Platelet activation, tocopherol and type 2 Diabetes Mellitus




The main role of vitamin E is as a chain-loosening free radical trapping antioxidant in plasma lipoproteins as well as cell membranes. Before it establishes a chain reaction, it first chemically reacts with lipid peroxide radicals formed by the peroxidation of polyunsaturated fatty acids. The individual need for Vitamin E depends on the level of intake of polyunsaturated fatty acids and they have direct relationship. The daily requirement in US is put at 7-10mg per day. With high intake of PUFAs, there is corresponding increase in the need for Vitamin E. Vitamin E family includes the naturally occurring compounds which are divided to tocopherols and tocotrienols each having 4 members with vitamin biologic functions. The most active of them is d-(or RRR) alpha tocopherols which exist naturally and is the most widely obtained in food and it also contributes close to 90% of Vitamin E in the human body (Katzung 1997).

A product formed tocopheroxyl free radical, is relatively inert and eventually gives rise to non radical compounds. A further reaction of the tocopheroxyl free radical with vitamin E from the plasma leads to its reduction back to tocopherol. The soluble nature of tocopheroxyl free radicals explains that it can enter farther into the cell. At high concentration it has been established that Vitamin E can have prooxidant and antioxidant effects .Despite studies that have charted a link between the reductions in rate of arthrosclerosis with high concentration of vitamin E, the effect of high doses of vitamin E has not been encouraging. Increased cardiovascular result following supplementation with alpha tocopherol has not been proven by clinical trial even though researches have demonstrated enormous advantages of vitamin E in the function of platelet. A high fatty diet has been associated in the aetiology of cardiovascular diseases, cancer of the breast, colon and prostate as well as type 2 diabetes mellitus. Vitamin E scavenges free radicals formed in the redox reactions all over the body.

Vitamin E has no unambiguous function that has been defined. It however has a function of lipid soluble antioxidant around the membranes of the cell and most of its functions can be mimicked by synthetic antioxidants. Tocopherols and tocotrienols are two groups of compounds that have Vitamin E as their generic categorizer. Different vitamers with similar vitamin activities exist for vitamin E with variable biologic performances with D-alpha-tocopherol being the most potent. However the synthetic form of the D-alpha tocopherol has a different biologic potency when compared with the naturally occurring form of the compound.

Objective of the study

The aim of the study is to examine for the similarities in the effect of addition of alpha tocopherol up to 500mg as well as gamma tocopherol rich material (containing up to 60% of the gamma tocopherol) will have on the concentration of both the serum as well as platelet activation in individuals with type 2 diabetes mellitus.


In this experiment about 58 individuals were haphazardly given one of either 500mg of alpha tocopherol each day or 500mg mixed tocopherol per day or a matching placebo. A baseline measurement of serum platelet as well as red blood cell urinary concentration of the metabolites was carried out and the measurement is repeated after 6 weeks of intervention. As part of the experiment, the following were also measured:

11-beta dehydro thromboxane B2,

Serum thromboxane B2,

Soluble P selectin,

Soluble CD 40 ligand,

Von Willibrand factor

These substances are the biomarkers of the invivo activation of the platelet and an increase in their concentration is a pointer to platelet activation.

The outcome shows that the concentration of serum alpha tocopherol shoots up with supplementation with both forms of tocopherol. It was also found out as a corollary of the trial, that both cellular as well as the serum concentration of gamma tocopherol increased 4 times with P<o.oo1 in the category of patients who received mixed tocopherol while on the other hand the erythrocyte concentration of gamma tocopherol significantly fell with administration of alpha tocopherol. The urinary concentration of the metabolite-alpha carboxyl-hydroxychroman also increased enormously following supplementation with mixed tocopherol and alpha tocopherol. This outcome may therefore suggest that there is displacement of the gamma tocopherol by alpha tocopherol as a result of the incorporation of alpha lipoprotein into the hepatic system .It was however found out that none of these two treatments had any remarkable effects on the biomarkers of platelet activation mentioned above.


Some studies have shown potential benefit of vitamin E on platelet function, but several clinical trials failed to show improved cardiovascular outcome with α-tocopherol supplementation. Γ-tocopherol, a major dietary form of vitamin E, may have protective properties different from those of α-tocopherol. Comparisons were made on the effects of supplementation with α-tocopherol (500 mg) and a γ-tocopherol-rich compound (500 mg, containing 60% γ-tocopherol) on serum and cellular tocopherol concentrations, urinary tocopherol metabolite excretion, and in vivo platelet activation in subjects with type 2 diabetes.

From the pathogenesis of type 2 diabetes, activation of protein kinase C with resultant impairment of vasodilatation raises procogulant PAI-1(platelet activator inhibitor-1) functions and may give rise to endothelial insult and accelerated arthrosclerosis in Diabetes patients (Defronzo 1991; Ferannini 2001). In another control  trial aimed at testing the effect of  alpha tocopherol supplementation  on markers of thrombosis,plasminogen  activator inhibitor and soluble P-selectin in type 2 diabetic with and without macrovascular complication in  comparison with control trial revealed that both diabetic groups had significantly increased levels of PAI-1 compared with control subjects (P < 0.025), whereas only type 2 diabetic patients with MVCs(macrovascular complication) had significantly elevated levels of sP-selectin(soluble p-selectin) compared with control subjects. Alpha tocopherol supplementation significantly lowered levels of PAI-1 and sP-selectin in all three groups. The reduction in PAI-1 levels with AT supplementation was significantly greater in type 2 diabetic patients with MVCs than in those without MVCs (P=0.005).This is in support of the fact that type 2 diabetic subjects have an increased tendency to premature atherothrombosis and that supplementation with alpha Tocopherol (AT), a potent antioxidant, has anti-inflammatory properties in a dose dependent pattern. Type 2 diabetes is associated with a fall in the fibrinoltic activity as seen in the increase in the level of PAI-1 and platelet activation as evidenced by the increased P-selectin.

It has been suggested that platelet hyperactivity in patients with diabetes mellitus is associated with increased platelet production of thromboxane. The trial therefore compared the excretion of a thromboxane metabolite and platelet function in 50 patients with Type II diabetes mellitus who had normal renal function and clinical evidence of macrovascular disease and in 32 healthy controls. The mean (+/- SD) excretion rate of urinary 11-dehydro-thromboxane B2 was significantly greater in the patients than in the controls (5.94 +/- 3.68 vs. 1.50 +/- 0.79 nmol per day; P less than 0.001), irrespective of the type of macrovascular complication. Tight metabolic control achieved with insulin therapy reduced the levels of 11-dehydro-thromboxane B2 by approximately half. The fractional conversion of exogenous thromboxane B2 (infused at a rate of 4.5, 45.3, or 226.4 fmol per kilogram of body weight per second) to urinary 11-dehydro-thromboxane B2 was assessed in four patients, in whom it averaged 5.4 +/- 0.1 percent; this value did not differ from that measured in healthy subjects. Aspirin in low doses (50 mg per day for seven days) decreased urinary excretion of the metabolite by approximately 80 percent in four patients. The fact that thromboxane biosynthesis recovered over the following 10 days was consistent with a platelet origin of the urinary metabolite

Conclusion and Recommendation

1) That supplementation with alpha tocopherol brings about a fall in the red blood cell level of gamma tocopherol

2) That mixed tocopherols cause an increased level of

a) Serum alpha tocopherol

b) Serum beta tocopherol

c) Cellular gamma tocopherol

It therefore means by extrapolation that any change in the serum level of tocopherol is a reflection of cellular changes in the concentration of tocopherols after it has been supplemented.      Research in the future will therefore need to focus on the link between insulin resistance of type 2 Diabetes mellitus and the pathogenesis. Increase platelet adhesiveness to the vessel wall has been put forward in states of insulin résistance in type 2 diabetes and the suggestion is that it is most likely due to the increased concentration of thromboxane A2 and fall in the concentration of prostacyclin synthesis. Some other risk factors for the insulin resistance in type 2 diabetes patients include hypertension, dyslipidemia and platelet dysfunction. Therefore for future research, a dose-response study is imperative to be able to define the threshold dose of Alpha tocopherol that suppresses inflammation (Goldberg 2001; Florez 2001). This may serve as adjunctive therapy for patients with type 2 diabetes in addition to improving glycemia and dyslipidemia and normalizing hypertension (Schneider etal 2004).




















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Alterations in Plasma Vitamin E Distribution in Type 2 Diabetic Patients With Elevated Plasma Phospholipids Transfer Protein Activity Diabetes, October 1, 2004; 53(10): 2633 – 2639.




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