AGEs Are Higher in People with Diabetes
How AGEs Accumulate
Protein glycation is a multi-stage reaction that begins with formation of a sugar adduct to protein, known as a fructosamine or Amadori compound, which gradually matures to form numerous stable adducts and crosslinks, collectively denoted ‘Advanced Glycation Endproducts’ (AGEs). Some AGEs require oxidation chemistry for their formation and are known as glycoxidation products. Collagen is a protein that readily undergoes glycation and glycoxidation. Because of its long half-life, the level of AGEs in collagen acts as a long-term integrator of overall glycemia that is insensitive to short- or intermediate-term fluctuations in glycemic control. Consequently, AGEs accumulate naturally during healthy aging, but at significantly accelerated rates in persons with diabetes.
Hemoglobin, the most abundant protein in red blood cells, also undergoes glycation. Glycated hemoglobin (A1C) is a useful indicator of how well the body controls blood sugar. The A1C test is a measure of the body’s average glucose metabolism over the past 90 days. However, the test is of limited value for detection and screening of diabetes because glycated hemoglobin tends to vary significantly over a period of weeks.
Skin AGEs as an Indicator of Systemic Damage
Two of the most frequently studied skin AGEs are pentosidine, a fluorescent crosslink between lysine and arginine residues, and the lysine derivative, carboxymethyl-lysine (CML). Levels of pentosidine and CML in the skin are positively correlated with the severity of retinopathy, nephropathy and neuropathy. Thus, skin AGEs are an indicator of systemic damage to protein in diabetes and a metric of a patient’s risk for complications. In addition, due to the mild to severe hyperglycemia associated with type 2 diabetes and pre-diabetes, individuals who are in the early stages of this continuum will accumulate AGEs at higher than normal rates in their tissues. Thus, given sufficient assay sensitivity, an AGE measurement offers the promise to detect early departure from normal glycemia.
Sources:
• N. Verzijl, J. DeGroot, S.R. Thorpe, R.A. Bank, J.N. Shaw, T.J. Lyons, J.W.J. Bijlsam, F.P.J.G. Lafeber, J.W. Baynes, and J.M. TeKoppele, “Effect of collagen turnover on the accumulation of advanced glycation end products,” J. Biol. Chem. 275, 39027-39031 (2000).
• D.G. Dyer, J.A. Dunn, S.R. Thorpe, K.E. Bailie, T.J. Lyons, D.R. McCance, and J.W. Baynes, “Accumulation of Maillard reaction products in skin collagen in diabetes and aging,” J. Clin. Invest. 91, 2463-2469 (1993).
• R. McCance, D.G. Dyer, J.A. Dunn, K.E. Bailie, S.R. Thorpe, J.W. Baynes, and T.J.Lyons, “Maillard reaction products and theor relation to complications in insulin-dependent diabetes mellitus,” J. Clin. Invest. 91, 2470-2478 (1993).
• B. Buckingham and K.M. Reiser, “Relationship between the Content of Lysyl Oxidase-dependent Crosslinks in Skin Collagen, Nonenzymatic Glycosylation, and Long-Term Complications in type 1 Diabetes Mellitus,” J. Clin. Invest. 86, 1046-1054 (1990).
• V.M. Monnier, O. Bautista, D. Kenny, D.R. Sell, J. Fogarty, W. Daahms, P.A. Cleary, J. Lachin, S. Genuth, and the DCCT Skin Collagen Ancillary Study Group, “Skin collagen glycation, glycoxidation, and crosslinking are lower in subjects with long-term intensive versus conventional therapy of type 1 diabetes,” Diabetes 48, 870-880 (1999).