014, 1174 geriatric patients with type 2 diabetes were enrolled in the study (579 males; age ≥ 60 years; from Fuzhou, Fujian, China). Cognitive function was measured with the Mini Mental State Examination (MMSE) and Montreal Cognitive Assessment (MoCA). A statistically significant, age-adjusted association was observed between the A1C levels and the scores on two cognitive tests (MMSE and MoCA). Specifically, a 1% higher A1C value was associated with a 0.21-point lower MMSE score (95% CI; compare -0.11 to -0.28; P < 0.0001), as well as a 0.11-point lower MoCA score (95% CI; compare -0.10 to -0.38; P < 0.0001). Higher A1C levels were not significantly associated with lower MMSE and MoCA test scores after adjusting for all variables. No significant correlation was found between the two variables in patients older than 80 years of age (n = 215; OR = 1.019; 95% CI = 0.968 - 1.099; p = 0.251). Evidence strongly suggests that chronic hyperglycemia is associated with a decline in cognitive function in nondemented elderly patients with type 2 diabetes. When cognitive assessments are made, comprehensive factors such as advanced age, education level, duration of diabetes, hypertension and other vascular risks should be taken into account. For older geriatric patients (age ≥ 80 years), there is no significant correlation between A1c levels and cognitive function.

Introduction: Hemoglobin A1C (HbA1c) reflects patient's glycemic status over the previous 3 months. Previous studies have reported that iron deficiency may elevate A1C concentrations, independent of glycemia. This study is aimed to analyze the effect of iron deficiency anemia on HbA1c levels in diabetic population having plasma glucose levels in control., Methods: Totally, 120 diabetic, iron-deficient anemic individuals (70 females and 50 males) having controlled plasma glucose levels with same number of iron-sufficient non-anemic individuals were streamlined for the study. Their data of HbA1c (Bio-Rad D-10 HPLC analyzer), ferritin (cobas e411 ECLIA hormone analyzer), fasting plasma glucose (FPG, Roche Hitachi P800/917 chemistry analyzer), hemoglobin (Beckman Coulter LH780), peripheral smear examination, red cell indices, and medical history were recorded. Statistical analysis was carried out by student's t-test, Chi-square test, and Pearson's coefficient of regression., Results: We found elevated HbA1c (6.8 ± 1.4%) in iron-deficient individuals as compared to controls, and elevation was more in women (7.02 ± 1.58%). On further classification on the basis of FPG levels, A1C was elevated more in group having fasting glucose levels between 100-126 mg/dl (7.33 ± 1.55%) compared to the those with normal plasma glucose levels (<100 mg/dl). No significant correlation was found between HbA1c and ferritin and hemoglobin., Conclusion: This study found a positive correlation between iron deficiency anemia and increased A1C levels, especially in the controlled diabetic women and individuals having FPG between 100-126 mg/dl. Hence, before altering the treatment regimen for diabetic patient, presence of iron deficiency anemia should be considered.

Patients with hyperglycemia, an acute coronary syndrome and poor glycemic control have increased platelet reactivity and poor prognosis. However, it is unclear the influence of a tight glycemic control on platelet reactivity in these patients. This is a subanalysis of the CHIPS study. This trial randomized patients with hyperglycemia to undergo an intensive glucose control (target blood glucose 80-120 mg/dL), or conventional glucose control (target blood glucose <180 mg/dL). We analyzed platelet function at discharge on the subgroup of patients with poor glycemic control, defined with admission levels of HbA1c higher than 6.5%. The primary endpoint was maximal platelet aggregation following stimuli with 20 μM ADP. We also measured aggregation following collagen, epinephrine, and thrombin receptor-activated peptide, as well as P2Y12 reactivity index and surface expression of glycoprotein IIb/IIIa and P-selectin. A total of 67 patients presented HbA1c ≥ 6.5% (37 intensive, 30 conventional), while 42 had HbA1c < 6.5% (20 intensive, 22 conventional). There were no differences in baseline characteristics between groups. At discharge, patients with HbA1c ≥6.5% had significantly reduced MPA with intensive glucose control compared with conventional control (46.1 ± 22.3 vs. 60.4 ± 20.0%; p = 0.004). Similar findings were shown with other measures of platelet function. However, glucose control strategy did not affect platelet function parameters in patients with HbA1c < 6.5%. Intensive glucose control in patients presenting with an acute coronary syndrome and hyperglycemia results in a reduction of platelet reactivity only in the presence of elevated HbA1c levels.

Non-enzymatic glycation is a complex series of reactions between reducing sugars and amino groups of proteins. Accumulation of AGEs (advanced glycation end-products) due to non-enzymatic glycation has been related to several diseases associated with aging and diabetes. The formation of AGEs is accelerated in hyperglycaemic conditions, which alters the structure and function of long-lived proteins, thereby contributing to long-term diabetic complications. The present study describes AGE inhibition and the mechanism of action of a new antiglycating agent, EA (ellagic acid), a flavonoid present in many dietary sources. Inhibition of AGE formation by EA was demonstrated with different proteins, namely eye lens TSP (total soluble protein), Hb (haemoglobin), lysozyme and BSA, using different glycating agents such as fructose, ribose and methylglyoxal by a set of complementary methods. These results suggest that the antiglycating action of EA seems to involve, apart from inhibition of a few fluorescent AGEs, predominantly inhibition of CEL [Nϵ-(carboxyethyl)lysine] through scavenging of the dicarbonyl compounds. Furthermore, MALDI-TOF-MS (matrix-assisted laser-desorption ionisation-time-of-flight MS) analysis confirms inhibition of the formation of CEL on lysozyme on in vitro glycation by EA. Prevention of glycation-mediated β-sheet formation in Hb and lysozyme by EA confirm its antiglycating ability. Inhibition of glycosylated Hb formation in human blood under ex vivo high-glucose conditions signifies the physiological antiglycating potential of EA. We have also determined the effectiveness of EA against loss of eye lens transparency through inhibition of AGEs in the lens organ culture system. These findings establish the antiglycating potential of EA and its in vivo utility in controlling AGE-mediated diabetic pathologies.

Aims/hypothesis: The primary aim of this completed multicentre randomised, parallel, double-blind placebo-controlled study was to elucidate the mechanisms of glucose-lowering with colesevelam and secondarily to investigate its effects on lipid metabolism (hepatic de novo lipogenesis, cholesterol and bile acid synthesis)., Methods: Participants with type 2 diabetes (HbA(1c) 6.7-10.0% [50-86 mmol/mol], fasting glucose <16.7 mmol/l, fasting triacylglycerols <3.9 mmol/l and LDL-cholesterol >1.55 mmol/l) treated with diet and exercise, sulfonylurea, metformin or a combination thereof, were randomised by a central coordinator to either 3.75 g/day colesevelam (n = 30) or placebo (n = 30) for 12 weeks at three clinical sites in the USA. The primary measure was the change from baseline in glucose kinetics with colesevelam compared to placebo treatment. Fasting and postprandial glucose, lipid and bile acid pathways were measured at baseline and post-treatment using stable isotope techniques. Plasma glucose, insulin, total glucagon-like peptide-1 (GLP-1), total glucose-dependent insulinotropic polypeptide (GIP), glucagon and fibroblast growth factor-19 (FGF-19) concentrations were measured during the fasting state and following a meal tolerance test. Data was collected by people blinded to treatment., Results: Compared with placebo, colesevelam improved HbA(1c) (mean change from baseline of 0.3 [SD 1.1]% for placebo [n = 28] and -0.3 [1.1]% for colesevelam [n = 26]), glucose concentrations, fasting plasma glucose clearance and glycolytic disposal of oral glucose. Colesevelam did not affect gluconeogenesis or appearance rate (absorption) of oral glucose. Fasting endogenous glucose production and glycogenolysis significantly increased with placebo but were unchanged with colesevelam (treatment effect did not reach statistical significance). Compared with placebo, colesevelam increased total GLP-1 and GIP concentrations and improved HOMA-beta cell function while insulin, glucagon and HOMA-insulin resistance were unchanged. Colesevelam increased cholesterol and bile acid synthesis and decreased FGF-19 concentrations. However, no effect was seen on fractional hepatic de novo lipogenesis., Conclusions/interpretation: Colesevelam, a non-absorbed bile acid sequestrant, increased circulating incretins and improved tissue glucose metabolism in both the fasting and postprandial states in a manner different from other approved oral agents., Trial Registration: ClinicalTrials.gov NCT00596427, Funding: The study was funded by Daiichi Sankyo.

Type 2 diabetes is a chronic, debilitating and often deadly disease that has reached epidemic proportions. The onset of diabetes can be delayed or prevented in high-risk individuals by diet and lifestyle changes and medications, and hence a key element for addressing the diabetes epidemic is to identify those most at risk of developing diabetes so that preventative measures can be effectively focused. The PreDx(®) Diabetes Risk Score is a multimarker tool for assessing a patient's risk of developing diabetes within the next 5 years. Requiring a simple blood draw using standard sample collection and handling procedures, the PreDx Diabetes Risk Score is easily implemented in clinical practice and provides an assessment of diabetes risk that is superior to other measures, including fasting plasma glucose, glycated hemoglobin, measures of insulin resistance and other clinical measures. In this article, we provide an overview of the PreDx Diabetes Risk Score.

Lower-extremity wounds are a major complication of diabetes. Hemoglobin A1c (HbA1c) reflects glycemia over 2-3 months and is the standard measure used to monitor glycemia in diabetic patients, but results from studies have not shown a consistent association of HbA1c with wound healing. We hypothesized that elevated HbA1c would be most associated with poor wound healing. To test this hypothesis, we conducted a retrospective cohort study of 183 diabetic individuals treated at the Johns Hopkins Wound Center. Our primary outcome was wound-area healing rate (cm(2) per day). Calibrated tracings of digital images were used to measure wound area. We estimated coefficients for healing rate using a multiple linear regression model controlling for clustering of wounds within individuals and other common clinic variables. The study population was 45% female and 41% African American, with a mean age of 61 years. Mean HbA1c was 8.0%, and there were 2.3 wounds per individual (310 wounds total). Of all measures assessed, only HbA1c was significantly associated with wound-area healing rate. In particular, for each 1.0% point increase in HbA1c, the daily wound-area healing rate decreased by 0.028 cm(2) per day (95% confidence interval: 0.003, 0.0054, P = 0.027). Our results suggest that glycemia, as assessed by HbA1c, may be an important biomarker in predicting wound-healing rate in diabetic patients.JID JOURNAL CLUB ARTICLE: For questions, answers, and open discussion about this article, please go to http://www.nature.com/jid/journalclub.

Objective: Abdominal aortic aneurysm (AAA) is a life-threatening disease as rupture of the aneurysm is associated with high mortality. The likelihood that an AAA will rupture is particularly influenced by the diameter of the aneurysm and the rate of expansion; the reasons for fast expansion are largely unknown. Applanation tonometry (APT) can predict outcome in certain cardiovascular diseases by measuring arterial stiffness (augmentation index, AIx) and central aortic blood pressure (CABP). We tested the hypothesis that AIx and CABP would be higher in patients with fast-progressing AAA., Methods: We performed APT and peripheral blood pressure measurements in 114 patients with AAA (11 women) with a mean ± SD age of 67.4±6.1 years. Annual AAA progression rate was determined by ultrasound. Patients were grouped into fast progressors (progression ≥2 mm/year) and slow progressors (progression <2 mm/year)., Results: Mean follow-up time after inclusion into the AAA surveillance programme was 22.1 ± 16.3 months. AIx was similar in fast progressors (27.3 ± 13.0%) and slow progressors (26.5 ± 12.6%) (P = 0.73). Fast progressors had a significantly higher CABP during systole (116.0 ± 16.0 mmHg) and diastole (95.7 ± 12.6 mmHg) than slow progressors (109.5 ± 16.3 and 90.0 ± 13.2 mmHg) (P = 0.04 and P = 0.02, respectively). Mean peripheral blood pressure was significantly higher in fast progressors (102.7 ± 12.8 mmHg) than in slow progressors (97.7 ± 12.9 mmHg) (P = 0.04)., Conclusion: Augmentation index did not differ in patients with fast and slow-progressing AAA. However, fast progressors had higher central aortic blood pressures suggesting that elevated aortic blood pressure is a risk factor for faster AAA progression, but this needs to be proven in controlled interventional studies.

Background: Proprotein convertase subtilisin kexin type 9 (PCSK9) is a secreted proprotein convertase acting as a natural inhibitor of the low-density lipoprotein (LDL) receptor. Here, we prospectively investigated the relationship between the circulating levels of PCSK9 and metabolic parameters in 117 diabetic patients., Results: Plasma PCSK9 level was significantly higher in type 2 than in type 1 diabetes (P=0.04), in diabetic patients under statins (P<10(-4)) and in those with macrovascular complications (P=0.002). Univariable regression analysis revealed that plasma PCSK9 level correlated positively with age (P=0.003), body mass index (P=0.04), systolic blood pressure (SBP) (P=0.01), gamma-glutamyl transferase (GGT) levels (P=0.0002) and statin treatment (P=0.001). In a multivariable linear regression analysis, PCSK9 correlated positively with GGT level (beta=21.91, P=0.0019) after adjustment for gender, age, type of diabetes, statin treatment, BMI, SBP and HbA1c., Conclusion: PCSK9 level was independently associated with GGT level in diabetic patients, suggesting potential interaction between PCSK9 and liver function., (Copyright 2010 Elsevier Ireland Ltd. All rights reserved.)

Objectives: To assess the efficacy and safety of rosiglitazone on saphenous vein graft (SVG) atherosclerosis prevention and on modification of the global cardiometabolic risk profile., Methods and Results: This was a double-blind, randomized, placebo-controlled, multicenter trial which enrolled 193 post-CABG patients with type 2 diabetes. Atherosclerosis changes in one SVG were assessed with intravascular ultrasound at baseline and at 12 months. Serial cardiometabolic assessments were performed. At baseline, both groups had mean HbA(1C)<7%, LDL-cholesterol (LDL-C)<2.3 mmol/l, HDL-cholesterol (HDL-C)>1.0 mmol/l and blood pressure<130/75 mmHg. After 12 months, plaque volume in SVG had increased (median [interquartile range]) by 7.7 mm(3) (-17.2 to 37.9) in the placebo group and decreased by 0.3mm(3) (-19.1 to 22.3) in the rosiglitazone group (P=0.22). Compared to placebo, rosiglitazone treated patients had a higher (mean + or - SD) body weight (89 + or - 15 kg vs. 84 + or - 15 kg, P=0.02) at the end of the study, mostly related to an increment in subcutaneous adipose tissue. Rosiglitazone treated patients also displayed further improvements in glycemic control compared to placebo (HbA(1C): 6.4 + or - 0.7% vs. 7.0 + or - 0.9%, P<0.001) as well as in several cardiometabolic parameters such as lipids (HDL-C: 1.16 + or - 0.28 mmol/l vs. 1.06 + or - 0.23 mmol/l, P=0.003), inflammatory profile (C-reactive protein: 0.92 mg/l [0.51-1.56] vs. 1.37 mg/l [0.79-3.08], P=0.02), and adiponectin levels (11.1 microg/ml [8.19-17.9] vs. 4.65 microg/ml [3.27-7.15], P<0.001). There was no significant difference in the incidence of serious adverse cardiovascular events. However, more patients in the rosiglitazone group had peripheral oedema (33% vs. 18%, P=0.0019)., Conclusion: After a 12-month follow-up, we found no evidence for a statistically significant effect of rosiglitazone on SVG atherosclerosis whereas significant effects on glycemic control and on the cardiometabolic risk profile appeared to be modulated in part by changes in subcutaneous adiposity., (Copyright 2010 Elsevier Ireland Ltd. All rights reserved.)

Background: Relative to hemoglobin A(1c) (HbA(1c)), glycated albumin (GA) more accurately reflects recent glycemic control in diabetic patients on hemodialysis and peritoneal dialysis. These assays have yet to be compared in patients with advanced chronic kidney disease (CKD)., Methods: HbA(1c) and GA were simultaneously measured in 303 diabetic subjects: 70 with CKD prior to dialysis (CKD-stage 4), 184 with CKD after transplantation (TXP-stage 3) and 49 non-nephropathy controls., Results: Mean estimated GFR was 76, 46 and 26 ml/min in controls, TXP-3 and CKD-4 cases, respectively. Mean (SD) HbA(1c) (%) and GA (%) concentrations were 7.30 (1.40) and 16.8 (4.9) in controls, 7.28 (1.66) and 21.5 (6.4) in CKD-4 cases, and 7.21 (1.62) and 21.2 (5.5) in TXP-3 cases, respectively. The GA:HbA(1c) ratio differed significantly between non-nephropathy controls and both groups of CKD patients (both p < 0.001), but not between CKD-4 and TXP-3 cases (p = 0.92). The glucose:HbA(1c) ratio was inversely associated with GFR in all 254 nephropathy cases (r = -0.13; p = 0.04), while glucose:GA did not vary significantly based upon GFR (r = -0.08; p = 0.24)., Conclusions: The relationship between glycated albumin and HbA(1c) is influenced by the presence of reduced GFR in diabetic patients with CKD. The accuracy of the HbA(1c) assay in diabetic subjects with severe nephropathy requires further investigation, although HbA(1c) performs relatively well with milder CKD., (2010 S. Karger AG, Basel.)

Clinical islet transplantation is limited by the availability of donor organs. We report two cases where islets were isolated from donors with elevated HbA1c (6.3% and 7.9%). Islet isolation yield was adequate in both cases (521,350 and 497,472 islet equivalents, respectively). Islet graft analyses revealed a decreased proportion of beta cells (21.6%) and an increase in alpha cells (51.0%) in the donor with the higher HbA1c, although graft characteristics of the other donor were similar to donors with normal HbA1c. Both islet preparations were transplanted into type 1 diabetes recipients with brittle diabetes. One recipient has remained insulin independent for 4 years to date with good glycemic control. The other recipient who received islets from the donor with the higher HbA1c had a 56% reduction in insulin requirement after transplant. Pancreases from donors with mild hyperglycemia may be a source of islets that could be considered for clinical islet transplantation.

We report 2 African-American boys with type 1 diabetes and hereditary persistence of hemoglobin F. The diagnosis came to light after both patients exhibited inconsistent hemoglobin A(1C) (HbA(1C)) levels with respect to serum glucose measurements. This demonstrates the importance of frequent glucose monitoring and interpreting the HbA(1C) level in light of serum glucose measurements.

Glycation and oxidative stress are two important processes known to play a key role in complications of many pathophysiological processes. The two traditional factors found to modulate the early glycation of proteins are the prevailing concentration of glucose and half life of the protein. But evidences in the literature have documented an increased glycated protein levels in some non-diabetic pathological states. So it stands to reason that hyperglycemia, while clearly the culprit in diabetes, is not the complete answer to the etiology of increased early glycated products in non-diabetic conditions. A common denominator in all these above mentioned non-diabetic pathological conditions is oxidative stress. Collective evidences from the literature reveal that malondialdehyde, reduced glutathione, vitamin C, vitamin E and drugs with antioxidant properties mitigate the process of protein glycation. Taking all the above factors into account, we hypothesis that oxidative stress either via increasing reactive oxygen species or by depleting the antioxidants may modulate the genesis of early glycated proteins in vivo.

Background: The auto-immune response leading to type 1 diabetes (T1D) is closely associated with the overproduction of T helper-1 (Th1) cytokines which activate macrophage production of inflammatory mediators such as interleukin (IL)-1beta. The principal aim of this study was to elucidate whether IL-1beta is associated with the development of the inflammatory state of disease and the altered circulating lipid levels in T1D., Material/methods: Sixty-nine T1D and 74 age-matched non-diabetic (ND) subjects were recruited from the outpatient department of Internal Medicine, University Medical Center, Tlemcen, Algeria., Results: The levels of IL-1beta, CRP, HbA1c, CHOL, and LDLc, but not of HDLc, were significantly higher in all T1D subjects than in the ND controls. IL-1beta and CRP were found to be associated with T1D (OR>1). Newly diagnosed T1D subjects exhibited significantly higher IL-1beta, but not CRP, concentrations than controls and long-standing diabetic subjects. TG and HbA1c levels were not statistically different in the two diabetic populations. However, CHOL and LDLc concentrations were significantly higher in long-standing patients than in newly diagnosed ones. HDLc fractions were lower in long-standing patients than in controls and newly diagnosed diabetic subjects. Furthermore, the plasmatic concentrations of IL-1beta, but not of CRP, negatively correlated with CHOL, LDLc, or TG levels and positively with those of CRP in T1D patients., Conclusions: IL-1beta seems to be associated with the type 1 diabetes inflammatory process. Moreover, a reciprocal relationship exists between newly diagnosed and long-standing T1D patients as far as the levels of this cytokine and circulating lipids are concerned.

Objective: Abnormal values of the transient ischemic dilation ratio (TID) according to an exercise myocardial SPECT are linked to severe coronary artery disease. The authors investigated the relationship between TID and the levels of VCAM, ICAM, E-selectin, microalbuminuria, intima-media thickness and HbA(1c) of diabetic subjects., Methods: We observed 38 subjects with diabetes type 2 (10 women, 28 men), of average age 56.08 +/- 8.24 years, with no past history of cardiovascular disease. All subjects were examined using an exercise myocardial SPECT. Transient ischemic dilation, summed stress score (SSS), summed rest score (SRS) and stress total severity score (STSS) were determined to quantify myocardial ischemia., Results: The average IMT value was 1.05 +/- 0.31 mm. The TID value was 1.02 +/- 0.154, VCAM 795.24 +/- 163.25 mg/l, ICAM 516.55 +/- 164.07, E-selectin 63.82 +/- 38.89, HbA(1c) 7.09 +/- 1.68%, microalbuminuria 68.01 +/- 55.21 mg/l. When ascertaining the relation of TID to the other factors we used Pearson's correlation at the level of significance p < 0.05. We proved a statistically significant correlation between the value of TID and glycosylated hemoglobin HbA(1c) (p = 0.035); the other factors did not show any significant correlation., Conclusion: Diabetes and its long- term unsatisfactory compensation can be one of the factors which affect left ventricular transient ischemic dilation.

Objective: Oxidative stress is increased in type 1 diabetes families. Since oxidative damage is a mediator of vascular injury and familial predisposition to hypertension increases the risk of hypertension and diabetic nephropathy, we studied blood pressure responses to exercise and cardiovascular risk factors in type 1 diabetes families., Methods: Thirty-five type 1 patients, 74 first-degree relatives, and 95 healthy individuals without established coronary heart disease underwent a cycle ergometer test. Examination included medical history, lifestyle questionnaire, body weight, blood pressure, and laboratory tests [fasting plasma glucose and insulin, haemoglobin A1c (HbA1c), plasma lipids, C-reactive protein, fibrinogen, folate, plasma thiols, and albumin excretion rate]., Results: Diabetic patients had higher plasma glucose, HbA1c, folate, and albuminuria, while lower plasma thiols than controls; relatives differed from controls in higher plasma total cholesterol and albuminuria, lower plasma thiols. No patient presented exercised-induced angina. Diabetic patients achieved a higher maximal exercise systolic blood pressure (similar workload); systolic pressure remained high during recovery. Relatives showed higher values of systolic pressure at peak exercise (same workload). The following were associated with an abnormal blood pressure response to exercise: diastolic blood pressure and HbA1c in the control sample; disease duration and fibrinogen in the diabetic group; plasma low-density lipoprotein (LDL) cholesterol, body mass index (BMI), housework, and plasma thiols among relatives., Conclusion: An abnormal blood pressure response to exercise testing has been identified for the first time in asymptomatic normotensive non-diabetic relatives of type 1 diabetics, which was associated with indices of metabolic syndrome and oxidative damage. Moreover, in healthy normotensive non-diabetic control individuals (without a family history of type 1 diabetes), the systolic blood pressure response to exercise was significantly correlated with HbA1c levels.

Background and Purpose: Hyperglycemia (HG) has a deleterious effect in stroke patients by accelerating ischemic brain damage; moreover, its antifibrinolytic effect may also influence reperfusion. We aimed to study the effect of acute/chronic HG on tissue-type plasminogen activator (tPA)-induced recanalization., Methods: We studied 139 consecutive stroke patients with documented intracranial artery occlusion treated with intravenous tissue-type plasminogen activator (tPA). Admission glucose levels were recorded (in mg/dL). The existence of previous chronic HG was determined by plasma levels of glycosylated hemoglobin (HbA1c, %) and fructosamine (in micromol/L). Transcranial Doppler monitoring assessed complete recanalization 2 hours after tPA bolus. National Institutes of Health Stroke Scale (NIHSS) scores were obtained at baseline and 48 hours., Results: On admission, the median NIHSS score was 18 and mean glucose value was 140+/-63 mg/dL. At 2 hours, 32% of patients(n=44) achieved complete recanalization. Patients who recanalized showed lower admission glucose levels (127 vs 146 mg/dL; P=0.039) but no differences in HbA1c (6.3% vs 6.3%; P=0.896) or fructosamine (292 vs 293 micromol/L; P=0.957) were observed. Other variables associated with recanalization were initial distal middle cerebral artery occlusion (P=0.011) and platelet count (P=0.015). Patients with an admission glucose level >158 mg/dL had lower recanalization rates (16% vs 36.1%; P=0.035) and a higher NIHSS score at 48 hours (7 vs 14.5; P=0.04). After adjustment for stroke etiology, age, and risk factors, the only independent predictors on admission of no recanalization were glucose value >158 mg/dL (odds ratio [OR], 7.3; 95% confidence interval [CI], 1.3 to 42.3; P=0.027), proximal middle cerebral artery occlusion (OR, 2.6; 95% CI, 1.1 to 6.5; P=0.034), and platelet count <219,000/mL (OR, 2.6; 95% CI, 1.1 to 6.1; P=0.029)., Conclusions: In tPA-treated patients, the acute but not chronic HG state may hamper the fibrinolytic process, delaying reperfusion of the ischemic penumbra. Early measures to reduce HG may favor early recanalization.

The expression of 76 sequences, previously isolated as differentially expressed in visceral white adipose tissue (WAT) of female rats, fed with a high-fat diet for 11 days (Lopez et al., Biochem Biophys Res Comm 318: 234-239, 2004), was analyzed in epidydimal WAT of male rats after a feeding period of 65 days with the same diet, using microarray technology. After Northern blot validation of the results, only three genes appeared upregulated (caveolin-2, the alpha-1 chain of haemoglobin and rat mammary tumor-7) and two downregulated (adiponectin and dystroglycan). We have also analyzed caveolin-1 gene expression and found that follows the opposite pattern of caveolin-2, indicating that they are inversely regulated. Our results suggest that if feeding with a high-fat diet is prolonged, many of the initial changes in gene expression, probably aimed to consume the energy surplus and prevent excessive fat deposition, are not maintained, and adaptation to an increased lipid storage is developed.

Aim: Recent data have suggested that effective control of postprandial blood glucose can reduce the risk of macroangiopathic complications of diabetes, especially cardiovascular risk. 1,5-Anhydro-D-glucitol (1,5-AG) has been proposed as a marker of short-term hyperglycaemic excursions. We aimed to evaluate its usefulness in patients with type 2 diabetes and have attempted to indicate when 1,5-AG monitoring should be used in ordinary diabetes care settings., Methods: The study group consisted of 130 type 2 diabetic patients aged 36-69 years. 1,5-AG plasma level, HbA&#95;1c concentrations and daily glucose profile were measured. Mean blood glucose (MBG), M-value were calculated and maximal daily glycaemia (MxG) was established as indicators of short-term hyperglycaemic episodes., Results: 1,5-AG plasma level was negatively and HbA&#95;1c was positively correlated with fasting glycaemia (FG), MBG, M-value and MxG. Multivariate regression analysis revealed that 1,5-AG plasma level is determined by MxG only, while FG determined HbA&#95;1c concentration in blood. The analysis of 1,5-AG level and HbA&#95;1c distributions in well and poorly controlled patients revealed that persons with low HbA&#95;1c values may have decreased 1,5-AG plasma level., Conclusion: 1,5-AG plasma level monitoring is the useful method to identify well controlled, exclusively based on HbA&#95;1c levels type 2 diabetic patients with transient hyperglycaemia, accordingly patients at high risk of macroangiopathic complications.

The relative inefficiency of the islet purification process may hamper obtaining enough islets for transplantation even with adequate pre-purification counts. In this study, we determined the effect of an additional purification step on total islet yields and pancreas utilization at our center. Twenty-five pancreata were processed using the automated method followed by continuous gradient purification (CGP), and the less pure islet fractions were subjected to additional rescue gradient purification (RGP). CGP and RGP islets were combined and transplanted into patients with type 1 diabetes. CGP and RGP islets showed no significant differences in cell viability, insulin secretion in vitro and function when transplanted into chemically diabetic mice. Mean RGP contribution to the final preparation was 27.9 +/- 19.9%. In 12 of 25 preparations, CGP yielded <5000 IEQ/kg of recipient body weight, and inclusion of RGP islets to the final preparation allowed to obtain the minimal islet number required for transplantation. Transplanted islets resulted in sustained C-peptide production, HbA1(C) normalization and insulin-independence or reduced insulin requirements. Taken together, our data suggest that RGP islets are comparable in terms of viability and potency to CGP islets. RGP may be of assistance in maximizing the number of islet preparations successfully used in transplant protocols.

Objective: To investigate serum concentration of tumor necrosis factor (TNF)-alpha and its correlation with insulin resistance in pregnant women with gestational diabetes mellitus (GDM)., Methods: Enzyme-linked immunosorbent assay was used to measure the fasting serum TNF-alpha levels of 42 women with GDM (28 approximately 39 gestational weeks), and 40 cases of normal pregnant women in the third trimester. Fasting plasma glucose, insulin, C-peptide and glycosylated hemoglobin (HbA1c) were also measured at the same time. Insulin sensitive index (ISI) was calculated., Results: (1) Significantly elevated serum TNF-alpha was found in the women with GDM (5.2 +/- 1.6) ng/L as compared with the healthy pregnant women in third trimester (4.5 +/- 0.5) ng/L (P < 0.01); ISI between the two groups was significantly different, (-4.3 +/- 0.5) and (...3.8 +/- 0.3) (P < 0.01). (2) fasting plasma glucose, insulin, C-peptide, HbA1c in GDM group were (5.5 +/- 0.7) mmol/L, (13.4 +/- 3.8) mU/L, (1.6 +/- 0.4) nmol/L, (5.6 +/- 0.5)%, being significantly higher than those in the normal pregnant women (P < 0.01 or P < 0.05). (3) Significant negative linear correlation was revealed between TNF-alpha and ISI (r = -0.703, P < 0.01), and positive linear correlations between TNF-alpha and plasma glucose, C-peptide, and HbA1c were found (r = 0.512, 0.629, 0.386); but no correlation between TNF-alpha and insulin was found in GDM group. In normal group the correlation between ISI and TNF-alpha was also found (r = -0.390, P < 0.05), but less significant than that in the GDM group., Conclusions: Fasting plasma TNF-alpha levels in pregnant women with GDM is significantly higher than in normal pregnant women. A negative relationship between TNF-alpha and insulin sensitivity index is found in GDM, suggesting increased TNF-alpha may contribute to insulin resistance in pregnant women with gestational diabetes.

Background: Glycated hemoglobin (HbA1C) levels are enhanced by elevated glucose concentrations. Glycation of hemoglobin is also modulated by lipid peroxides, ascorbic acid and reduced glutathione (GSH). We determined the strength of the relationships among these variables in a group of hyperthyroid patients., Methods: Twenty-two untreated hyperthyroid patients and 17 healthy controls were recruited for the study. Whole blood GSH, HbA1C, plasma lipid peroxides, ascorbic acid and fasting glucose were analyzed in both the groups. Direct and partial correlation analysis was performed to explore the possible relationships between these variables., Results: In hyperthyroid patients, HbA1C and lipid peroxides levels were found to be significantly increased than the controls. Ascorbic acid and GSH were decreased significantly in the test group when compared with the healthy control group. With partial correlation analysis, fasting glucose and lipid peroxides were found to have a significant positive correlation with HbA1C. Ascorbic acid and GSH showed no significant association with HbA1C levels., Conclusion: These data suggest that HbA1C levels are closely associated with fasting glucose and lipid peroxides in hyperthyroid patients. Therefore, serum lipid peroxides level should be kept in mind while interpreting HbA1C as a long-term glycemic index in hyperthyroid cases.

Background: In subjects with type 1 diabetes, persisting elevations of fetal hemoglobin (HbF) have been demonstrated. This study evaluated whether HbF levels typically seen in type 1 diabetes (up to 3%) interfere with glycohemoglobin determinations using a common immunologic method (DCA 2000)., Methods: HbA(1c) was measured by high-performance liquid chromatography (HPLC) using a Diamat analyzer in 90 type 1 diabetics with parallel determinations of HbF. Results were compared with HbA(1c) concentrations obtained using DCA 2000., Results: Reproducibility was good for both methods with coefficients of variation <5% and correlation between the two methods was good (r(2)=0.939, p<0.0001). Mean difference between the two methods was small (0.007%). Limits of agreement varied between -0.92% and +0.93% (95% confidence interval [95% CI]) and constant bias (intercept: 0.73 95% CI 0.28-1.18) as well as a proportional bias (slope: 0.92 95% CI 0.87-0.97) were detected. At low concentrations of HbF, the DCA 2000 immunologic method tended to underestimate and at higher concentrations tended to overestimate HbA(1c) when compared with Diamat. Stepwise linear regression with HbA(1c) (DCA 2000) as dependent variable included HbA(1c) (Diamat) and HbF in the model (r(2)=0.946, p<0.0001), explaining 94.6% of the variability of HbA(1c) (DCA 2000). Partial correlation coefficient between HbA(1c) (DCA 2000) and HbF corrected for HbA(1c) (Diamat) was 0.337 (p=0.0012)., Conclusions: DCA 2000 allowed measurements of HbA(1c) rapidly and with precision adequate for clinical purposes. However, agreement with Diamat results was comparatively weak with both constant as well as proportional biases. The 95% limits of agreement between Diamat and DCA 2000 fell within a range that significantly limited traceability between these two methods; therefore, the two methods should not be used interchangeably. Small but persistent elevations of HbF concentrations were identified as a significant cofactor, which may be relevant for limited traceability between the two methods.

Previous studies have shown that approximately 20% of hemoglobin is lost from circulating red blood cells (RBCs), mainly during the second half of the cells' life span. Because hemoglobin-containing vesicles are known to circulate in plasma, these vesicles were isolated. Flow cytometry studies showed that most RBC-derived vesicles contain hemoglobin with all hemoglobin components present. The hemoglobin composition of the vesicles resembled that of old RBCs. RBC cohort studies using isotope-labeled glycine have been described, which showed a continuous presence of this label in hemoglobin degradation products. The label concentration of these products increased during the second half of the RBC life span, accompanied by a decrease within the RBC. It is concluded that the hemoglobin loss from circulating RBCs of all ages can be explained by shedding hemoglobin-containing vesicles. This loss occurs predominantly in older RBCs. Apparently the spleen facilitates this process since asplenia vesicle retention within RBCs of all ages has been described, accompanied by an increase in the percentage of total HbA(1). The present study shows that in old RBCs of asplenic individuals, the decrease of hemoglobin content per cell such as seen in old RBCs of control individuals is absent due to an increase in the absolute amount of HbA(1c) and HbA(1e2). It is concluded that hemoglobin-containing vesicles within old RBCs are "pitted" by the spleen.