Abstract
The purpose of this investigation was to evaluate the effects of experimental hyperglycemia on oxidative damage (OX), advanced glycation end products (AGEs), and the receptor for AGEs (RAGE) through an in vivo approach. Obese subjects (n = 10; 31.2 ± 1.2 kg·m−2; 56 ± 3 years) underwent 24 h of hyperglycemic clamp (+5.4 mM above basal), where plasma at basal and after 2 h and 24 h of hyperglycemic challenge were assayed for OX (methionine sulfoxide, MetSO, and aminoadipic acid, AAA) and AGE-free adducts (Ne-carboxymethyllysine, CML; Ne-carboxyethyllysine, CEL; glyoxal hydroimidazolone-1, GH-1; methylglyoxal hydroimidazolone-1, MG-H1; and 3-deoxyglucosone hydroimidazolone, 3DG-H) via liquid chromatography–tandem mass spectrometry (LC–MS/MS). Urine was also analyzed at basal and after 24 h for OX and AGE-free adducts and plasma soluble RAGE (sRAGE) isoforms (endogenous secretory RAGE, esRAGE, and cleaved RAGE, cRAGE), and inflammatory markers were determined via enzyme-linked immunosorbent assay (ELISA). Skeletal muscle tissue collected via biopsy was probed at basal, 2 h, and 24 h for RAGE and OST48 protein expression. Plasma MetSO, AAA, CEL, MG-H1, and G-H1 decreased (−18% to −47%; p < 0.05), while CML increased (72% at 24 h; p < 0.05) and 3DG-H remained unchanged (p > 0.05) with the hyperglycemic challenge. Renal clearance of MetSO, AAA, and G-H1 increased (599% to 1077%; p < 0.05), CML decreased (−30%; p < 0.05), and 3DG-H, CEL, and MG-H1 remained unchanged (p > 0.05). Fractional excretion of MetSO, AAA, CEL, G-H1, and MG-H1 increased (5.8% to 532%; p < 0.05) and CML and 3DG-H remained unchanged (p > 0.05). Muscle RAGE and OST48 expression, plasma sRAGE, IL-1β, IL-1Ra, and TNFα remained unchanged (p > 0.05), while IL-6 increased (159% vs. basal; p > 0.05). These findings suggest that individuals who are obese but otherwise healthy have the capacity to prevent accumulation of OX and AGEs during metabolic stress by increasing fractional excretion and renal clearance.
Highlights
Diabetes mellitus is an increasingly prevalent public health concern [1]
The primary goal of this investigation was to evaluate the effects of experimental hyperglycemia on the advanced glycation end products (AGEs)–receptor for AGEs (RAGE) axis in humans
Glucose and other reactive dicarbonyls stimulate the formation of oxidative damage (OX) and AGEs individuals with type 2 diabetes possessing higher basal circulating concentration of these
Summary
30 million individuals in the U.S alone have diabetes [2]. The reduced ability to handle glucose disposal highlights the chronic state of hyperglycemia that individuals with diabetes experience. A primary consequence of hyperglycemia is the formation of oxidative damage (OX) and advanced glycation end products (AGEs) [5]. AGEs are long-lasting reactive intermediates formed from nonenzymatic reactions between glucose or other glycating dicarbonyls (i.e., methylglyoxal, glyoxal, and 3-deoxyglucosone) and a target protein, [6,7,8], while OX markers are formed through oxidative processes [9]. The degree of AGE formation is related to glucose concentrations and accessibility to specific protein amine groups (e.g., lysine and arginine). In addition to endogenous production of AGEs and OXs, other factors, such as a diet utilizing high-heat cooking methods [10,11]
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