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Correction of HDL dysfunction in individuals with diabetes and the haptoglobin 2-2 genotype.

Asleh R, Blum S, Kalet-Litman S, Alshiek J, Miller-Lotan R, Asaf R, Rock W, Aviram M, Milman U, Shapira C, Abassi Z, Levy AP - Diabetes (2008)

Bottom Line: RESULTS-Hb and lipid peroxides associated with HDL were increased and HDL function was impaired in Hp 2-2 diabetic individuals and mice.Vitamin E decreased oxidative modification of HDL and improved HDL function in Hp 2-2 diabetes but had no effect in Hp 1-1 diabetes.Vitamin E significantly improves the quality of HDL in Hp 2-2 diabetic individuals.

View Article: PubMed Central - PubMed

Affiliation: Department of Anatomy and Cell Biology, Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel.

ABSTRACT

Objective: Pharmacogenomics is a key component of personalized medicine. The Israel Cardiovascular Events Reduction with Vitamin E Study, a prospective placebo-controlled study, recently demonstrated that vitamin E could dramatically reduce CVD in individuals with diabetes and the haptoglobin (Hp) 2-2 genotype (40% of diabetic individuals). However, because of the large number of clinical trials that failed to demonstrate benefit from vitamin E coupled with the lack of a mechanistic explanation for why vitamin E should be beneficial only in diabetic individuals with the Hp 2-2 genotype, enthusiasm for this pharmacogenomic paradigm has been limited. In this study, we sought to provide such a mechanistic explanation based on the hypothesis that the Hp 2-2 genotype and diabetes interact to promote HDL oxidative modification and dysfunction.

Research design and methods: Hb and lipid peroxides were assessed in HDL isolated from diabetic individuals or mice with the Hp 1-1 or Hp 2-2 genotypes. HDL function was assessed based on its ability to promote cholesterol efflux from macrophages. A crossover placebo-controlled study in Hp 2-2 diabetic humans and in Hp 1-1 and Hp 2-2 diabetic mice assessed the ability of vitamin E to favorably modify these structural and functional parameters. RESULTS-Hb and lipid peroxides associated with HDL were increased and HDL function was impaired in Hp 2-2 diabetic individuals and mice. Vitamin E decreased oxidative modification of HDL and improved HDL function in Hp 2-2 diabetes but had no effect in Hp 1-1 diabetes.

Conclusions: Vitamin E significantly improves the quality of HDL in Hp 2-2 diabetic individuals.

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Related in: MedlinePlus

Vitamin E improves HDL function and reduces HDL oxidative modification in Hp 2-2 diabetic humans. Crossover-design, placebo-controlled, double-blind trial. Eighteen Hp 2-2 diabetic individuals divided into two cohorts were randomized to either vitamin E or placebo and treated for 2 months. After a 2-week washout, patients were crossed over to the other treatment and treated for an additional 2 months. Blood samples were taken at baseline (test 1), after 2 months of the initial treatment (test 2), and after 2 months with the second treatment (test 3). A: Improvement in cholesterol efflux stimulated by Hp 2-2 serum with vitamin E in humans. There was a significant improvement in efflux with vitamin E treatment (test 1-test 2 in cohort 1, P = 0.004; test 2-test 3 in cohort 2, P = 0.04) and no change with placebo treatment (test 1-test 2 in cohort 2, P = 0.33). Of note in cohort 1, test 3 is not significantly different from the baseline value, demonstrating that even though vitamin E improved HDL function (compare test 1-test 2), after a 2-month period without vitamin E, HDL function deteriorated to baseline levels (P = 0.13 comparing test 1-test 3 in cohort 1). B: Reduction in HDL-associated lipid peroxides with vitamin E. There was a significant reduction in lipid peroxides with vitamin E treatment (test 1-test 2 in cohort 1, P = 0.03; test 2-test 3 in cohort 2, P = 0.01) and no change with placebo treatment (test 1-test 2 in cohort 2, P = 0.35). Of note in cohort 1, test 3 was not significantly different from the baseline value, demonstrating that even though vitamin E reduced lipid peroxides (compare test 1-test 2), 2 months after the vitamin E was stopped, lipid peroxides returned to baseline levels (P = 0.31 comparing test 1-test 3 in cohort 1).
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f6: Vitamin E improves HDL function and reduces HDL oxidative modification in Hp 2-2 diabetic humans. Crossover-design, placebo-controlled, double-blind trial. Eighteen Hp 2-2 diabetic individuals divided into two cohorts were randomized to either vitamin E or placebo and treated for 2 months. After a 2-week washout, patients were crossed over to the other treatment and treated for an additional 2 months. Blood samples were taken at baseline (test 1), after 2 months of the initial treatment (test 2), and after 2 months with the second treatment (test 3). A: Improvement in cholesterol efflux stimulated by Hp 2-2 serum with vitamin E in humans. There was a significant improvement in efflux with vitamin E treatment (test 1-test 2 in cohort 1, P = 0.004; test 2-test 3 in cohort 2, P = 0.04) and no change with placebo treatment (test 1-test 2 in cohort 2, P = 0.33). Of note in cohort 1, test 3 is not significantly different from the baseline value, demonstrating that even though vitamin E improved HDL function (compare test 1-test 2), after a 2-month period without vitamin E, HDL function deteriorated to baseline levels (P = 0.13 comparing test 1-test 3 in cohort 1). B: Reduction in HDL-associated lipid peroxides with vitamin E. There was a significant reduction in lipid peroxides with vitamin E treatment (test 1-test 2 in cohort 1, P = 0.03; test 2-test 3 in cohort 2, P = 0.01) and no change with placebo treatment (test 1-test 2 in cohort 2, P = 0.35). Of note in cohort 1, test 3 was not significantly different from the baseline value, demonstrating that even though vitamin E reduced lipid peroxides (compare test 1-test 2), 2 months after the vitamin E was stopped, lipid peroxides returned to baseline levels (P = 0.31 comparing test 1-test 3 in cohort 1).

Mentions: In humans, we assessed the ability of vitamin E to improve HDL function and reduce HDL-associated lipid peroxides in Hp 2-2 diabetes in a crossover study. We found that vitamin E significantly improved HDL function by 30–40% and reduced HDL lipid peroxides by 20–30%. Notably, in this crossover design we found that after vitamin E had restored HDL function and reduced lipid peroxides and the vitamin E was then withdrawn, HDL function deteriorated, and HDL-associated lipid peroxides increased to levels seen at baseline within 2 months after cessation of vitamin E supplementation (Fig. 6).


Correction of HDL dysfunction in individuals with diabetes and the haptoglobin 2-2 genotype.

Asleh R, Blum S, Kalet-Litman S, Alshiek J, Miller-Lotan R, Asaf R, Rock W, Aviram M, Milman U, Shapira C, Abassi Z, Levy AP - Diabetes (2008)

Vitamin E improves HDL function and reduces HDL oxidative modification in Hp 2-2 diabetic humans. Crossover-design, placebo-controlled, double-blind trial. Eighteen Hp 2-2 diabetic individuals divided into two cohorts were randomized to either vitamin E or placebo and treated for 2 months. After a 2-week washout, patients were crossed over to the other treatment and treated for an additional 2 months. Blood samples were taken at baseline (test 1), after 2 months of the initial treatment (test 2), and after 2 months with the second treatment (test 3). A: Improvement in cholesterol efflux stimulated by Hp 2-2 serum with vitamin E in humans. There was a significant improvement in efflux with vitamin E treatment (test 1-test 2 in cohort 1, P = 0.004; test 2-test 3 in cohort 2, P = 0.04) and no change with placebo treatment (test 1-test 2 in cohort 2, P = 0.33). Of note in cohort 1, test 3 is not significantly different from the baseline value, demonstrating that even though vitamin E improved HDL function (compare test 1-test 2), after a 2-month period without vitamin E, HDL function deteriorated to baseline levels (P = 0.13 comparing test 1-test 3 in cohort 1). B: Reduction in HDL-associated lipid peroxides with vitamin E. There was a significant reduction in lipid peroxides with vitamin E treatment (test 1-test 2 in cohort 1, P = 0.03; test 2-test 3 in cohort 2, P = 0.01) and no change with placebo treatment (test 1-test 2 in cohort 2, P = 0.35). Of note in cohort 1, test 3 was not significantly different from the baseline value, demonstrating that even though vitamin E reduced lipid peroxides (compare test 1-test 2), 2 months after the vitamin E was stopped, lipid peroxides returned to baseline levels (P = 0.31 comparing test 1-test 3 in cohort 1).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2551691&req=5

f6: Vitamin E improves HDL function and reduces HDL oxidative modification in Hp 2-2 diabetic humans. Crossover-design, placebo-controlled, double-blind trial. Eighteen Hp 2-2 diabetic individuals divided into two cohorts were randomized to either vitamin E or placebo and treated for 2 months. After a 2-week washout, patients were crossed over to the other treatment and treated for an additional 2 months. Blood samples were taken at baseline (test 1), after 2 months of the initial treatment (test 2), and after 2 months with the second treatment (test 3). A: Improvement in cholesterol efflux stimulated by Hp 2-2 serum with vitamin E in humans. There was a significant improvement in efflux with vitamin E treatment (test 1-test 2 in cohort 1, P = 0.004; test 2-test 3 in cohort 2, P = 0.04) and no change with placebo treatment (test 1-test 2 in cohort 2, P = 0.33). Of note in cohort 1, test 3 is not significantly different from the baseline value, demonstrating that even though vitamin E improved HDL function (compare test 1-test 2), after a 2-month period without vitamin E, HDL function deteriorated to baseline levels (P = 0.13 comparing test 1-test 3 in cohort 1). B: Reduction in HDL-associated lipid peroxides with vitamin E. There was a significant reduction in lipid peroxides with vitamin E treatment (test 1-test 2 in cohort 1, P = 0.03; test 2-test 3 in cohort 2, P = 0.01) and no change with placebo treatment (test 1-test 2 in cohort 2, P = 0.35). Of note in cohort 1, test 3 was not significantly different from the baseline value, demonstrating that even though vitamin E reduced lipid peroxides (compare test 1-test 2), 2 months after the vitamin E was stopped, lipid peroxides returned to baseline levels (P = 0.31 comparing test 1-test 3 in cohort 1).
Mentions: In humans, we assessed the ability of vitamin E to improve HDL function and reduce HDL-associated lipid peroxides in Hp 2-2 diabetes in a crossover study. We found that vitamin E significantly improved HDL function by 30–40% and reduced HDL lipid peroxides by 20–30%. Notably, in this crossover design we found that after vitamin E had restored HDL function and reduced lipid peroxides and the vitamin E was then withdrawn, HDL function deteriorated, and HDL-associated lipid peroxides increased to levels seen at baseline within 2 months after cessation of vitamin E supplementation (Fig. 6).

Bottom Line: RESULTS-Hb and lipid peroxides associated with HDL were increased and HDL function was impaired in Hp 2-2 diabetic individuals and mice.Vitamin E decreased oxidative modification of HDL and improved HDL function in Hp 2-2 diabetes but had no effect in Hp 1-1 diabetes.Vitamin E significantly improves the quality of HDL in Hp 2-2 diabetic individuals.

View Article: PubMed Central - PubMed

Affiliation: Department of Anatomy and Cell Biology, Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel.

ABSTRACT

Objective: Pharmacogenomics is a key component of personalized medicine. The Israel Cardiovascular Events Reduction with Vitamin E Study, a prospective placebo-controlled study, recently demonstrated that vitamin E could dramatically reduce CVD in individuals with diabetes and the haptoglobin (Hp) 2-2 genotype (40% of diabetic individuals). However, because of the large number of clinical trials that failed to demonstrate benefit from vitamin E coupled with the lack of a mechanistic explanation for why vitamin E should be beneficial only in diabetic individuals with the Hp 2-2 genotype, enthusiasm for this pharmacogenomic paradigm has been limited. In this study, we sought to provide such a mechanistic explanation based on the hypothesis that the Hp 2-2 genotype and diabetes interact to promote HDL oxidative modification and dysfunction.

Research design and methods: Hb and lipid peroxides were assessed in HDL isolated from diabetic individuals or mice with the Hp 1-1 or Hp 2-2 genotypes. HDL function was assessed based on its ability to promote cholesterol efflux from macrophages. A crossover placebo-controlled study in Hp 2-2 diabetic humans and in Hp 1-1 and Hp 2-2 diabetic mice assessed the ability of vitamin E to favorably modify these structural and functional parameters. RESULTS-Hb and lipid peroxides associated with HDL were increased and HDL function was impaired in Hp 2-2 diabetic individuals and mice. Vitamin E decreased oxidative modification of HDL and improved HDL function in Hp 2-2 diabetes but had no effect in Hp 1-1 diabetes.

Conclusions: Vitamin E significantly improves the quality of HDL in Hp 2-2 diabetic individuals.

Show MeSH
Related in: MedlinePlus