Hidden complexities in the measurement of fructosyl-lysine and advanced glycation end products for risk prediction of vascular complications of diabetes.

Abstract

Diabetes is associated with increased glycation of proteins by glucose and methylglyoxal (MG). Early-stage glycation by glucose forms fructosamine adducts, mainly Ne-fructosyl-lysine (FL), which can be exploited for assessment of glycemic control in the measurement of A1C (FL and Nα-fructosyl-valine). Later- or advanced-stage glycation processes involving degradation of FL and glycation of proteins by MG and related physiological dicarbonyl metabolites form advanced glycation end products (AGEs) (1). AGEs contribute to the pathogenesis of vascular complications of diabetes, and their measurement may provide improved complications-risk prediction. Stable isotopic dilution analysis liquid chromatography-tandem mass spectrometry has markedly improved the measurement of AGEs, providing robust quantitation of multiple AGEs concurrently in tissues and body fluids (2). Examples of AGEs formed from fructosamine degradation are Ne-carboxymethyl-lysine (CML) and crosslink glucosepane, and examples of AGEs formed from MG are hydroimidazolone MG-H1 and Ne-(carboxymethyl)lysine (CEL). Liquid chromatography-tandem mass spectrometry also revealed two major forms of each AGE: AGE moieties of proteins, called AGE residues by conventional biochemical nomenclature (also known by the trivial nomenclature of “protein-bound AGEs”), and AGE free adducts (glycated amino acids) formed mainly by the proteolysis of AGE-modified proteins. Protein AGE residues have low renal clearance and biodistribution limited to that of the protein on which they are formed, whereas free adducts have high renal clearance and membrane permeability via amino acid and other transporters and are the major form in which AGEs are cleared from the body by urinary …