Increased Glycation and Oxidative Damage to Apolipoprotein B100 of LDL Cholesterol in Patients With Type 2 Diabetes and Effect of Metformin

Abstract

OBJECTIVEThe aim of this study was to investigate whether apolipoprotein B100 of LDL suffers increased damage by glycation, oxidation, and nitration in patients with type 2 diabetes, including patients receiving metformin therapy.RESEARCH DESIGN AND METHODSFor this study, 32 type 2 diabetic patients and 21 healthy control subjects were recruited; 13 diabetic patients were receiving metformin therapy (median dose: 1.50 g/day). LDL was isolated from venous plasma by ultracentrifugation, delipidated, digested, and analyzed for protein glycation, oxidation, and nitration adducts by stable isotopic dilution analysis tandem mass spectrometry.RESULTSAdvanced glycation end product (AGE) content of apolipoprotein B100 of LDL from type 2 diabetic patients was higher than from healthy subjects: arginine-derived AGE, 15.8 vs. 5.3 mol% (P < 0.001); and lysine-derived AGE, 2.5 vs. 1.5 mol% (P < 0.05). Oxidative damage, mainly methionine sulfoxide residues, was also increased: 2.5 vs. 1.1 molar equivalents (P < 0.001). 3-Nitrotyrosine content was decreased: 0.04 vs. 0.12 mol% (P < 0.05). In diabetic patients receiving metformin therapy, arginine-derived AGE and methionine sulfoxide were lower than in patients not receiving metformin: 19.3 vs. 8.9 mol% (P < 0.01) and 2.9 vs. 1.9 mol% (P < 0.05), respectively; 3-nitrotyrosine content was higher: 0.10 vs. 0.03 mol% (P < 0.05). Fructosyl-lysine residue content correlated positively with fasting plasma glucose. Arginine-derived AGE residue contents were intercorrelated and also correlated positively with methionine sulfoxide.CONCLUSIONSPatients with type 2 diabetes had increased arginine-derived AGEs and oxidative damage in apolipoprotein B100 of LDL. This was lower in patients receiving metformin therapy, which may contribute to decreased oxidative damage, atherogenicity, and cardiovascular disease.

Levels of Apolipoprotein A1, B100 and Lipoprotein (a) in Controlled and Uncontrolled Diabetic Patients and in Non-Diabetic Healthy People

“…As a result there is a need to closely evaluate newer approach in case of DM because even if dyslipidemia is treated, there is always a risk of CVDs in DM patients. The reason is hyperglycemia itself, so lipid abnormalities should be assessed aggressively and treated as part of comprehensive diabetes care [6]. Apolipoprotein B100 (Apo B100) is the protein part of Low Density Lipoprotein (LDL), Very Low Density Lipoprotein (VLDL) and Intermediate Density Lipoprotein (IDL).…”

Improved glycemic control induced by both metformin and repaglinide is associated with a reduction in blood levels of 3-deoxyglucosone in nonobese patients with type 2 diabetes

“…Given the similarities in structure between metformin and aminoguanidine, it has been proposed that metformin reacts with the dicarbonyl groups of a-oxoaldehydes in a similar way to aminoguanidine, thereby preventing the toxicity of these a-oxoaldehydes and the subsequent production of AGEs (9)(10)(11). In this study, we indeed found a decrease in 3DG levels after treatment with metformin, which is in agreement with earlier observations of lower levels of a-oxoaldehydes and AGEs in patients with type 2 diabetes treated with this drug (9,11). Remarkably, we found a similar decrease in 3DG levels after treatment with another antihyperglycemic agent, repaglinide, which is a short-acting insulin secretagogue belonging to the meglitinide analogues.…”

“…Metformin, an antihyperglycemic agent, which enhances insulin sensitivity and lowers hepatic glucose output, may also have antiglycation properties, with a working mechanism similar to aminoguanidine due to a similarity in structure between both the agents (9)(10)(11). The observation of reduced levels of methylglyoxal in patients using metformin as compared with controls supports this view (9).…”

Modified Forms of LDL in Plasma

“…Minimal modification by methylglyoxal renders LDL particles with atherogenic properties, including binding to PG and susceptibility to aggregation . LDL particles with this low level of modification are increased in diabetic patients (Rabbani, 2010).…”