Increased glycation and oxidative damage to apolipoprotein B100 of LDL cholesterol in patients with type 2 diabetes and effect of metformin.
OBJECTIVE
The 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.


METHODS
For 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.


RESULTS
Advanced 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.


CONCLUSIONS
Patients 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.
Rabbani
Naila
N
Clinical Sciences Research Institute, Warwick Medical School, University of Warwick, University Hospital, Coventry, UK. n.rabbani@warwick.ac.uk
Chittari
Madhu Varma
MV
Bodmer
Charles W
CW
Zehnder
Daniel
D
Ceriello
Antonio
A
Thornalley
Paul J
PJ
D000368:Aged; D053299:Apolipoprotein B-100 / Q000097:blood* / Q000187:drug effects; D001120:Arginine / Q000378:metabolism; D001794:Blood Pressure; D002784:Cholesterol / Q000097:blood; D008078:Cholesterol, LDL / Q000097:blood* / Q000187:drug effects; D003924:Diabetes Mellitus, Type 2 / Q000097:blood* / Q000188:drug therapy* / Q000503:physiopathology; D005260:Female; D006442:Glycated Hemoglobin / Q000378:metabolism; D017127:Glycation End Products, Advanced / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D007004:Hypoglycemic Agents / Q000627:therapeutic use*; D008074:Lipoproteins / Q000097:blood; D008077:Lipoproteins, LDL / Q000097:blood / Q000302:isolation & purification; D008297:Male; D008687:Metformin / Q000627:therapeutic use*; D008875:Middle Aged; D012016:Reference Values
D053299:Apolipoprotein B-100; D001120:Arginine; D002784:Cholesterol; D008078:Cholesterol, LDL; D006442:Glycated Hemoglobin; D017127:Glycation End Products, Advanced; D007004:Hypoglycemic Agents; D008074:Lipoproteins; D008077:Lipoproteins, LDL; D008687:Metformin