Review ArticleBiomarkers in diabetes: hemoglobin A1c, vascular and tissue markers
Section snippets
Definitions: Biomarkers and Risk Factors
The term “biomarker”, alternatively called “molecular marker” or a “signature molecule” requires clear definition and must be distinguished from “risk factor.” A biomarker has been defined as “a biological molecule found in blood, other bodily fluids, or tissue which represents a sign of a normal or abnormal process or of a condition or disease. A biomarker may be used to see how well the body responds to a treatment for a disease or condition”. 1, 2 Examples by this definition include prostate
Utility of Biomarkers
Biomarkers provide the ability to identify people with subclinical disease before the development of overt clinical disease. They enable preventive measures to be applied at the subclinical stage, and the responses to preventive or therapeutic measures to be monitored. They facilitate studies of disease mechanisms, and they enable the assessment of new preventive and therapeutic measures by providing surrogate end points for intervention studies. In short, biomarkers enable us to monitor the
Challenges
The development and characterization of an effective biomarker is arduous. In the context of diabetes, the slow development of vascular complications in humans means that very long-term studies are necessary. Biomarker utility must be confirmed in at least two, and ideally more, independent populations. In addition, while the utility of biomarkers may be high when diseases are considered at the population level, this may not apply to the individual patient: for example, the significance of PSA
Hemoglobin A1c (HbA1c) as a Biomarker in Diabetes
The use of HbA1c as a diagnostic criterion for diabetes (≥6.5%) and prediabetes (5.7%–6.4%) was recently added to the standards of care by the American Diabetes Association (ADA) based on the recommendations of the International Expert Committee.10, 19 The consensus recognized several advantages of HbA1c in comparison to fasting plasma glucose levels or glucose level 2-h post-75g oral glucose load. Specifically, HbA1c was viewed as a better standardized assay than glucose, a better index of
Metabolic Biomarkers in Diabetes: Glycation, Oxidation, and Carbonyl Stress
Consideration of HbA1c serves as an introduction to a much wider field of actual and potential biomarkers for diabetes and its complications. The discovery of HbA1c, and its identification as a glycated form of hemoglobin,33 opened a field of diabetes research that has since been burgeoning for over forty years: the chemistry of glycation (nonenzymatic glycosylation) and its consequences, including the role of advanced glycation end-products (AGEs), free-radical damage mediated by reactive
Biomarkers of Vascular Function in Diabetes
Endothelial activation leading to vascular dysfunction has been regarded as an early, preclinical component in the development of vascular diseases.45 The endothelium is a monolayer of cells lining blood vessels throughout the body; it may be regarded as an organ weighing in total over 1 kg.46 It has numerous functions, acting as a structural barrier between the circulation and the tissue, as a source of growth factors and angiogenic and anti-angiogenic factors, controlling thrombosis and
Tissue Biomarkers in Diabetes: Skin and Retina
The glycation of skin collagen and the accumulation of advanced glycation end products (AGEs) has been strongly correlated with long-term diabetes complications, even after adjusting for HbA1c.14 A newly-described noninvasive method to assess tissue AGEs involves skin autofluorescence. This method is based on the specific fluorescence characteristics of AGEs and has been employed in both skin and lens.57, 58 Studies by our group and others have shown that autofluorescence is increased in the
Conclusions
In summary, biomarkers for diabetes and its vascular complications will, in future, be sought more widely, and in affected tissues, not only in serum, plasma, or urine (Fig). Not all of the new biomarkers will be “biomolecules”: some will depend upon functional measures and some on new imaging techniques. The tissue-specific markers are especially needed in diabetes, since the disease may affect different organs (eg, heart, eye, kidney, nerve) to different extents within the same individual:
References (73)
- et al.
Implications of using hemoglobin A1C for diagnosing diabetes mellitus
Am J Med
(2011) - et al.
Lung cancer: epidemiology, etiology, and prevention
Clin Chest Med
(2011) - et al.
Red cell life span heterogeneity in hematologically normal people is sufficient to alter HbA1c
Blood
(2008) - et al.
Association of diet with glycated hemoglobin during intensive treatment of type 1 diabetes in the Diabetes Control and Complications Trial
Am J Clin Nutr
(2009) An abnormal hemoglobin in red cells of diabetics
Clin Chim Acta
(1968)The Maillard reaction in the human body. The main discoveries and factors that affect glycation
Pathol Biol (Paris)
(2010)- et al.
Endothelial cells in physiology and in the pathophysiology of vascular disorders
Blood
(1998) - et al.
Visit-to-visit variability in systolic blood pressure is correlated with diabetic nephropathy and atherosclerosis in patients with type 2 diabetes
Atherosclerosis
(2012) - et al.
Eicosapentaenoic acid reduces the progression of carotid intima-media thickness in patients with type 2 diabetes
Atherosclerosis
(2007) - et al.
Independent inverse relationship between serum lycopene concentration and arterial stiffness
Atherosclerosis
(2010)
Association of serum lycopene and brachial-ankle pulse wave velocity with metabolic syndrome
Metabolism
National Institutes of Health Director's Initiative on Biomarkers and Surrogate Endpoints. Biomarkers and surrogate endpoints: preferred definitions and conceptual framework
Clin Pharmacol Ther
Molecular pathology of prostate cancer
Cancer Biomark
Trends in cardiovascular disease risk factors in individuals with and without diabetes mellitus in the Framingham Heart Study
Circulation
Postprandial hyperglycemia and diabetes complications: is it time to treat?
Diabetes
Prognostic value of serial serum thyroglobulin determinations after total thyroidectomy for differentiated thyroid cancer
J Endocrinol Invest
Long-term effects of a randomised trial of a 6-year lifestyle intervention in impaired glucose tolerance on diabetes-related microvascular complications: the China Da Qing Diabetes Prevention Outcome Study
Diabetologia
International Expert Committee report on the role of the A1C assay in the diagnosis of diabetes
Diabetes Care
What if Minkowski had been ageusic? An alternative angle on diabetes
Science
Biomarkers for the prediction of type 2 diabetes and cardiovascular disease
Clin Pharmacol Ther
Metabolomics and cardiovascular biomarker discovery
Clin Chem
Skin collagen glycation, glycoxidation, and crosslinking are lower in subjects with long-term intensive versus conventional therapy of type 1 diabetes: relevance of glycated collagen products versus HbA1c as markers of diabetic complications. DCCT Skin Collagen Ancillary Study Group. Diabetes Control and Complications Trial
Diabetes
Effect of intensive glycemic control on levels of markers of inflammation in type 1 diabetes mellitus in the diabetes control and complications trial
Circulation
Long-term effects of intensive glucose lowering on cardiovascular outcomes
N Engl J Med
Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). UK Prospective Diabetes Study (UKPDS) Group
Lancet
Emerging applications of metabolomic and genomic profiling in diabetic clinical medicine
Diabetes Care
Diagnosis and classification of diabetes mellitus
Diabetes Care
HbA1c for the diagnosis of diabetes and prediabetes: is it time for a mid-course correction?
J Clin Endocrinol Metab
Translating the A1C assay into estimated average glucose values
Diabetes Care
Evidence for interindividual heterogeneity in the glucose gradient across the human red blood cell membrane and its relationship to hemoglobin glycation
Diabetes
A Diabetes Outcome Progression Trial (ADOPT): baseline characteristics of type 2 diabetic patients in North America and Europe
Diabet Med
Differences in A1C by race and ethnicity among patients with impaired glucose tolerance in the Diabetes Prevention Program
Diabetes Care
Racial and ethnic differences in mean plasma glucose, hemoglobin A1c, and 1,5-anhydroglucitol in over 2000 patients with type 2 diabetes
J Clin Endocrinol Metab
10-year follow-up of diabetes incidence and weight loss in the Diabetes Prevention Program Outcomes Study
Lancet
Modern-day clinical course of type 1 diabetes mellitus after 30 years’ duration: the diabetes control and complications trial/epidemiology of diabetes interventions and complications and Pittsburgh epidemiology of diabetes complications experience (1983–2005)
Arch Intern Med
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Research included in this review has been supported by grants from the American Diabetes Association (ADA), National Institutes of Health (NIH), and the Oklahoma Center for the Advancement of Science and Technology (OCAST)(T.J.L.).
Conflict of interest: None.