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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 mice but not in Hp 1-1 diabetic mice. A: Vitamin E improves the ability of serum of Hp 2-2 diabetic mice, but not Hp 1-1 diabetic mice, to promote cholesterol efflux from macrophages. There was a significant difference in efflux elicited by serum from Hp 1-1 and Hp 2-2 diabetic mice (P = 0.002 comparing placebo groups). Vitamin E significantly improved cholesterol efflux in Hp 2-2 diabetic mice (P = 0.0006 comparing Hp 2-2 placebo vs. Hp 2-2 vitamin E). Efflux elicited by the serum of Hp 2-2 diabetic mice treated with vitamin E was not significantly different from that elicited by Hp 1-1 diabetic mice. Vitamin E had no effect on efflux in Hp 1-1 diabetic mice (P = 0.29). B: Vitamin E reduces HDL-associated lipid peroxides in Hp 2-2 diabetic mice but not in Hp 1-1 diabetic mice. There was a significant difference in HDL-associated lipid peroxides between Hp 1-1 and Hp 2-2 diabetic mice (P = 0.0001). Vitamin E significantly reduced lipid peroxides in Hp 2-2 diabetic mice (P = 0.001 comparing Hp 2-2 placebo vs. Hp 2-2 vitamin E) but had no effect on efflux in Hp 1-1 diabetic mice (P = 0.74 comparing Hp 1-1 placebo vs. Hp 1-1 vitamin E).
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f5: Vitamin E improves HDL function and reduces HDL oxidative modification in Hp 2-2 diabetic mice but not in Hp 1-1 diabetic mice. A: Vitamin E improves the ability of serum of Hp 2-2 diabetic mice, but not Hp 1-1 diabetic mice, to promote cholesterol efflux from macrophages. There was a significant difference in efflux elicited by serum from Hp 1-1 and Hp 2-2 diabetic mice (P = 0.002 comparing placebo groups). Vitamin E significantly improved cholesterol efflux in Hp 2-2 diabetic mice (P = 0.0006 comparing Hp 2-2 placebo vs. Hp 2-2 vitamin E). Efflux elicited by the serum of Hp 2-2 diabetic mice treated with vitamin E was not significantly different from that elicited by Hp 1-1 diabetic mice. Vitamin E had no effect on efflux in Hp 1-1 diabetic mice (P = 0.29). B: Vitamin E reduces HDL-associated lipid peroxides in Hp 2-2 diabetic mice but not in Hp 1-1 diabetic mice. There was a significant difference in HDL-associated lipid peroxides between Hp 1-1 and Hp 2-2 diabetic mice (P = 0.0001). Vitamin E significantly reduced lipid peroxides in Hp 2-2 diabetic mice (P = 0.001 comparing Hp 2-2 placebo vs. Hp 2-2 vitamin E) but had no effect on efflux in Hp 1-1 diabetic mice (P = 0.74 comparing Hp 1-1 placebo vs. Hp 1-1 vitamin E).

Mentions: We assessed the ability of vitamin E to reduce HDL oxidative modification (HDL-associated lipid peroxides) and to improve HDL function in Hp 1-1 or Hp 2-2 diabetic mice. We found that vitamin E had no effect on HDL lipid peroxides or function in Hp 1-1 diabetic mice. However, vitamin E significantly improved HDL function and reduced HDL lipid peroxides in Hp 2-2 diabetic mice, restoring function and reducing lipid peroxides to levels similar to those found in Hp 1-1 diabetes (Fig. 5).


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 mice but not in Hp 1-1 diabetic mice. A: Vitamin E improves the ability of serum of Hp 2-2 diabetic mice, but not Hp 1-1 diabetic mice, to promote cholesterol efflux from macrophages. There was a significant difference in efflux elicited by serum from Hp 1-1 and Hp 2-2 diabetic mice (P = 0.002 comparing placebo groups). Vitamin E significantly improved cholesterol efflux in Hp 2-2 diabetic mice (P = 0.0006 comparing Hp 2-2 placebo vs. Hp 2-2 vitamin E). Efflux elicited by the serum of Hp 2-2 diabetic mice treated with vitamin E was not significantly different from that elicited by Hp 1-1 diabetic mice. Vitamin E had no effect on efflux in Hp 1-1 diabetic mice (P = 0.29). B: Vitamin E reduces HDL-associated lipid peroxides in Hp 2-2 diabetic mice but not in Hp 1-1 diabetic mice. There was a significant difference in HDL-associated lipid peroxides between Hp 1-1 and Hp 2-2 diabetic mice (P = 0.0001). Vitamin E significantly reduced lipid peroxides in Hp 2-2 diabetic mice (P = 0.001 comparing Hp 2-2 placebo vs. Hp 2-2 vitamin E) but had no effect on efflux in Hp 1-1 diabetic mice (P = 0.74 comparing Hp 1-1 placebo vs. Hp 1-1 vitamin E).
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f5: Vitamin E improves HDL function and reduces HDL oxidative modification in Hp 2-2 diabetic mice but not in Hp 1-1 diabetic mice. A: Vitamin E improves the ability of serum of Hp 2-2 diabetic mice, but not Hp 1-1 diabetic mice, to promote cholesterol efflux from macrophages. There was a significant difference in efflux elicited by serum from Hp 1-1 and Hp 2-2 diabetic mice (P = 0.002 comparing placebo groups). Vitamin E significantly improved cholesterol efflux in Hp 2-2 diabetic mice (P = 0.0006 comparing Hp 2-2 placebo vs. Hp 2-2 vitamin E). Efflux elicited by the serum of Hp 2-2 diabetic mice treated with vitamin E was not significantly different from that elicited by Hp 1-1 diabetic mice. Vitamin E had no effect on efflux in Hp 1-1 diabetic mice (P = 0.29). B: Vitamin E reduces HDL-associated lipid peroxides in Hp 2-2 diabetic mice but not in Hp 1-1 diabetic mice. There was a significant difference in HDL-associated lipid peroxides between Hp 1-1 and Hp 2-2 diabetic mice (P = 0.0001). Vitamin E significantly reduced lipid peroxides in Hp 2-2 diabetic mice (P = 0.001 comparing Hp 2-2 placebo vs. Hp 2-2 vitamin E) but had no effect on efflux in Hp 1-1 diabetic mice (P = 0.74 comparing Hp 1-1 placebo vs. Hp 1-1 vitamin E).
Mentions: We assessed the ability of vitamin E to reduce HDL oxidative modification (HDL-associated lipid peroxides) and to improve HDL function in Hp 1-1 or Hp 2-2 diabetic mice. We found that vitamin E had no effect on HDL lipid peroxides or function in Hp 1-1 diabetic mice. However, vitamin E significantly improved HDL function and reduced HDL lipid peroxides in Hp 2-2 diabetic mice, restoring function and reducing lipid peroxides to levels similar to those found in Hp 1-1 diabetes (Fig. 5).

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