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Concept: Anthony Cerami

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The One Drop | Mobile app supports manual and passive (via HealthKit and One Drop’s glucose meter) tracking of self-care and glycated hemoglobin A1c (HbA1c).

Concepts: Diabetes mellitus, Diabetes, Glycated hemoglobin, Glycation, Anthony Cerami

30

Glycated hemoglobin (HbA1c) is used to diagnose type 2 diabetes (T2D) and assess glycemic control in patients with diabetes. Previous genome-wide association studies (GWAS) have identified 18 HbA1c-associated genetic variants. These variants proved to be classifiable by their likely biological action as erythrocytic (also associated with erythrocyte traits) or glycemic (associated with other glucose-related traits). In this study, we tested the hypotheses that, in a very large scale GWAS, we would identify more genetic variants associated with HbA1c and that HbA1c variants implicated in erythrocytic biology would affect the diagnostic accuracy of HbA1c. We therefore expanded the number of HbA1c-associated loci and tested the effect of genetic risk-scores comprised of erythrocytic or glycemic variants on incident diabetes prediction and on prevalent diabetes screening performance. Throughout this multiancestry study, we kept a focus on interancestry differences in HbA1c genetics performance that might influence race-ancestry differences in health outcomes.

Concepts: Genetics, Biology, Diabetes mellitus type 2, Diabetes mellitus, Diabetes, Glycated hemoglobin, Glycation, Anthony Cerami

28

Since the discovery of the relation between increased concentrations of fast haemoglobin fractions in patients with diabetes mellitus compared to concentrations in subjects without diabetes mellitus by Samuel Rahbar and co-workers in 1969, glycated haemoglobin A1c (HbA1c) has become a “gold standard” for glucose management in patients with diabetes mellitus. Recently, HbA1c has been advocated as a diagnostic marker for diabetes mellitus, which further underlines the importance of HbA1c. There are currently more than 30 methods available on the market with an analytical performance ranging from poor to state of the art. This review describes the biochemistry of HbA1c and the concepts of analytical and biological variation with respect to the measurement of HbA1c. Subsequently, aspects regarding the discovery of HbA1c are described. In addition, an overview is given on the assays methods that are currently available for the measurement of HbA1c. Finally, recommendations for the minimally required analytical performance characteristics of the current HbA1c assays are presented.

Concepts: Insulin, Diabetes mellitus, Glucose, Diabetes, Blood sugar, Glycated hemoglobin, Glycation, Anthony Cerami

4

Glycemic targets in diabetes have been developed to minimize complication risk. Patients with heterozygous, inactivating glucokinase (GCK) mutations have mild fasting hyperglycemia from birth, resulting in an elevated glycated hemoglobin (HbA1c) level that mimics recommended levels for type 1 and type 2 diabetes.

Concepts: Nutrition, Diabetes mellitus type 2, Diabetes mellitus, Diabetes, Glycated hemoglobin, Glycation, Anthony Cerami

3

To evaluate the utility of glycated haemoglobin A1c (HbA1c) alone and in combination with haematocrit (HCT) for screening gestational diabetes mellitus (GDM) between 12-16 gestational weeks.

Concepts: Pregnancy, Diabetes mellitus, Diabetes, Obstetrics, Gestational diabetes, Glycated hemoglobin, Glycation, Anthony Cerami

3

The association of chronic glycemia, measured by HbA1c, with long-term complications of type 1 diabetes has been well established in the Diabetes Control and Complications Trial (DCCT) and other studies. The role of intermediate-term and acute glycemia and of glucose variability on microvascular and cardiovascular disease is less clear. In order to examine the inter-relationships among long-term, intermediate-term and acute measures of glucose and its daily variability, we compared HbA1c, glycated albumin (GA), and 7-point glucose profile concentrations measured longitudinally in a case-cohort subpopulation of the DCCT. HbA1c and GA were closely correlated with each other and with the mean blood glucose concentrations (MBG) calculated from the 7-point profile. The associations of glucose variability and post-prandial concentrations with HbA1c and GA were relatively weak and were further attenuated when MBG was included in multivariate models. In the case-cohort analyses, HbA1c and GA had similar associations with retinopathy and nephropathy, which were strengthened when both measures were considered together. Only HbA1c was significantly associated with cardiovascular disease. The demonstrated inter-relationships among different measures of glycemia will need to be considered in future analyses of their roles in the development of long-term complications of type 1 diabetes.

Concepts: Diabetes mellitus, Diabetes, Blood sugar, Glycated hemoglobin, Glycation, Blood proteins, Diabetes control and complications trial, Anthony Cerami

2

Although the medical community acknowledges the importance of preoperative glycemic control, the literature is inconclusive and the proper metric for assessment of glycemic control remains unclear. Serum fructosamine reflects the mean glycemic control in a shorter time period compared with glycated hemoglobin (HbA1c). Our aim was to examine its role in predicting adverse outcomes following total joint arthroplasty.

Concepts: Diabetes mellitus, Diabetes, Glycated hemoglobin, Glycation, Arthroplasty, Anthony Cerami

2

Long-term data validating glycated hemoglobin (HbA1c) in assessing the risk of type 2 diabetes in children are limited. HbA1c, fasting plasma glucose (FPG), and 2-h postload plasma glucose (2hPG) concentrations were measured in a longitudinal study of American Indians to determine their utility in predicting incident diabetes, all of which is thought to be type 2 in this population.

Concepts: Diabetes mellitus, Diabetes, Blood sugar, Sociology, Blood tests, Glycated hemoglobin, Glycation, Anthony Cerami

2

Many studies have reported an association between glycated hemoglobin A1c (HbA1c) and metabolic syndrome (MetS) in non-diabetes patients. Each component of MetS is in fact related to chronic kidney disease (CKD) incidence and progression. Therefore, HbA1c in non-diabetic mellitus (DM) may be intrinsically associated with the prevalence of CKD. The hypothesis of the present study was that high HbA1c in non-DM patients is associated with CKD.

Concepts: Chronic kidney disease, Diabetes mellitus, Diabetes, Glycated hemoglobin, Glycation, Anthony Cerami

1

The αV β3integrin plays an important role in many physiological functions and pathological disorders. αV β3is minimally expressed in normal quiescent endothelial cells, but significantly upregulated during neovascularization. In this study, we evaluated a64Cu-labeled dimeric cRGD tracer targeted at αV β3integrin and report its applicability to assess peripheral angiogenesis in diabetes mellitus (DM). We established a murine model of type-1 DM characterized by elevated glucose, glycated serum protein (GSP), and glycated hemoglobin A1c (HbA1c). We demonstrated that our imaging probe is specific to αV β3integrin under both normo- and hyperglycemic conditions. We found that the analysis of in vivo PET-CT images correlated well with gamma well counting (GWC). Both GWC and PET-CT imaging demonstrated increased uptake of64Cu-NOTA-PEG4-cRGD2in the ischemic hindlimb in contrast to non-ischemic control. GWC of the distal ischemic tissue from DM mice showed significantly lower probe accumulation than in non-DM mice. The immunofluorescence staining of the ischemic tissues showed a 3-fold reduction in CD31 and 4-fold reduction in the αV β3expression in DM vs. non-DM animals. In conclusion, we successfully demonstrated that diabetes-associated reductions in peripheral angiogenesis can be non-invasively detected with PET-CT imaging using targeted dimeric-cRGD probe.

Concepts: Diabetes mellitus, Glucose, Blood vessel, Diabetes, Blood sugar, Glycated hemoglobin, Glycation, Anthony Cerami