Accuracy of glycated haemoglobin in screening for pre-diabetes in Asian Indians-a community survey: the Chandigarh Urban Diabetes Study (CUDS)

Aim To compare American Diabetes Association and International Expert Committee recommended cut-off values of HbA(1c) for detecting the presence of pre-diabetes against plasma glucose values obtained from oral glucose tolerance tests in Asian Indians. Methods A cross-sectional randomly sampled population survey involving 2368 adults, aged ≥?20?years. HbA(1c) was measured on a Bio-Rad 10 system in 1972 subjects. Results Of the 1972 subjects studied, 329 were detected to have pre-diabetes based on isolated impaired fasting glucose in 125 subjects (6.3%), isolated impaired glucose tolerance in 141 subjects (7.1%) and the presence of both in 63 subjects (3.2%). The HbA(1c) cut-off of 34?mmol/mol (5.7%), as recommended by the American Diabetes Association for detecting the presence of pre-diabetes, showed sensitivity of 62%, specificity 77%, with a positive predictive value of 34.7%, a negative predictive value of 89.5% and accuracy of 67.8%; whereas the HbA(1c) cut-off recommended by the International Expert Committee of 42?mmol/mol (6%) had a sensitivity of 36%, specificity of 90%, positive predictive value of 42.7%, negative predictive of 85.4% and an accuracy of 77%. However, both these HbA(1c) cut-offs underdiagnosed the presence of pre-diabetes in 38 and 64% of these subjects, respectively. Conclusions The American Diabetes Association and the International Expert Committee recommended HbA(1c) cut-off values and oral glucose tolerance tests identify different pre-diabetes cohorts. Long-term prospective studies are required to define the usefulness of one over the other.     

Knowledge of A1c Predicts Diabetes Self-Management and A1c Level among Chinese Patients with Type 2 Diabetes

This study was to identify current A1c understanding status among Chinese patients with type 2 diabetes, assess if knowledge of A1c affects their diabetes self-management and their glycemic control and recognize the factors influencing knowledge of A1c among patients with type 2 diabetes. A multi-center, cross-sectional survey was conducted between April and July 2010 in 50 medical centers in the Mainland China. Participants were recruited from inpatients and outpatients who were admitted to or visited those medical centers. The survey included core questions about their demographic characteristics, diabetes self-management behavior, and A1c knowledge. Overall, of 5957 patients, the percentage of patients with good understanding was 25.3%. In the multivariable logistic regression model, the variables related to the knowledge of A1c status are presented. We discovered that patients with longer diabetes duration (OR = 1.05; 95%CI = 1.04–1.06) and having received diabetes education (OR = 1.80; 95%CI = 1.49–2.17) were overrepresented in the good understanding of A1c group. In addition, compared to no education level, higher education level was statistically associated with good understanding of A1c (P<0.001). The percentage of patients with good understanding varied from region to region (P<0.001), with Eastern being highest (OR = 1.54; 95%CI = 1.32–1.80), followed by Central (OR = 1.25; 95%CI = 1.02–1.53), when referring to Western. Only a minority of patients with type 2 diabetes in China understood their A1c value. The patients who had a good understanding of their A1c demonstrated significantly better diabetes self-management behavior and had lower A1c levels than those who did not.     

Analysis of glycated hemoglobin A1c by capillary electrophoresis and capillary isoelectric focusing

Two capillary electrophoretic methods were developed and evaluated for measurement of glycated hemoglobin A1c (HbA1c). First, a capillary electrophoresis analysis is performed with a sodium tetraborate buffer (pH 9.3) as background electrolyte in a neutrally coated capillary. HbA1c is separated from HbA0 due to specific interactions of borate anions with the cis–diol pattern in the saccharide moiety of glycohemoglobin. Second, a capillary isoelectric focusing method, which exploits a difference in pI values of HbA0 and HbA1c, is performed with Servalyt pH 6–8 or alternatively with Biolyte pH 6–8 carrier ampholytes spiked with a narrow pH cut of pH 7.2 prepared by preparative fractionation of Servalyt pH 4–9 carrier ampholytes. Both methods reflect recent developments in the methodology of capillary electrophoresis. They allow quantifying HbA1c in generic capillary electrophoresis analyzer with specificity that is consistent with previously reported electrophoretic assays in slab gels and capillaries.     

Comparison of tests for glycated haemoglobin and fasting and two hour plasma glucose concentrations as diagnostic methods for diabetes.

OBJECTIVE--To compare the ability of tests measuring two hour plasma glucose, fasting plasma glucose, and glycated haemoglobin concentrations in predicting the specific microvascular complications of non-insulin dependent diabetes mellitus. DESIGN--Cross sectional and longitudinal analysis of the relation between complications and concomitant results of the three tests. SETTING--Gila River Indian Community, Arizona. SUBJECTS--Pima Indians (cross sectional, n = 960), aged 25 years or above who were not receiving insulin or oral hypoglycaemic treatment at the baseline examination. MAIN OUTCOME MEASURES--Development of retinopathy and nephropathy. RESULTS--Cross sectionally, frequency distributions of logarithms of the three sets of results were bimodal, with the prevalence of retinopathy and nephropathy being, respectively, 12.0-26.7 and 3.9-4.2 times as high above as below cut off points which minimised overlap (two hour plasma glucose concentration 12.6 mmol/l; fasting plasma glucose concentration 9.3 mmol/l; glycated haemoglobin (HbA1c) concentration 7.8%). Longitudinally, each of the three measures of glycaemia significantly predicted the development of retinopathy (P < 0.0001) and nephropathy (P < 0.05). Receiver operating characteristic curves showed that two hour plasma glucose concentration was superior to fasting plasma glucose concentration (P < 0.05) for prevalent cases of retinopathy, but otherwise no variable had a significant advantage for detecting incident or prevalent cases of either complication. CONCLUSIONS--These findings suggest that determination of glycated haemoglobin or fasting plasma glucose concentrations alone may be acceptable alternatives to measuring glucose concentration two hours after challenge with 75 g glucose for the diagnosis of diabetes.     

Relationship between glycated hemoglobin and glucose concentrations in the adult Galician population: selection of optimal glycated hemoglobin cut-off points as a diagnostic tool of diabetes mellitus

Aims/hypothesisTo analyze the relationship between glucose and glycated hemoglobin (HbA_1c) in the adult Galician population, evaluate the use of HbA_1c for the screening and diagnosis of diabetes, and calculate the diagnostic threshold required for this purpose.MethodsWe analyzed data on 2848 subjects (aged 18–85 years) drawn from a study undertaken in 2004 to assess the prevalence of diabetes in Galicia. For study purposes, diabetes was defined using the criteria recommended in 2002. Participants were classified into four glucose-based groups. The relationship between glucose and HbA_1c was described using linear regression models, generalized additive models and Spearman's correlation. Diagnostic capacity was assessed, and optimal HbA_1c cut-off points were calculated as a diabetes marker using the receiver operating characteristic curve.ResultsPrevalence of pre-diabetes, unknown diabetes and known diabetes was 20.86, 3.37 and 4.39%, respectively. The correlations between HbA_1c and fasting glucose were higher than those obtained for HbA_1c and glycemia at 2 h of the oral glucose overload (0.344 and 0.270, respectively). Taking glucose levels as the gold standard, a greater discriminatory capacity was obtained for HbA_1c (area under de cruve: 0.839, 95% confidence intervals: 0.788–0.890). Based on the study criteria, the optimal minimum and maximum HbA_1c values were 5.9% and 6.7%, respectively.Conclusions/interpretationHbA_1c did not prove superior to glycemia for diagnosis of diabetes in the adult Galician population, and cannot therefore be used to replace the oral glucose tolerance test for screening and diagnosis purposes. Indeed, determination of glucose is essential to verify the diagnosis in the majority of cases.     

CHE1 UF serum cholinesterase phenotype in whites and non-whites from southern Brazil as determined by a new method

A sample of 251 Whites and 818 Non-Whites, from Curitiba (southern Brazil), was typed with a new method with the aim of estimating the frequency of the CHE1*F allele. The frequency of this allele did not differ between Whites (0.60 +/- 0.34%) and Non-Whites (0.49 +/- 0.17%), being estimated as 0.51 +/- 0.15% for the whole sample. The use of the inhibitors DL-propranolol and RO2-0683 with alpha-naphthylacetate as substrate (at 37 degrees C) was efficient for discriminating between the CHE1 U and CHE1 UF phenotypes.     

Interaction of haemoglobin and cytochrome c with aliphatic alcohols as studied by 1H NMR spectroscopy

Association of haeme proteins, haemoglobin and cytochrome c, with eight aliphatic alcohols (methanol, ethanol. two isomeric propanols and four butanols) was studied by 1H NMR spectroscopy. NMR spectra of alcohols were monitored at 60 MHz at increasing concentration of the proteins. Selective broadening of the NMR signals of individual segments of alcohols was observed only in the case of alcohol-haemoglobin systems. Its quantitative evaluation and interpretation in terms of formation of low affinity intermolecular alcohol--protein complexes led to the conclusion that haemoglobin associates with alcohol molecules in a way depending on the length and isomeric branching of the alkyl chains; in particular, the methylene and methine groups vicinal to the hydroxyl are subject to stronger immobilization than the terminal methyls or other groups. Thus, the model of hydrophobic complexes stabilized by hydrogen bonds described previously for association of bovine serum albumin with alcohols (Lubas et al., Biochemistry, 18, 4943-4951, 1979) seems to apply also to haemoglobin association. In the case of cytochrome c association, 1H NMR data alone are insufficient for structural evaluation of the mechanism of formation of the alcohol--cytochrome c complexes.     

Determination of haemoglobin A(1c) by liquid chromatography using a new cation-exchange column

The use of a new cation-exchange column, ProPac SCX-10, for the determination of haemoglobin A(1c) (HbA(1c)) by high-performance liquid chromatography is described. After optimization of the analytical method for the separation of the various isoforms of haemoglobin with the ProPac SCX-10 column, the method was applied to the determination of HbA(1c) in blood from 59 volunteers. Three of the 59 had previously been diagnosed as diabetics. Interference studies for carbamylation, acetylation and pre-HbA(1c) were carried out via "in-vitro" experiments. No interference due to carbamylation was observed at the urea values normally found in uremic patients undergoing dialysis. No interference from pre-HbA(1c) was detected either. The method is able to separate haemoglobin A (alpha(2)beta(2)), haemoglobin S (haemoglobin from sickle cell anaemia patients) and haemoglobin A(2) (alpha(2)delta(2)) without interference. The method of Hampel was applied to detect outliers. A value of 3.29+/-0.44% (2sigma) for HbA(1c) was obtained in the analysis of 56 blood samples from non-diabetics. This average value is lower than that reported by most of the methods currently used in routine analyses.     

A simple strategy for screening for glucose intolerance, using glycated haemoglobin, in individuals admitted with acute coronary syndrome

Glucose intolerance is common but often remains undiagnosed and untreated in people with acute coronary syndrome. The best approach to screening for glucose intolerance post-acute coronary syndrome remains debated. The World Health Organization has recently advocated the use of HbA(1c) in diagnosing Type 2 diabetes. A screening strategy using HbA(1c) as the preferred test would be pragmatic and improve early detection and management of glucose intolerance in acute coronary care practice. In this commentary, we discuss the relevant literature and guidelines in this area and propose a simple and pragmatic algorithm based on the use of HbA(1c) to screen for glucose intolerance during and after admission with acute coronary syndrome.     

Effects of MTNR1B variants on fasting glucose levels in a Korean population

Fasting glucose level is the most basic and widely used indicator of diabetes. Several genome wide association studies have reported that the gene encoding melatonin receptor 1B (MTNR1B) exerts a major effect on serum fasting glucose levels. We tested for the association between single nucleotide polymorphisms (SNPs) in the MTNR1B gene and fasting glucose levels in a Korean population consisting of 8,229 subjects taken from two community-based cohorts. The mean age of the subjects in the study population was 51.9 years. For this study, we selected 363 SNPs located in the MTNR1B gene, which is located on chromosome 11. Multivariate linear regression models were used to test for genotypic effects on fasting glucose levels while adjusting for age and sex under an additive model. The MTNR1B SNP most highly associated with fasting glucose levels was rs10830962 (p=1.95×10^?5), followed by rs3847554 (p=3.16×10^?4). Replication of these initial findings is important to better understand the correlation between MTNR1B variations and their effects, especially in Asian populations.     

Evaluation for fasting and 2-hour glucose and HbA1c for diagnosing diabetes based on prevalence of retinopathy in a Chinese population

Background

The glycemic thresholds for diabetes diagnosis have long been at the forefront of discussion. However, no information about glycemic cutoff points has been made available for the Chinese population. The aim of the present study was to examine the association of fasting plasma glucose (FPG), 2-h plasma glucose (2-h PG) and HbA₁c levels with diabetic retinopathy (DR) and determine the associated cutoff levels in a Chinese population.

Methodology and Principal Findings

In a cross-sectional population-based sample of 2551 Chinese (representing a population of 1,660,500 in a Beijing district) between 18–79 years of age, the three glycemic measures were measured in a 75 g oral glucose tolerance test, and DR was assessed by two 45° color digital retinal images. The prevalence of DR increased in the ninth decile of each variable, corresponding to an FPG of ≥7.2 mmol/l, a 2-h PG of ≥10.7 mmol/l, and HbA₁c of ≥6.4%, according to the Joinpoint regression method. After excluding individuals receiving antihyperglycemic medication, the prevalence significantly increased at an FPG of ≥6.8 mmol/l, a 2-h PG of ≥12.0 mmol/l, and HbA₁c of ≥6.7%. The area under the ROC curve for all three measures showed no significant differences for detecting DR. After excluding individuals receiving antihyperglycemic medication, the three measures also showed no significant differences.

Conclusions and Significance

A significant increase in retinopathy prevalence occurs among individuals with FPG ≥7.2 mmol/l, 2-h PG ≥10.5 mmol/and HbA₁c ≥6.4%; and measuring FPG or HbA₁c are equally reliable methods as measuring 2-h PG for the diagnosis of diabetes in the Chinese population.     

Association of glycosylated haemoglobin HbA1c levels with outcome in patients with COVID-19: A Retrospective Study

Patients with hyperglycemia tend to be susceptible to Coronavirus disease 2019 (COVID-19). However, the association of HbA1c level with outcome of COVID-19 patients was unclear. We performed a retrospective study of 2880 cases of COVID-19 admitted in Tongji Hospital, Wuhan, China, among which 922 had detected the HbA1c levels. We found that COVID-19 patients with either lower levels of HbAlc (3%-4.9%) or higher levels of HbAlc (≥6%) were associated with elevated all-cause mortality. Meanwhile, we observed that HbAlc levels were highly correlated with haemoglobin (Hb) and total cholesterol (TC) (P < .0001), moderately correlated with albumin (ALB) and high-sensitive C reaction protein (hs-CRP) (0.0001 < P<.001), and relatively low correlated with low-density lipoprotein cholesterol (LDL-C) (.001 < P<.01). These associated cofactors might together contribute to the clinical outcome of COVID-19 patients. Furthermore, the mortality was higher in COVID-19 patients with newly diagnosed diabetes mellitus (DM) compared with COVID-19 patients with history of DM. Moreover, in patients with history of DM, the mortality was decreased in patients treated with anti-hyperglycaemic drugs. In summary, our data showed that the in-hospital mortality was increased in COVID-19 patients with lower or higher levels of HbAlc. Meanwhile, initiation of appropriate anti-hyperglycaemic treatment might improve the clinical outcome in COVID-19 patients.     

The link between vascular deterioration and branched chain amino acids in a population with high glycated haemoglobin: the SABPA study

Globally the prevalence of non-communicable diseases, such as hypertension and type 2 diabetes, are escalating. Metabolomic studies indicated that circulating branched chain amino acids (BCAAs) are associated with insulin resistance, coronary artery disease and increased risk for cardiovascular events. We aimed to extend the current understanding of the cardiovascular risk associated with BCAAs. We explored whether BCAAs are related to markers of cardiovascular disease in a bi-ethnic population and whether this relationship was influenced by chronic hyperglycaemia. We included 200 African and 209 Caucasian participants, and determined their ambulatory blood pressure and carotid intima-media thickness (cIMT). We analysed blood samples for glycated haemoglobin (HbA1c) and BCAAs. Participants were stratified into two groups according to their HbA1c value using the median cut-off value of 5.6 %. Ambulatory BP, cIMT and BCAAs were significantly higher (all p < 0.001) in the high HbA1c group. Single regression analyses indicated significant positive associations of ambulatory blood pressure and cIMT with BCAAs (all p < 0.05) in both the groups. These associations between ambulatory systolic blood pressure (SBP) (r = 0.16, p = 0.035) and cIMT (r = 0.22, p = 0.004) with BCAAs remained in the high HbA1c group after adjusting for age, gender, ethnicity and body mass index (BMI) and were confirmed in multiple regression analyses (ambulatory SBP: R ² = 0.17, β = 0.21, p = 0.005 and cIMT: R ² = 0.30, β = 0.19, p = 0.003). Our results demonstrate that BCAAs are independently related to ambulatory BP and cIMT in individuals with high HbA1c levels and suggest that potential cardiovascular deterioration accompany the rise in BCAAs in conditions of hyperglycaemia.     

On hyperglicemic glucose basal levels in Type 1 Diabetes Mellitus from dynamic analysis

Compartmental-Physiological Models (CPM's) have been used to derive feedback controllers for the glucose regulation in Diabetes Mellitus (DM). Despite these important advances, there are two criticisms about the use of the CPM's in DM: (i) Can this class of model reproduce severe basal glucose levels (e.g., larger than 300 mg/dl)? and (ii) Does a CPM reproduce a distinct glucose level as its parameters change or is it unique even if its parameters change? This contribution aims these criticisms from the study of the parametric sensitivity of a CPM. The results exploit the analysis of the dynamic properties of the chosen CPM and permit to show that such model can reproduce distinct severe basal levels by modifying the values of the metabolic parameters, which agree with expectations on a realistic model. Mainly, the chosen CPM has been selected due to the following two reasons. (i) It includes the main organs related to the glucose metabolism in Type 1 Diabetes Mellitus (T1DM); as, for example, the liver, brain and kidney. (ii) It models metabolic phenomena as, for instance, the counter-regulatory effects by glucagon and the hepatic glucose uptake/production. Additionally, the chosen model has been recently used to design feedback controllers for the glucose regulation with very promissory results.     

HbA1c Test as a Tool in the Diagnosis of Gestational Diabetes Mellitus

Aims

Gestational diabetes mellitus (GDM) is a prevalent and potentially serious condition which may put both mothers and neonates at risk. The current recommendation for diagnosis is the oral glucose tolerance test (OGTT). This study aimed to determine the usefulness of HbA1c test as a diagnostic tool for GDM as compared to the traditional criteria based on the OGTT.

Methods

This was a diagnostic test accuracy study. We performed OGTT and HbA1c test in women attending prenatal visits at a tertiary hospital. GDM was defined according to WHO1999 or ADA/WHO 2013 criteria. ROC curve was used to evaluate the diagnostic performance of HbA1c. Sensitivity, specificity and likelihood ratios for different HbA1c cut-off points were calculated.

Results

Of the 262 women in the third trimester of gestation enrolled in the study, 86 (33%) were diagnosed with GDM. Only five of these women presented HbA1c ≥48 mmol/mol (6.5%). This cut-off point presented 100% specificity but very low sensitivity (7%). Based on ROC curve, and considering OGTT as the reference criterion, HbA1c ≥40 mmol/mol (5.8%) showed adequate specificity in diagnosing GDM (94.9%) but low sensitivity (26.4%). Unlike, HbA1c values of 31 mmol/mol (5.0%) presented adequate sensitivity (89.7%) but low specificity (32.6%) to detect GDM. For women with HbA1c ≥40 mmol/mol (5.8%), the positive and negative likelihood ratios were 5.14 (95%CI 2.49–10.63) and 0.78 (0.68–0.88), respectively. The post-test probability of GDM was about 40%, representing a 4.0-fold increase in the mean pre-test probability. This cut-off point could eliminate the need for the unpleasant and laborious OGTT tests in almost one third of cases, as 38% of patients with GDM may be diagnosable by HbA1c test alone.

Conclusions

Our results show that combined HbA1c and OGTT measurements may be useful in diagnosing GDM.     

Relationship between diurnal glucose levels and HbA1c in type 2 diabetes.

AIMS AND METHODS: Study results still conflict on the contribution of diurnal blood glucose (BG) values to Hb (A1c) in type 2 diabetes. We investigated the relationship between Hb (A1c) and diurnal BG obtained under standardized conditions - before breakfast, two hours after breakfast, before lunch, two hours after lunch, before dinner, two hours after dinner, and at 10 PM, 12 midnight and 3 AM in 68 type 2 diabetic patients before and after optimizing glycemic control. The areas under the curve above fasting BG (AUC1) and above 5.6 mmol/l (AUC2) were calculated for further evaluation. Hb (A1c) was measured at baseline and after a mean of 89 (74 to 108) days. RESULTS: Each BG value at baseline and after treatment optimization significantly correlated with baseline and follow-up Hb (A1c), respectively. The pre-breakfast BG showed the closest correlation with Hb (A1c). The relative contribution of postprandial BG concentrations (AUC1) to overall hyperglycemia (AUC2) decreased with poorer glycemic control. However, treatment optimization mainly resulted in improved blood glucose values in patients with the poorest glycemic control at baseline. Multiple regression analysis demonstrated that fasting (AUC2-AUC1) and postprandial (AUC1) hyperglycemia independently determined Hb (A1c) or the change in Hb (A1c) after treatment optimization. CONCLUSIONS: Our findings indicate that intensive blood glucose monitoring during fasting and postprandial states is important for glycemic control, and is therefore an essential part of good clinical practice.     

Muscle interstitial glucose and lactate levels during dynamic exercise in humans determined by microdialysis.

The purpose of the present study was to use the microdialysis technique to determine skeletal muscle interstitial glucose and lactate concentrations during dynamic incremental exercise in humans. Microdialysis probes were inserted into the vastus lateralis muscle, and subjects performed knee extensor exercise at workloads of 10, 20, 30, 40, and 50 W. The in vivo probe recoveries determined at rest by the internal reference method for glucose and lactate were 28.7 +/- 2.5 and 32.0 +/- 2.7%, respectively. As exercise intensity increased, probe recovery also increased, and at the highest workload probe recovery for glucose (61.0 +/- 3.9%) and lactate (66. 3 +/- 3.6%) had more than doubled. At rest the interstitial glucose concentration (3.5 +/- 0.2 mM) was lower than both the arterial (5.6 +/- 0.2 mM) and venous (5.3 +/- 0.3 mM) plasma water glucose levels. The interstitial glucose levels remained lower (P < 0.05) than the arterial and venous plasma water glucose concentrations during exercise at all intensities and at 10, 20, 30, and 50 W, respectively. At rest the interstitial lactate concentration (2.5 +/- 0.2 mM) was higher (P < 0.05) than both the arterial (0.9 +/- 0. 2 mM) and venous (1.1 +/- 0.2 mM) plasma water lactate levels. This relationship was maintained (P < 0.05) during exercise at workloads of 10, 20, and 30 W. These data suggest that interstitial glucose delivery at rest is flow limited and that during exercise changes in the interstitial concentrations of glucose and lactate mirror the changes observed in the venous plasma water compartments. Furthermore, skeletal muscle contraction results in an increase in the diffusion coefficient of glucose and lactate within the interstitial space as reflected by an elevation in probe recovery during exercise.