HbA<Subscript>1c</Subscript> Variability and Cardiovascular Events

Due to its high and increasing prevalence, type 2 diabetes mellitus is becoming more and more of a global public health burden. Effective measures are required to prevent diabetes-related morbidity and the resulting premature death. The effect of long-term glycemic fluctuations in patients with diabetes mellitus, referred to as HbA1c variability, has been the subject of intensive discussion. Whereas the mean HbA1c value is already established as a risk factor for vascular complications, an accumulation of findings makes a compelling case that HbA_1c variability adds further predictive value. Recent studies raise the possibility that a reduced HbA_1c variability may inhibit hyperglycemia-related diseases without increasing the risk of hypoglycemia. Taken as a whole, the present evidence demonstrates a clear association between HbA_1c variability and cardiovascular events in patients with type 1 and type 2 diabetes. Nevertheless, there exists to date no standardized definition or method of measuring HbA_1c variability. To advance further research, it would be helpful to reach consensus on a precise definition of HbA_1c variability.     

Associations between physical fitness and HbA<Subscript>1c</Subscript> in type 2 diabetes mellitus

Aim/hypothesis  

In people with type 2 diabetes, exercise improves glucose control (as reflected in HbA_1c) and physical fitness, but it is not clear to what extent these exercise-induced improvements are correlated with one another. We hypothesised that reductions in HbA_1c would be related: (1) to increases in aerobic fitness and strength respectively in patients performing aerobic training or resistance training; and (2) to changes in strength and aerobic fitness in patients performing aerobic and resistance training.     

Size and shape of the associations of glucose,HbA<Subscript>1c</Subscript>, insulin and HOMA-IR with incident type 2 diabetes: the Hoorn Study

Aims/hypothesis

Glycaemic markers and fasting insulin are frequently measured outcomes of intervention studies. To extrapolate accurately the impact of interventions on the risk of diabetes incidence, we investigated the size and shape of the associations of fasting plasma glucose (FPG), 2 h post-load glucose (2hPG), HbA_1c, fasting insulin and HOMA-IR with incident type 2 diabetes mellitus.

Methods

The study population included 1349 participants aged 50–75 years without diabetes at baseline (1989) from a population-based cohort in Hoorn, the Netherlands. Incident type 2 diabetes was defined by the WHO 2011 criteria or known diabetes at follow-up. Logistic regression models were used to determine the associations of the glycaemic markers, fasting insulin and HOMA-IR with incident type 2 diabetes. Restricted cubic spline logistic regressions were conducted to investigate the shape of the associations.

Results

After a mean follow-up duration of 6.4 (SD 0.5) years, 152 participants developed diabetes (11.3%); the majority were screen detected by high FPG. In multivariate adjusted models, ORs (95% CI) for incident type 2 diabetes for the highest quintile in comparison with the lowest quintile were 9.0 (4.4, 18.5) for FPG, 6.1 (2.9, 12.7) for 2hPG, 3.8 (2.0, 7.2) for HbA_1c, 1.9 (0.9, 3.6) for fasting insulin and 2.8 (1.4, 5.6) for HOMA-IR. The associations of FPG and HbA_1c with incident diabetes were non-linear, rising more steeply at higher values.

Conclusions/interpretation

FPG was most strongly associated with incident diabetes, followed by 2hPG, HbA_1c, HOMA-IR and fasting insulin. The strong association with FPG is probably because FPG is the most frequent marker for diabetes diagnosis. Non-linearity of associations between glycaemic markers and incident type 2 diabetes should be taken into account when estimating future risk of type 2 diabetes based on glycaemic markers.

     

Translating HbA<Subscript>1c</Subscript> measurements into estimated average glucose values in pregnant women with diabetes

Aims/hypothesis

This study aimed to examine the relationship between average glucose levels, assessed by continuous glucose monitoring (CGM), and HbA_1c levels in pregnant women with diabetes to determine whether calculations of standard estimated average glucose (eAG) levels from HbA_1c measurements are applicable to pregnant women with diabetes.

Methods

CGM data from 117 pregnant women (89 women with type 1 diabetes; 28 women with type 2 diabetes) were analysed. Average glucose levels were calculated from 5–7 day CGM profiles (mean 1275 glucose values per profile) and paired with a corresponding (±1 week) HbA_1c measure. In total, 688 average glucose–HbA_1c pairs were obtained across pregnancy (mean six pairs per participant). Average glucose level was used as the dependent variable in a regression model. Covariates were gestational week, study centre and HbA_1c.

Results

There was a strong association between HbA_1c and average glucose values in pregnancy (coefficient 0.67 [95% CI 0.57, 0.78]), i.e. a 1% (11 mmol/mol) difference in HbA_1c corresponded to a 0.67 mmol/l difference in average glucose. The random effects model that included gestational week as a curvilinear (quadratic) covariate fitted best, allowing calculation of a pregnancy-specific eAG (PeAG). This showed that an HbA_1c of 8.0% (64 mmol/mol) gave a PeAG of 7.4–7.7 mmol/l (depending on gestational week), compared with a standard eAG of 10.2 mmol/l. The PeAG associated with maintaining an HbA_1c level of 6.0% (42 mmol/mol) during pregnancy was between 6.4 and 6.7 mmol/l, depending on gestational week.

Conclusions/interpretation

The HbA_1c–average glucose relationship is altered by pregnancy. Routinely generated standard eAG values do not account for this difference between pregnant and non-pregnant individuals and, thus, should not be used during pregnancy. Instead, the PeAG values deduced in the current study are recommended for antenatal clinical care.

     

HbA<Subscript>1c</Subscript> in type 2 diabetes diagnostic criteria: addressing the right questions to move the field forwards

This commentary aims to move the debate regarding the adoption of HbA_1c for diagnosis of type 2 diabetes forwards by highlighting the need to avoid addressing irrelevant questions, in particular, comparison of individuals diagnosed with different diagnostic criteria. Instead, we provide a list of important future questions, including whether adoption of HbA_1c as the primary diagnostic test improves uptake of diabetes screening, with resultant earlier diagnosis and improvement in outcomes.     

HbA<Subscript>1c</Subscript> levels in schoolchildren with type 1 diabetes are seasonally variable and dependent on weather conditions

Aims/hypothesis  

We evaluated seasonal HbA_1c changes in children with type 1 diabetes and its relation with measures of weather conditions.     

Mean blood glucose compared with HbA<Subscript>1c</Subscript> in the prediction of cardiovascular disease in patients with type 1 diabetes

Aims/hypothesis It is not known whether mean blood glucose (MBG) predicts the risk of macrovascular complications in diabetes any differently from HbA_1c. In this study we therefore analysed data from the Diabetes Control and Complications Trial (DCCT) to assess the relationship between MBG, HbA_1c and glucose variability with regard to the risk of cardiovascular disease in patients with type 1 diabetes. Methods Pre- and postprandial seven-point glucose profiles were collected quarterly during the DCCT in 1441 individuals. The relationship between time to first cardiovascular event and MBG, HbA_1c and daily SD of blood glucose was assessed by Cox regression after adjusting for the known risk factors of macrovascular disease and the treatment groups of the patients. Results Cox regression showed MBG to be predictive of a cardiovascular event (p = 0.019), but not HbA_1c (p = 0.858). A rise of 1 mmol/l in MBG was associated with an 11% rise in cardiovascular risk. MBG remained highly predictive (p = 0.015) even after adjustment for HbA_1c values and glucose variability. Conclusions/interpretation This study has shown that during the DCCT MBG was a better predictor of the macrovascular complications of type 1 diabetes than HbA_1c. It indicates that the cardiovascular risk associated with hyperglycaemia appeared within the time period of the study and that blood glucose rather than HbA_1c may be the preferred means of assessing this risk.     

HbA<Subscript>1c</Subscript> levels and erythrocyte transport functions in complication-free type 1 diabetic children and adolescents

Higher erythrocyte sodium-lithium countertransport activity (SLC) is implicated in the development of diabetic nephropathy. Altered glucose homeostasis and genetic susceptibility are claimed to play a role in the elevation of SLC. We aimed to test whether metabolic control or the genetic variants of G protein beta 3 (Gb3) subunits determine SLC and other erythrocyte transport activities in complication-free stage of type 1 diabetes. A total of 96 complication-free type 1 diabetic children and adolescents were enrolled. SLC, Na⁺/K⁺-ATPase (NAK) and Ca²⁺-ATPase (CA) were measured by functional assays in erythrocytes. Gb3-C825T polymorphism was determined by PCR-RFLP. Results were related to HbA_1c and were compared to those of 97 healthy controls. SLC activity was higher in diabetics (387±146 vs. 280±65 mmol/RBC · hour) and correlated with HbA_1c levels (y=0.004x+6.42, r=0.33, n=96, p<0.01). NAK and CA activities were unaltered. The prevalence of ⁸²⁵T allele was similar in the patient and control groups (0.34 vs 0.37) and no differences in enzyme activities were observed between the ⁸²⁵T allele-positive and negative subjects. Although metabolic control correlated with SLC, other membrane functions were not affected. Therefore we hypothesize that the relationship between advanced glycation and SLC elevation is not causative. Rather, a genetic susceptibility for the coexistence of poor metabolic control and higher SLC is more likely. However, the presence of Gb3-C825T variant is not likely to be a risk factor for SLC-elevation and altered metabolic control diabetes. Received: 4 December 2001 / Accepted in revised form: 28 August 2002 Correspondence to B. Vásárhelyi     

HbA<Subscript>1c</Subscript> is associated with altered expression in blood of cell cycle- and immune response-related genes

Aims/hypothesis

Individuals with type 2 diabetes are heterogeneous in their glycaemic control as tracked by blood HbA_1c levels. Here, we investigated the extent to which gene expression levels in blood reflect current and future HbA_1c levels.

Methods

HbA_1c levels at baseline and 1 and 2 year follow-up were compared with gene expression levels in 391 individuals with type 2 diabetes from the Hoorn Diabetes Care System Cohort (15,564 genes, RNA sequencing). The functions of associated baseline genes were investigated further using pathway enrichment analysis. Using publicly available data, we investigated whether the genes identified are also associated with HbA_1c in the target tissues, muscle and pancreas.

Results

At baseline, 220 genes (1.4%) were associated with baseline HbA_1c. Identified genes were enriched for cell cycle and complement system activation pathways. The association of 15 genes extended to the target tissues, muscle (n = 113) and pancreatic islets (n = 115). At follow-up, expression of 25 genes (0.16%) associated with 1 year HbA_1c and nine genes (0.06%) with 2 year HbA_1c. Five genes overlapped across all time points, and 18 additional genes between baseline and 1 year follow-up. After adjustment for baseline HbA_1c, the number of significant genes at 1 and 2 years markedly decreased, suggesting that gene expression levels in whole blood reflect the current glycaemic state and but not necessarily the future glycaemic state.

Conclusions/interpretation

HbA_1c levels in individuals with type 2 diabetes are associated with expression levels of genes that link to the cell cycle and complement system activation.

     

HbA<Subscript>1c</Subscript> as a risk factor for heart failure in persons with diabetes: the Atherosclerosis Risk in Communities (ARIC) study

Aims/hypothesis  Heart failure (HF) incidence in diabetes in both the presence and absence of CHD is rising. Prospective population-based studies can help describe the relationship between HbA_1c, a measure of glycaemia control, and HF risk. Methods  We studied the incidence of HF hospitalisation or death among 1,827 participants in the Atherosclerosis Risk in Communities (ARIC) study with diabetes and no evidence of HF at baseline. Cox proportional hazard models included age, sex, race, education, health insurance status, alcohol consumption, BMI and WHR, and major CHD risk factors (BP level and medications, LDL- and HDL-cholesterol levels, and smoking). Results  In this population of persons with diabetes, crude HF incidence rates per 1,000 person-years were lower in the absence of CHD (incidence rate 15.5 for CHD-negative vs 56.4 for CHD-positive, p<0.001). The adjusted HR of HF for each 1% higher HbA_1c was 1.17 (95% CI 1.11–1.25) for the non-CHD group and 1.20 (95% CI 1.04–1.40) for the CHD group. When the analysis was limited to HF cases which occurred in the absence of prevalent or incident CHD (during follow-up) the adjusted HR remained 1.20 (95% CI 1.11–1.29). Conclusions/interpretations  These data suggest HbA_1c is an independent risk factor for incident HF in persons with diabetes with and without CHD. Long-term clinical trials of tight glycaemic control should quantify the impact of different treatment regimens on HF risk reduction.     

Clinical significance of HbA<Subscript>1c</Subscript> as a marker of circulating lipids in male and female type 2 diabetic patients

Diabetic patients with accompanied (but often unnoticed) dyslipidemia are soft targets of cardiovascular deaths. An early intervention to normalize circulating lipids has been shown to reduce cardiovascular complications and mortality. Glycated hemoglobin (HbA_1c) is a routinely used marker for long-term glycemic control. This investigation is an attempt to evaluate the diagnostic value of HbA_1c in predicting diabetic dyslipidemia. Venous blood samples were collected from 2,220 type 2 diabetic patients (ages, 35–91 years; male/female ratio, 1.07). The sera were analyzed for HbA_1c, fasting blood glucose (FBG), total cholesterol, triglycerides, high-density lipoprotein cholesterol (HDL) and low-density lipoprotein cholesterol (LDL). The levels of HbA_1c did not differ significantly between males (8.33 ± 0.06%) and females (8.47 ± 0.07%), whereas female patients had significantly higher FBG (10.01 ± 0.13 mmol/l) than males (9.31 ± 0.11 mmol/l). HbA_1c showed direct and significant correlations with cholesterol, triglycerides and LDL and inverse correlation with HDL. Female diabetic patients had significantly higher levels of serum cholesterol (5.42 ± 0.03 vs. 5.18 ± 0.03 mmol/l) and HDL (1.32 ± 0.01 vs. 1.12 ± 0.01 mmol/l) as compared to males. There was no significant difference in triglycerides and LDL between the two genders. Older patients (>70 years) had significantly lower FBG, cholesterol, triglycerides and LDL. There was a linear and significant increase in triglycerides in the patients of both genders with impaired glycemic control. Both male and female patients with worse glycemic control (HbA_1c > 9%) had significantly high cholesterol and LDL levels. Serum HDL showed a significant and inverse relationship with uncontrolled hyperglycemia in females but not in males. These findings clearly suggest that HbA_1c can provide valuable supplementary information about the extent of circulating lipids besides its primary role in monitoring long-term glycemic control. Further studies are warranted to reinforce the potential of HbA_1c as a biomarker for screening of high-risk diabetic patients.     

Poor lung function accelerates cognitive decline in middle-aged and older adults: Evidence from the English Longitudinal Study of Ageing

Background/objectivePrevious studies have linked lung function to cognitive performance. However, it is not clear whether baseline lung function has an effect on the trajectory of cognitive decline during normal aging. This study aimed to examine the association of baseline lung function with long-term changes in cognition among the middle-aged and older adults.MethodsLung function as indicated by forced expiratory volume 1 s (FEV1) and forced vital capacity (FVC), was measured at the baseline examination. Cognition, including memory, time orientation, executive function and processing speed, were tested four times over six years. Generalized estimating equation (GEE) models were used to test the associations between baseline lung function and four visits of cognition in 6080 participants aged 50 years or over from the English Longitudinal Study of Ageing (ELSA).ResultsCompared to participants with higher lung function, those who had lower lung function at baseline experienced a faster rate of decline in memory (joint test: χ²_interaction = 12.07, df = 3, P = 0.007 for FVC), time orientation (joint test: χ²_interaction = 9.49, df = 3, P = 0.023 for FVC) and executive function (joint test: χ²_interaction = 9.13, df = 3, P = 0.028 for FEV1 and joint test: χ²_interaction = 12.76, df = 3, P = 0.005 for FVC). No association was found between baseline lung function and the rate of decline in processing speed (joint test: χ²_interaction = 1.29, df = 3, P=0.733 for FEV1 and joint test: χ²_interaction = 2.35, df = 3, P = 0.503 for FVC).ConclusionsPoor lung function at baseline predicted a faster rate of cognitive decline in memory, time orientation and executive function. The mechanism for this association deserves further investigation.     

Genetic Determinants of Variability in Glycated Hemoglobin (HbA<Subscript>1c</Subscript>) in Humans: Review of Recent Progress and Prospects for Use in Diabetes Care

Glycated hemoglobin A_1c (HbA_1c) indicates the percentage of total hemoglobin that is bound by glucose, produced from the nonenzymatic chemical modification by glucose of hemoglobin molecules carried in erythrocytes. HbA_1c represents a surrogate marker of average blood glucose concentration over the previous 8 to 12 weeks, or the average lifespan of the erythrocyte, and thus represents a more stable indicator of glycemic status compared with fasting glucose. HbA_1c levels are genetically determined, with heritability of 47% to 59%. Over the past few years, inroads into understanding genetic predisposition by glycemic and nonglycemic factors have been achieved through genome-wide analyses. Here I review current research aimed at discovering genetic determinants of HbA_1c levels, discussing insights into biologic factors influencing variability in the general and diabetic population, and across different ethnicities. Furthermore, I discuss briefly the relevance of findings for diabetes monitoring and diagnosis.     

The dynamic relationship between cognitive function and walking speed: the English Longitudinal Study of Ageing

Cognitive deficiency and oxidative stress have been well documented in aging and in neurodegenerative disorders such as Alzheimer’s disease. In this study, we assessed the therapeutic effect of polyprenols on d-galactose-induced cognitive impairment in mice by testing on of behavioral and cognitive performance. In order to explore the possible role of polyprenols against d-galactose-induced oxidative damages, we assessed various biochemical indicators. Chronic administration of d-galactose (150 mg/kg·d, s.c.) for 7 weeks significantly impaired cognitive performance (both in step-through passive and active avoidance tests) and locomotor activity (in open-field test) and the ability of spatial learning and memory (in Morris water maze test) compared with the control group. The results revealed that polyprenols treatment for 2 weeks significantly ameliorated model mice’s cognitive performance and oxidative defense. All groups of polyprenols enhanced the learning and memory ability in step-through passive and active avoidance tests, locomotor activity in open-field test, and the ability of spatial learning and memory in Morris water maze test. Furthermore, high and middle level of polyprenols significantly increased total antioxidative capacity (T-AOC), glutathione peroxidase (GSH-Px), super oxide dismutase (SOD) activity, neprilysin (NEP), and β-site AβPP cleaving enzyme 1 (BACE1) expression, while nitric oxide (NO), nitric oxide synthase (NOS) activity, malondialdehyde (MDA) concentration, and the level of Aβ1-42 and presenilin 1 (PS1) were decreased. Polyprenols have a significant relieving effect on learning, memory, and spontaneous activities in a d-galactose-induced mouse model and ameliorates cognitive impairment and biochemical dysfunction in mice. In summary, we have demonstrated that polyprenols may ameliorate memory and cognitive impairment via enhancing oxidative defense and affecting generation and dissimilation of Aβ-related enzymes, suggesting that polyprenols represent a novel drug for treating Alzheimer’s disease.     

Haemoglobin A<Subscript>1c</Subscript> levels and subsequent cardiovascular disease in persons without diabetes: a meta-analysis of prospective cohorts

Aims/hypothesis  

The aim of this meta-analysis was to determine the relationship between HbA_1c levels and subsequent cardiovascular outcomes in individuals without diabetes.