High dose supplementation of RRR-alpha-tocopherol decreases cellular hemostasis but accelerates plasmatic coagulation in type 2 diabetes mellitus.
BACKGROUND
Diabetes mellitus is associated with increased generation of free oxygen radicals and depleted scavenging potential (oxidative stress), leading to increased LDL oxidation and platelet hyperreactivity, the major components of atherothrombotic vascular lesions. A main goal of antioxidant therapy is to protect the LDL particle from atherogenic oxidation and to reduce the activated cellular hemostasis.


METHODS
We evaluated the influence of a high dose supplementation with 800 IU of the natural antioxidant RRR-alpha-tocopherol (vitamin E) per day for six months on serum levels, vitamin E load of LDL particles (HPLC), lag phase of LDL oxidation (Esterbauer's assay), platelet adhesion molecules, leukocyte-platelet coaggregation (flow cytometry, D-III protocol) and coagulation (INR/PTT) in a group of 36 patients with type 2 diabetes (f/m 22/14; age 58+/-8.0; HbA1 at baseline 10.25+/-1.7).


RESULTS
Average vitamin E levels increased 2.65-fold accompanied by a 1.83-fold increase of LDL-associated vitamin E and a 12.3 min prolongation of the lag-phase of LDL oxidation (p<0.001 for all parameters at six months). Platelet expression of PECAM-1 (CD31) (-30.2% positive cells, p<0.001; antigen density -25%, p<0.001), ICAM-2 (CD102) (-2.9% positive cells, p<0.01; antigen density -10.6%, p<0.001) and fibrinogen (-1.6% positive cells, p<0.001; antigen density - 16.1 %, p<0.001) decreased. Concomitantly, platelet-leukocyte-coaggregation increased by 44% (p<0.001), correlating to an INR reduction of 10.4% (1.06+/-0.09 to 0.95+/-0.09, p<0.001, r = - 0.34). The PTT remained constant.


CONCLUSIONS
The antioxidant protection from the increased vitamin E was accompanied by a decreased expression of constitutive and function-dependent platelet adhesion molecules. However, increases in platelet-leukocyte coaggregates and a shortened INR time suggest extrinsic coagulation activation, possibly by induction of a leukocyte tissue factor dependent mechanism. High dose supplements of alpha-tocopherol may override the available redox balance in well controlled type 2 diabetes. However, intrinsic effects of alpha-tocopherol must be discussed.
Ferber
P
P
German Diabetes Research Institute at the Heinrich-Heine University, Düsseldorf.
Moll
K
K
Koschinsky
T
T
Rösen
P
P
Susanto
F
F
Schwippert
B
B
Tschöpe
D
D
D000368:Aged; D015703:Antigens, CD / Q000032:analysis; D000975:Antioxidants / Q000008:administration & dosage; D001161:Arteriosclerosis / Q000188:drug therapy / Q000378:metabolism; D016022:Case-Control Studies; D015815:Cell Adhesion Molecules / Q000032:analysis; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy* / Q000378:metabolism*; D005260:Female; D005340:Fibrinogen / Q000032:analysis; D006487:Hemostasis / Q000187:drug effects*; D006801:Humans; D007962:Leukocytes / Q000737:chemistry / Q000378:metabolism; D008077:Lipoproteins, LDL / Q000032:analysis; D008297:Male; D008875:Middle Aged; D018384:Oxidative Stress / Q000187:drug effects; D010974:Platelet Aggregation / Q000187:drug effects; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000032:analysis; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000032:analysis; D013927:Thrombosis / Q000188:drug therapy / Q000378:metabolism; D014810:Vitamin E / Q000008:administration & dosage* / Q000097:blood
D015703:Antigens, CD; D000975:Antioxidants; D015815:Cell Adhesion Molecules; C065289:ICAM2 protein, human; D008077:Lipoproteins, LDL; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; C099252:oxidized low density lipoprotein; D014810:Vitamin E; D005340:Fibrinogen