Advertisement

Biomarkers in diabetes: hemoglobin A1c, vascular and tissue markers

  • Timothy J. Lyons
    Correspondence
    Reprint requests: Timothy J. Lyons, MD, FRCP, Harold Hamm Diabetes Center and Section of Endocrinology and Diabetes, University of Oklahoma Health Sciences Center, 1000 N. Lincoln Blvd., Suite 2900, Oklahoma City, OK 73104-5020.
    Affiliations
    Harold Hamm Diabetes Center and Section of Endocrinology and Diabetes, University of Oklahoma Health Sciences Center, Oklahoma City, Okla
    Search for articles by this author
  • Arpita Basu
    Affiliations
    Department of Nutritional Sciences, Oklahoma State University, Stillwater, Okla
    Search for articles by this author
Published:February 10, 2012DOI:https://doi.org/10.1016/j.trsl.2012.01.009
      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.

      Abbreviations:

      AGEs (advanced glycation-end products), ALEs (advanced lipoxidation-end products), CML (Nέ-(carboxymethyl) lysine), FL (fructoselysine), HbA1c (hemoglobin A1c), MetSO (methionine sulfoxide), PSA (prostate specific antigen), PEDF (pigment epithelial derived factor), RAGE (receptors for advanced glycation-end products), RBC (red blood cell)
      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to Translational Research
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Biomarkers definitions working group
        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; 69: 89-95
      1. National Cancer Institute at the National Institutes of Health. Dictionary of Cancer Terms. Available at: http://www.cancer.gov/dictionary. Accessed December 1, 2011.

        • Cazares L.H.
        • Drake R.R.
        • Esquela-Kirscher A.
        • Lance R.S.
        • Semmes O.J.
        • Troyer D.A.
        Molecular pathology of prostate cancer.
        Cancer Biomark. 2011; 9: 441-459
        • Malkani S.
        • Mordes J.P.
        Implications of using hemoglobin A1C for diagnosing diabetes mellitus.
        Am J Med. 2011; 124: 395-401
        • Preis S.R.
        • Pencina M.J.
        • Hwang S.J.
        • et al.
        Trends in cardiovascular disease risk factors in individuals with and without diabetes mellitus in the Framingham Heart Study.
        Circulation. 2009; 120: 212-220
        • Dela Cruz C.S.
        • Tanoue L.T.
        • Matthay R.A.
        Lung cancer: epidemiology, etiology, and prevention.
        Clin Chest Med. 2011; 32: 605-644
        • Ceriello A.
        Postprandial hyperglycemia and diabetes complications: is it time to treat?.
        Diabetes. 2005; 54: 1-7
        • Lima N.
        • Cavaliere H.
        • Tomimori E.
        • Knobel M.
        • Medeiros-Neto G.
        Prognostic value of serial serum thyroglobulin determinations after total thyroidectomy for differentiated thyroid cancer.
        J Endocrinol Invest. 2002; 25: 110-115
        • Gong Q.
        • Gregg E.W.
        • Wang J.
        • 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; 54: 300-307
      2. International Expert Committee report on the role of the A1C assay in the diagnosis of diabetes.
        Diabetes Care. 2009; 32: 1327-1334
        • McGarry J.D.
        What if Minkowski had been ageusic? An alternative angle on diabetes.
        Science. 1992; 258: 766-770
        • Herder C.
        • Karakas M.
        • Koenig W.
        Biomarkers for the prediction of type 2 diabetes and cardiovascular disease.
        Clin Pharmacol Ther. 2011; 90: 52-66
        • Rhee E.P.
        • Gerszten R.E.
        Metabolomics and cardiovascular biomarker discovery.
        Clin Chem. 2012; 58: 139-147
        • Monnier V.M.
        • Bautista O.
        • Kenny D.
        • 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; 48: 870-880
        • Schaumberg D.A.
        • Glynn R.J.
        • Jenkins A.J.
        • 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; 111: 2446-2453
        • Gerstein H.C.
        • Miller M.E.
        • Genuth S.
        • et al.
        Long-term effects of intensive glucose lowering on cardiovascular outcomes.
        N Engl J Med. 2011; 364: 818-828
      3. 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; 352: 854-865
        • McKillop A.M.
        • Flatt P.R.
        Emerging applications of metabolomic and genomic profiling in diabetic clinical medicine.
        Diabetes Care. 2011; 34: 2624-2630
      4. Diagnosis and classification of diabetes mellitus.
        Diabetes Care. 2010; 33: S62-S69
        • Cohen R.M.
        • Haggerty S.
        • Herman W.H.
        HbA1c for the diagnosis of diabetes and prediabetes: is it time for a mid-course correction?.
        J Clin Endocrinol Metab. 2010; 95: 5203-5206
        • Nathan D.M.
        • Kuenen J.
        • Borg R.
        • Zheng H.
        • Schoenfeld D.
        • Heine R.J.
        Translating the A1C assay into estimated average glucose values.
        Diabetes Care. 2008; 31: 1473-1478
        • Cohen R.M.
        • Franco R.S.
        • Khera P.K.
        • et al.
        Red cell life span heterogeneity in hematologically normal people is sufficient to alter HbA1c.
        Blood. 2008; 112: 4284-4291
        • Khera P.K.
        • Joiner C.H.
        • Carruthers A.
        • 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; 57: 2445-2452
        • Viberti G.
        • Lachin J.
        • Holman R.
        • et al.
        A Diabetes Outcome Progression Trial (ADOPT): baseline characteristics of type 2 diabetic patients in North America and Europe.
        Diabet Med. 2006; 23: 1289-1294
        • Herman W.H.
        • Ma Y.
        • Uwaifo G.
        • et al.
        Differences in A1C by race and ethnicity among patients with impaired glucose tolerance in the Diabetes Prevention Program.
        Diabetes Care. 2007; 30: 2453-2457
        • Herman W.H.
        • Dungan K.M.
        • Wolffenbuttel B.H.
        • 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; 94: 1689-1694
        • Knowler W.C.
        • Fowler S.E.
        • Hamman R.F.
        • et al.
        10-year follow-up of diabetes incidence and weight loss in the Diabetes Prevention Program Outcomes Study.
        Lancet. 2009; 374: 1677-1686
        • Nathan D.M.
        • Zinman B.
        • Cleary P.A.
        • 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; 169: 1307-1316
        • Hansen D.
        • Dendale P.
        • Jonkers R.A.
        • et al.
        Continuous low- to moderate-intensity exercise training is as effective as moderate- to high-intensity exercise training at lowering blood HbA(1c) in obese type 2 diabetes patients.
        Diabetologia. 2009; 52: 1789-1797
        • Davis W.A.
        • Bruce D.G.
        • Davis T.M.
        Economic impact of moderate weight loss in patients with Type 2 diabetes: the Fremantle Diabetes Study.
        Diabet Med. 2011; 28: 1131-1135
        • Best J.H.
        • Lavillotti K.
        • Deyoung M.B.
        • Garrison L.P.
        The effects of exenatide BID on metabolic control, medication use, and hospitalization in patients with type 2 diabetes mellitus in clinical practice: a systematic review.
        Diabetes Obes Metab. 2011; ([e-pub ahead of print])
        • Delahanty L.M.
        • Nathan D.M.
        • Lachin J.M.
        • 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; 89: 518-524
        • Rahbar S.
        An abnormal hemoglobin in red cells of diabetics.
        Clin Chim Acta. 1968; 22: 296-298
        • Tessier F.J.
        The Maillard reaction in the human body. The main discoveries and factors that affect glycation.
        Pathol Biol (Paris). 2010; 58: 214-219
        • Negre-Salvayre A.
        • Salvayre R.
        • Auge N.
        • Pamplona R.
        • Portero-Otin M.
        Hyperglycemia and glycation in diabetic complications.
        Antioxid Redox Signal. 2009; 11: 3071-3109
        • Rodino-Janeiro B.K.
        • Gonzalez-Peteiro M.
        • Ucieda-Somoza R.
        • Gonzalez-Juanatey J.R.
        • Alvarez E.
        Glycated albumin, a precursor of advanced glycation end-products, up-regulates NADPH oxidase and enhances oxidative stress in human endothelial cells: molecular correlate of diabetic vasculopathy.
        Diabetes Metab Res Rev. 2010; 26: 550-558
        • Kalea A.Z.
        • Schmidt A.M.
        • Hudson B.I.
        RAGE: a novel biological and genetic marker for vascular disease.
        Clin Sci (Lond). 2009; 116: 621-637
        • Colhoun H.M.
        • Betteridge D.J.
        • Durrington P.
        • et al.
        Total soluble and endogenous secretory receptor for advanced glycation end products as predictive biomarkers of coronary heart disease risk in patients with type 2 diabetes: an analysis from the CARDS trial.
        Diabetes. 2011; 60: 2379-2385
        • Katakami N.
        • Matsuhisa M.
        • Kaneto H.
        • et al.
        Decreased endogenous secretory advanced glycation end product receptor in type 1 diabetic patients: its possible association with diabetic vascular complications.
        Diabetes Care. 2005; 28: 2716-2721
        • Lyons T.J.
        • Jenkins A.J.
        glycation, oxidation, and lipoxidation in the development of the complications of diabetes: a carbonyl stress hypothesis.
        Diabetes Rev. 1997; 5: 365-391
        • Curtis T.M.
        • Hamilton R.
        • Yong P.H.
        • et al.
        Muller glial dysfunction during diabetic retinopathy in rats is linked to accumulation of advanced glycation end-products and advanced lipoxidation end-products.
        Diabetologia. 2011; 54: 690-698
        • Boulanger E.
        • Moranne O.
        • Wautier M.P.
        • et al.
        Changes in glycation and oxidation markers in patients starting peritoneal dialysis: a pilot study.
        Perit Dial Int. 2006; 26: 207-212
        • Shanmugam N.
        • Figarola J.L.
        • Li Y.
        • Swiderski P.M.
        • Rahbar S.
        • Natarajan R.
        Proinflammatory effects of advanced lipoxidation end products in monocytes.
        Diabetes. 2008; 57: 879-888
        • Meerwaldt R.
        • Lutgers H.L.
        • Links T.P.
        • et al.
        Skin autofluorescence is a strong predictor of cardiac mortality in diabetes.
        Diabetes Care. 2007; 30: 107-112
        • Libby P.
        • Aikawa M.
        • Jain M.K.
        Vascular endothelium and atherosclerosis.
        Handb Exp Pharmacol. 2006; : 285-306
        • Cines D.B.
        • Pollak E.S.
        • Buck C.A.
        • et al.
        Endothelial cells in physiology and in the pathophysiology of vascular disorders.
        Blood. 1998; 91: 3527-3561
        • Beckman J.A.
        • Creager M.A.
        • Libby P.
        Diabetes and atherosclerosis: epidemiology, pathophysiology, and management.
        JAMA. 2002; 287: 2570-2581
        • Okada H.
        • Fukui M.
        • Tanaka M.
        • 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; 220: 155-159
        • Verbeke F.
        • Marechal C.
        • Van Laecke S.
        • et al.
        Aortic stiffness and central wave reflections predict outcome in renal transplant recipients.
        Hypertension. 2011; 58: 833-838
        • Jenkins A.J.
        • Zhang S.X.
        • Rowley K.G.
        • et al.
        Increased serum pigment epithelium-derived factor is associated with microvascular complications, vascular stiffness and inflammation in Type 1 diabetes.
        Diabet Med. 2007; 24: 1345-1351
        • Mita T.
        • Watada H.
        • Ogihara T.
        • et al.
        Eicosapentaenoic acid reduces the progression of carotid intima-media thickness in patients with type 2 diabetes.
        Atherosclerosis. 2007; 191: 162-167
        • Kim O.Y.
        • Yoe H.Y.
        • Kim H.J.
        • et al.
        Independent inverse relationship between serum lycopene concentration and arterial stiffness.
        Atherosclerosis. 2010; 208: 581-586
        • Yeo H.Y.
        • Kim O.Y.
        • Lim H.H.
        • Kim J.Y.
        • Lee J.H.
        Association of serum lycopene and brachial-ankle pulse wave velocity with metabolic syndrome.
        Metabolism. 2011; 60: 537-543
        • Mukherjee S.
        • Mukhopadhyay P.
        • Pandit K.
        • Chowdhury S.
        Atorvastatin improves arterial stiffness in normotensive normolipidaemic persons with type 2 diabetes.
        J Indian Med Assoc. 2008; 106: 716-719
        • Webb D.R.
        • Davies M.J.
        • Gray L.J.
        • et al.
        Searching for the right outcome? A systematic review and meta-analysis of controlled trials using carotid intima-media thickness or pulse wave velocity to infer antiatherogenic properties of thiazolidinediones.
        Diabetes Obes Metab. 2010; 12: 124-132
        • Madden K.M.
        • Lockhart C.
        • Cuff D.
        • Potter T.F.
        • Meneilly G.S.
        Short-term aerobic exercise reduces arterial stiffness in older adults with type 2 diabetes, hypertension, and hypercholesterolemia.
        Diabetes Care. 2009; 32: 1531-1535
        • Maynard J.D.
        • Rohrscheib M.
        • Way J.F.
        • Nguyen C.M.
        • Ediger M.N.
        Noninvasive type 2 diabetes screening: superior sensitivity to fasting plasma glucose and A1C.
        Diabetes Care. 2007; 30: 1120-1124
        • Kessel L.
        • Hougaard J.L.
        • Sander B.
        • Kyvik K.O.
        • Sorensen T.I.
        • Larsen M.
        Lens ageing as an indicator of tissue damage associated with smoking and non-enzymatic glycation–a twin study.
        Diabetologia. 2002; 45: 1457-1462
        • Gerrits E.G.
        • Lutgers H.L.
        • Kleefstra N.
        • et al.
        Skin autofluorescence: a tool to identify type 2 diabetic patients at risk for developing microvascular complications.
        Diabetes Care. 2008; 31: 517-521
        • Yu Y.
        • Thorpe S.R.
        • Jenkins A.J.
        • et al.
        Advanced glycation end-products and methionine sulphoxide in skin collagen of patients with type 1 diabetes.
        Diabetologia. 2006; 49: 2488-2498
        • Lyons T.J.
        • Bailie K.E.
        • Dyer D.G.
        • Dunn J.A.
        • Baynes J.W.
        Decrease in skin collagen glycation with improved glycemic control in patients with insulin-dependent diabetes mellitus.
        J Clin Invest. 1991; 87: 1910-1915
        • Stirban A.
        • Nandrean S.
        • Negrean M.
        • Koschinsky T.
        • Tschoepe D.
        Skin autofluorescence increases postprandially in human subjects.
        Diabetes Technol Ther. 2008; 10: 200-205
        • Goh S.Y.
        • Cooper M.E.
        Clinical review: the role of advanced glycation end products in progression and complications of diabetes.
        J Clin Endocrinol Metab. 2008; 93: 1143-1152
        • Varani J.
        • Perone P.
        • Merfert M.G.
        • Moon S.E.
        • Larkin D.
        • Stevens M.J.
        All-trans retinoic acid improves structure and function of diabetic rat skin in organ culture.
        Diabetes. 2002; 51: 3510-3516
        • Rajasekar P.
        • Anuradha C.V.
        L-Carnitine inhibits protein glycation in vitro and in vivo: evidence for a role in diabetic management.
        Acta Diabetol. 2007; 44: 83-90
        • Thirunavukkarasu V.
        • Nandhini A.T.
        • Anuradha C.V.
        Fructose diet-induced skin collagen abnormalities are prevented by lipoic acid.
        Exp Diabesity Res. 2004; 5: 237-244
        • Feke G.T.
        • Tagawa H.
        • Deupree D.M.
        • Goger D.G.
        • Sebag J.
        • Weiter J.J.
        Blood flow in the normal human retina.
        Invest Ophthalmol Vis Sci. 1989; 30: 58-65
        • Wu M.
        • Chen Y.
        • Wilson K.
        • et al.
        Intraretinal leakage and oxidation of LDL in diabetic retinopathy.
        Invest Ophthalmol Vis Sci. 2008; 49: 2679-2685
        • Nagaoka T.
        • Sato E.
        • Takahashi A.
        • Yokota H.
        • Sogawa K.
        • Yoshida A.
        Impaired retinal circulation in patients with type 2 diabetes mellitus: retinal laser Doppler velocimetry study.
        Invest Ophthalmol Vis Sci. 2010; 51: 6729-6734
        • Lorenzi M.
        • Feke G.T.
        • Cagliero E.
        • et al.
        Retinal haemodynamics in individuals with well-controlled type 1 diabetes.
        Diabetologia. 2008; 51: 361-364
        • Lorenzi M.
        • Feke G.T.
        • Pitler L.
        • Berisha F.
        • Kolodjaschna J.
        • McMeel J.W.
        Defective myogenic response to posture change in retinal vessels of well-controlled type 1 diabetic patients with no retinopathy.
        Invest Ophthalmol Vis Sci. 2010; 51: 6770-6775
        • Wright A.D.
        • Dodson P.M.
        Medical management of diabetic retinopathy: fenofibrate and ACCORD Eye studies.
        Eye (Lond). 2011; 25: 843-849
        • Wu M.
        • Lyons T.J.
        Treatment approaches for diabetes and dyslipidemia.
        Horm Res Paediatr. 2011; 76: 76-80