The True Value of HbA1c as a Predictor of Diabetic Complications: Simulations of HbA1c Variables

Aim

The updated mean HbA1c has been used in risk estimates of diabetic complications, but it does not take into account the temporal relationship between HbA1c and diabetic complications. We studied whether the updated mean HbA1c underestimated the risk of diabetic complications.

Method

Continuous HbA1c curves for 10,000 hypothetical diabetes patients were simulated over an average of 7 years. Simulations were based on HbA1c values encountered in clinical practice. We assumed that each short time interval of the continuous HbA1c curves had a long-lasting effect on diabetic complications, as evidenced by earlier studies. We tested several different HbA1c variables including various profiles, e.g. different duration, of such a long-lasting effect. The predictive power of these variables was compared with that of the updated mean HbA1c.

Results

The predictive power of the constructed HbA1c variables differed considerably compared to that of the updated mean HbA1c. The risk increase per standard deviation could be almost 100% higher for a constructed predictor than the updated mean HbA1c.

Conclusions

The importance of good glycemic control in preventing diabetic complications could have been underestimated in earlier hallmark studies by not taking the time-dependent effect of HbA1c into account.     

GM crops: science, politics and communication

As the public debate in Europe about genetically modified (GM) crops heats up and the trade row between the United States and the European Union over GM food escalates, what better time to examine the issues with an international group of experts (Box 1). Their views are diverse, but they all agree that we need more impartial communication, less propaganda and an effective regulatory regime that is based on a careful case-by-case consideration of GM technology. It seems that GM crops are here to stay, so let us hope that these requirements are met and that the developing nations that perhaps have the most to gain from this technology can start to reap its benefits.     

Ecotoxicity testing: science, politics and ethics

Animal welfare organisations have long been concerned about the use of animals for ecotoxicity testing. Ecotoxicity testing is a necessary part of the statutory risk assessment of chemicals that may be released into the environment. It is sometimes also carried out during the development of new chemicals and in the investigation of pollution in the field. This review considers the existing requirements for ecotoxicity testing, with particular reference to practices in the European Union, including the recent REACH system proposals, before discussing criticisms that have been made of existing practices for environmental risk assessment. These criticisms have been made on scientific and ethical grounds, as well as on questions of cost. A case is made for greater investment in the development of alternative testing methods, which could improve the science, as well as serving the cause of animal welfare. It has frequently been suggested that the statutory requirements for environmental risk assessment are too rigid and bureaucratic. A case is made for flexibility and the greater involvement of scientists in the risk assessment procedure, in the interests of both improved science and improved animal welfare.     

HbA1c standardisation destination--global IFCC Standardisation. How, why, where and when--a tortuous pathway from kit manufacturers, via inter-laboratory lyophilized and whole blood comparisons to designated national comparison schemes

Glycohaemoglobins were first used in routine clinical laboratories for diabetes monitoring around 1977 and at the time all methods had either no calibrators, or used material with assayed values derived from individual manufacturers' assays. Over the next five to fifteen years, lyophilised and whole blood sample exchanges were shown to improve inter-laboratory variability markedly. The use of a precise HPLC method as the "standard method" in the Diabetes Control and Complications Trial (DCCT) led to significant further improvement. National standardisation schemes in the mid to late 1990s in the USA, Japan and Sweden further improved the quality and accuracy of HbA1c assays in clinical use. The work of the IFCC Working Group on Standardisation of HbA1c in establishing true International Reference Methods for HbA1c and the successful preparation of pure HbA1c calibration material should lead to further improvements in inter-method and inter-laboratory variability, essential to the long-term monitoring of patients with diabetes.     

Alteration of T-state binding properties of naturally glycated hemoglobin, HbA1c

The thermodynamic and kinetic properties of the most abundant glycated hemoglobin in human blood, HbA1c, have been studied in detail. They display significant differences as compared to normal hemoglobin, HbA0, in that (1) the shape of the oxygen binding curve of HbA1c in the Hill plot is markedly asymmetrical, with a lower asymptote extending up to approximately 40% oxygen saturation, and the oxygen affinity of the T state being tenfold higher than in HbA0; (2) oxygen pulse experiments on HbA1c show a slower rate of ligand dissociation (k = 25 s-1) even at low levels of oxygen saturation, where the T state is largely predominant; (3) kinetics of CO combination to deoxy HbA1c followed by means of stopped-flow experiments reveal the presence of a quickly reacting component, whose fraction increases upon dilution of hemoglobin. These results show that in contrast to what has been stated by other authors, HbA1c displays functional properties markedly different from HbA0. Analysis indicates that glycation of human hemoglobin affects the T quaternary structure, bringing about a more "relaxed" T state and leading to preferential binding to one type of chain (which is unaffected by chloride ions).     

Correlation between HbA1c, purified insulins, diabetic control, and insulin antibodies in diabetic children

Insulin antibodies were determined in sera from 38 children diagnosed as having juvenile diabetes for a duration of 0.7-15.2 years (median = 4.9 years). 8 children were treated with purified porcine insulins from the beginning of their disease, 16 children with bovine insulin NPH alone, and 14 children with non-purified, of whom 9 were later transferred to purified insulins. Serum insulin antibodies were measured by non-specific and specific methods using beef (B) and pork (P) antigens as described by Welborne and Sebriakova, respectively. 12/38 children had insulin binding levels similar to those of normal children, irrespective of the type of insulin used. The concentration of antibodies using radiolabelled B or P insulins as antigens were strongly correlated, by both the non-specific (p less than 0.01) and the specific (p less than 0.01) methods. Children with better score for diabetic control had significantly lower levels of insulin antibodies against B (p less than 0.05) and P (p less than 0.05) than those with poor diabetic control. There was also a significant positive correlation between mean HbA1c concentration and both B and P mean insulin antibody concentration (p less than 0.01). Finally, patients treated with purified porcine insulin had significantly lower levels of antibodies than patients with non-purified bovine insulin (p less than 0.05).     

Trajectories of HbA1c Levels in Children and Youth with Type 1 Diabetes

Purpose

To illustrate the distribution of Hemoglobin A1c (HbA1c) levels according to age and gender among children, adolescents and youth with type 1 diabetes (T1DM).

Methods

Consecutive HbA1c measurements of 349 patients, aged 2 to 30 years with T1DM were obtained from 1995 through 2010. Measurement from patients diagnosed with celiac disease (n = 20), eating disorders (n = 41) and hemoglobinopathy (n = 1) were excluded. The study sample comprised 4815 measurements of HbA1c from 287 patients. Regression percentiles of HbA1c were calculated as a function of age and gender by the quantile regression method using the SAS procedure QUANTREG.

Results

Crude percentiles of HbA1c as a function of age and gender, and the modeled curves produced using quantile regression showed good concordance. The curves show a decline in HbA1c levels from age 2 to 4 years at each percentile. Thereafter, there is a gradual increase during the prepubertal years with a peak at ages 12 to 14 years. HbA1c levels subsequently decline to the lowest values in the third decade. Curves of females and males followed closely, with females having HbA1c levels about 0.1% (1.1 mmol/mol) higher in the 25^th 50^th and 75^th percentiles.

Conclusion

We constructed age-specific distribution curves for HbA1c levels for patients with T1DM. These percentiles may be used to demonstrate the individual patient''s measurements longitudinally compared with age-matched patients.     

Anthropology and the politics of facts,knowledge, and history

Conclusions In this paper I have tried to discuss several levels of the politics of facts, knowledge and history in relation to contemporary anthropology. Taking off on the current school of anthropology known as interpretive anthropology or anthropology as text, I have suggested that issues involving the representation and documentation of knowledge and history are not primarily found in the process of writing an ethnographic text, but in the arenas of power relations which fall outside of ethnographic production. The power dynamics of unequal language as described by Asad operate in the political, economic, cultural and social lives of real individuals who carried on a historical existence before the entrance of the anthropologist and who continue to struggle, day to day, to survive and retain a sense of autonomous identity after the anthropologist leaves.Here the politics of facts, knowledge, and history have been explored in relation to my own fieldwork in the Zapotec community of Teotitlan del Valle in Oaxaca, Mexico. My discussion focused on the power relations of history and language reflected in the community archives, the ways in which different sectors of the community use history to defend their own agendas and differential access to power in a gendered and economically stratified community, and the ways in which collaborative projects can highlight different bases of linguistic and historical authority within a community.Unlike many indigenous peasant communities in Mexico, Teotitlan is not in the throes of an economic or political crisis. In fact, it probably has one of the highest standards of living of all the indigenous communities in Oaxaca. The community's protection of its many histories has been used, particularly by the merchant sector, as a way of asserting a claim to Zapotec weavings. The cultural claim to the textiles has been used to facilitate the community's insertion into the international capitalist economy. A claim to Zapotec ethnicity has been critical to the community's autonomy struggle as it has worked to gain independence from the Mexican state, first through circumventing documentation of production, and later, by avoiding deep involvement in craft development programs, which put the state in the role of middleman.Other indigenous communities and populations in Mexico and throughout Latin America face a much more severe crisis of autonomy, usually linked first to physical survival, and secondly, to maintaining control over natural resources. In the state of Oaxaca, significant numbers of the human rights violations which have occurred in the 1970s and 1980s involved indigenous peoples who were murdered, beaten, jailed or harassed for ethnically based political activities. Particularly outstanding were abuses leveled against the Trique living in and around San Juan Copala who have engaged in confrontations involving 13,705 hectares of disputed woodlands and communal land.For indigenous communities waging battles for self-determination and autonomy, the representation of history and facts are linked to political struggles to improve material conditions and gain greater control over their place in the larger political-economy. At the level of struggle at which the Trique are engaged in the crisis over authority and representation is played out in armed incursions by troops, police and gunmen, assassinations of Triqui leaders, torture, and rape. In the community of Teotitlan, it is played out more subtly in negotiations with American importers and within the community over prices and who controls the production and distribution of Zapotec weavings. In both instances the politics of facts, knowledge, and history reappear in the colonial encounter people live on a day to day basis and which anthropologists focused on in the 1970s. While the enterprise of ethnography winds itself through changing epistemologies in the pages of journals and at conferences, the lives of indigenous peasants continue in a struggle of empowerment against a history of marginalization.Lynn Stephen is Professor of Anthropology, Center for U.S.-Mexican Studies, University of California, San Diego.     

Variables Involved in the Discordance between HbA1c and Fructosamine: The Glycation Gap Revisited

Aims

Glycation gap (GG) is defined as the difference between the measured level of HbA1c and the level that would be predicted from its regression on the fructosamine level. The aims of the study were: 1) To determine the reproducibility and consistency of GC; 2) To discover factors related to GG value. Given that metformin might increase glucose transport through the erythrocyte membrane, this treatment was also considered in the analyses of the results.

Methods

GG was calculated in two blood samples separated 30.6 (SD 7.3) weeks, obtained in 508 type 2 diabetic patients. The following variables were considered: HbA1c, fructosamine, glucose, creatinine, hematological parameters and treatment with metformin. Multivariate and logistic regression analyses were performed to explore the variables independently related to CG.

Results

GG was reproducible and consistent over time. Creatinine, mean corpuscular hemoglobin concentration (MCHC), and glycemia (inverse relationship); and HbA1c and treatment with metformin (direct relationship) were independently related to GG. Patients treated with metformin showed higher HbA1c values, despite similar fructosamine concentrations, than patients not treated with the drug.

Conclusions

GG is independently related to serum levels of creatinine, MCHC and treatment with metformin. The spurious effect of metformin on Hb glycation could have serious clinical implications and should be considered when interpreting the results of clinical trials.     

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.     

The Clinical Significance of HbA1c in Operable Chronic Thromboembolic Pulmonary Hypertension

Background

Glycosylated hemoglobin A1c (HbA1c) has been proposed as an independent predictor of long-term prognosis in pulmonary arterial hypertension. However, the clinical relevance of HbA1c in patients with operable chronic thromboembolic pulmonary hypertension (CTEPH) remains unknown. The aim of the present study was to investigate the clinical significance of HbA1c as a biomarker in CTEPH.

Methods

Prospectively, 102 patients underwent pulmonary endarterectomy (PEA) in our national referral center between March 2013 and March 2014, of which after exclusion 45 patients were analyzed. HbA1c- levels, hemodynamic and exercise parameters were analyzed prior and one-year post-PEA.

Results

45 patients (BMI: 27.3 ± 6.0 kg/m²; age: 62.7 ± 12.3 years) with a mean pulmonary arterial pressure (mPAP) of 43.6 ± 9.4 mmHg, a pulmonary vascular resistance (PVR) of 712.1 ± 520.4 dyn*s/cm⁵, a cardiac index (CI) of 2.4 ± 0.5 l/min/m² and a mean HbA1c-level of 39.8 ± 5.6 mmol/mol were included. One-year post-PEA pulmonary hemodynamic and functional status significantly improved in our cohort. Baseline HbA1c-levels were significantly associated with CI, right atrial pressure, peak oxygen uptake and the change of 6-minute walking distance using linear regression analysis. However, using logistic regression analysis baseline HbA1c-levels were not significantly associated with residual post-PEA PH.

Conclusions

This is the first prospective study to describe an association of HbA1c-levels with pulmonary hemodynamics and exercise capacity in operable CTEPH patients. Our preliminary results indicate that in these patients impaired glucose metabolism as assessed by HbA1c is of clinical significance. However, HbA1c failed as a predictor of the hemodynamic outcome one-year post-PEA.     

A two-step screening, measurement of HbA1c in association with FPG, may be useful in predicting diabetes

Backgrounds

We compared the usefulness of fasting plasma glucose (FPG), or hemoglobin A1c (HbA1c), or both in predicting type 2 diabetes.

Methods

This retrospective cohort study investigated 9,322 Japanese adults (4,786 men and 4,536 women), aged 19–69 yrs, free of diabetes at baseline. Usefulness was assessed by predictive values (PV), sensitivity, specificity, and the area under the receiver operating characteristic curve (AUROC) maximised under the best cut-off point.

Results

During the average 6 years of follow-up, 221 men (4.6%) and 92 women (2%) developed diabetes. The best cut-off points for FPG (i.e., 5.67 mmol/l for men and 5.5 mmol/l for women) gave excellent AUROC, and the highest positive PV (13% for men and 9% for women) in predicting diabetes. In high risk subjects with FPG 6.1–6.9 mmol/l, 119 men (26.8%) and 39 women (28.3%) developed diabetes. Under the best cut-off points of FPG 6.39 mmol/l and A1c 5.8, AUROC and positive PV for FPG slightly decreased indicating FPG became less useful and were statistically indistinguishable from those for HbA1c in men. In fact, HbA1c was the most useful in women: HbA1c of 6.0% gave the highest positive likelihood ratio of 2.74 and larger AUROC than did FPG. Although AUROC for HbA1c was acceptable and indistinguishable from that for the combined use, HbA1c had higher specificity and positive LR than did the combined use.

Conclusions

This study demonstrated that FPG was the most useful to predict diabetes in the general population. However, in subjects with FPG 6.1–6.9 mmol/l, FPG became less useful and diagnostic performance of FPG was indistinguishable from that of HbA1c in men whereas HbA1c was the most useful in women. Thus, a two-step screening, measurement of HbA1c in association with FPG, may be useful in predicting diabetes.