Review Article
Biomarkers in diabetes: hemoglobin A1c, vascular and tissue markers

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Biomarkers are conventionally defined as “biological molecules that represent health and disease states.” They typically are measured in readily available body fluids (blood or urine), lie outside the causal pathway, are able to detect subclinical disease, and are used to monitor clinical and subclinical disease burden and response to treatments. Biomarkers can be “direct” endpoints of the disease itself, or “indirect” or surrogate endpoints. New technologies (such as metabolomics, proteomics, genomics) bring a wealth of opportunity to develop new biomarkers. Other new technologies enable the development of nonmolecular, functional, or biophysical tissue-based biomarkers. Diabetes mellitus is a complex disease affecting almost every tissue and organ system, with metabolic ramifications extending far beyond impaired glucose metabolism. Biomarkers may reflect the presence and severity of hyperglycemia (ie, diabetes itself) or the presence and severity of the vascular complications of diabetes. Illustrative examples are considered in this brief review. In blood, hemoglobin A1c (HbA1c) may be considered as a biomarker for the presence and severity of hyperglycemia, implying diabetes or prediabetes, or, over time, as a “biomarker for a risk factor,” ie, hyperglycemia as a risk factor for diabetic retinopathy, nephropathy, and other vascular complications of diabetes. In tissues, glycation and oxidative stress resulting from hyperglycemia and dyslipidemia lead to widespread modification of biomolecules by advanced glycation end products (AGEs). Some of these altered species may serve as biomarkers, whereas others may lie in the causal pathway for vascular damage. New noninvasive technologies can detect tissue damage mediated by AGE formation: these include indirect measures such as pulse wave analysis (a marker of vascular dysfunction) and more direct markers such as skin autofluorescence (a marker of long-term accumulation of AGEs). In the future, we can be optimistic that new blood and tissue-based biomarkers will enable the detection, prevention, and treatment of diabetes and its complications long before overt disease develops.

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)

  • H.Y. Yeo et al.

    Association of serum lycopene and brachial-ankle pulse wave velocity with metabolic syndrome

    Metabolism

    (2011)
  • National Institutes of Health Director's Initiative on Biomarkers and Surrogate Endpoints. Biomarkers and surrogate endpoints: preferred definitions and conceptual framework

    Clin Pharmacol Ther

    (2001)
  • National Cancer Institute at the National Institutes of Health. Dictionary of Cancer Terms. Available at:...
  • L.H. Cazares et al.

    Molecular pathology of prostate cancer

    Cancer Biomark

    (2011)
  • S.R. Preis et al.

    Trends in cardiovascular disease risk factors in individuals with and without diabetes mellitus in the Framingham Heart Study

    Circulation

    (2009)
  • A. Ceriello

    Postprandial hyperglycemia and diabetes complications: is it time to treat?

    Diabetes

    (2005)
  • N. Lima et al.

    Prognostic value of serial serum thyroglobulin determinations after total thyroidectomy for differentiated thyroid cancer

    J Endocrinol Invest

    (2002)
  • Q. Gong et al.

    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

    (2011)
  • International Expert Committee report on the role of the A1C assay in the diagnosis of diabetes

    Diabetes Care

    (2009)
  • J.D. McGarry

    What if Minkowski had been ageusic? An alternative angle on diabetes

    Science

    (1992)
  • C. Herder et al.

    Biomarkers for the prediction of type 2 diabetes and cardiovascular disease

    Clin Pharmacol Ther

    (2011)
  • E.P. Rhee et al.

    Metabolomics and cardiovascular biomarker discovery

    Clin Chem

    (2012)
  • V.M. Monnier et al.

    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

    (1999)
  • D.A. Schaumberg et al.

    Effect of intensive glycemic control on levels of markers of inflammation in type 1 diabetes mellitus in the diabetes control and complications trial

    Circulation

    (2005)
  • H.C. Gerstein et al.

    Long-term effects of intensive glucose lowering on cardiovascular outcomes

    N Engl J Med

    (2011)
  • 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

    (1998)
  • A.M. McKillop et al.

    Emerging applications of metabolomic and genomic profiling in diabetic clinical medicine

    Diabetes Care

    (2011)
  • Diagnosis and classification of diabetes mellitus

    Diabetes Care

    (2010)
  • R.M. Cohen et al.

    HbA1c for the diagnosis of diabetes and prediabetes: is it time for a mid-course correction?

    J Clin Endocrinol Metab

    (2010)
  • D.M. Nathan et al.

    Translating the A1C assay into estimated average glucose values

    Diabetes Care

    (2008)
  • P.K. Khera et al.

    Evidence for interindividual heterogeneity in the glucose gradient across the human red blood cell membrane and its relationship to hemoglobin glycation

    Diabetes

    (2008)
  • G. Viberti et al.

    A Diabetes Outcome Progression Trial (ADOPT): baseline characteristics of type 2 diabetic patients in North America and Europe

    Diabet Med

    (2006)
  • W.H. Herman et al.

    Differences in A1C by race and ethnicity among patients with impaired glucose tolerance in the Diabetes Prevention Program

    Diabetes Care

    (2007)
  • W.H. Herman et al.

    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

    (2009)
  • W.C. Knowler et al.

    10-year follow-up of diabetes incidence and weight loss in the Diabetes Prevention Program Outcomes Study

    Lancet

    (2009)
  • D.M. Nathan et al.

    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

    (2009)
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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.

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