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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

HDL function is impaired in Hp 2-2 diabetic mice and humans. Cholesterol efflux from macrophages incubated with serum from Hp 2-2 diabetic mice and Hp 2-2 humans with type 1 diabetes and with type 2 diabetes is significantly decreased compared with Hp 1-1 diabetic mice and Hp 1-1 type 1 and type 2 diabetic humans (P = 0.0001, n = 10 comparing Hp 1-1 vs. Hp 2-2 diabetic mice; P < 0.0006, n = 15 comparing Hp 1-1 vs. Hp 2-2 type 1 diabetic individuals; P < 0.001, n = 30 comparing Hp 1-1 vs. Hp 2-2 type 2 diabetic individuals). Efflux is expressed as the percentage of that obtained for Hp 1-1 diabetic mice, type 1 diabetic, and type 2 diabetic individuals, respectively.
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f4: HDL function is impaired in Hp 2-2 diabetic mice and humans. Cholesterol efflux from macrophages incubated with serum from Hp 2-2 diabetic mice and Hp 2-2 humans with type 1 diabetes and with type 2 diabetes is significantly decreased compared with Hp 1-1 diabetic mice and Hp 1-1 type 1 and type 2 diabetic humans (P = 0.0001, n = 10 comparing Hp 1-1 vs. Hp 2-2 diabetic mice; P < 0.0006, n = 15 comparing Hp 1-1 vs. Hp 2-2 type 1 diabetic individuals; P < 0.001, n = 30 comparing Hp 1-1 vs. Hp 2-2 type 2 diabetic individuals). Efflux is expressed as the percentage of that obtained for Hp 1-1 diabetic mice, type 1 diabetic, and type 2 diabetic individuals, respectively.

Mentions: We assessed the ability of serum from Hp 1-1 or Hp 2-2 diabetic mice or humans with type 1 or type 2 diabetes to promote cholesterol efflux from macrophages in vitro. We found a significant 30–40% decrease in HDL function in Hp 2-2 diabetes compared with Hp 1-1 diabetes (Fig. 4). No differences were found between Hp 1-1 and Hp 2-2 in the absence of diabetes or between Hp 1-1 with and without diabetes (data not shown) (26).


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)

HDL function is impaired in Hp 2-2 diabetic mice and humans. Cholesterol efflux from macrophages incubated with serum from Hp 2-2 diabetic mice and Hp 2-2 humans with type 1 diabetes and with type 2 diabetes is significantly decreased compared with Hp 1-1 diabetic mice and Hp 1-1 type 1 and type 2 diabetic humans (P = 0.0001, n = 10 comparing Hp 1-1 vs. Hp 2-2 diabetic mice; P < 0.0006, n = 15 comparing Hp 1-1 vs. Hp 2-2 type 1 diabetic individuals; P < 0.001, n = 30 comparing Hp 1-1 vs. Hp 2-2 type 2 diabetic individuals). Efflux is expressed as the percentage of that obtained for Hp 1-1 diabetic mice, type 1 diabetic, and type 2 diabetic individuals, respectively.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f4: HDL function is impaired in Hp 2-2 diabetic mice and humans. Cholesterol efflux from macrophages incubated with serum from Hp 2-2 diabetic mice and Hp 2-2 humans with type 1 diabetes and with type 2 diabetes is significantly decreased compared with Hp 1-1 diabetic mice and Hp 1-1 type 1 and type 2 diabetic humans (P = 0.0001, n = 10 comparing Hp 1-1 vs. Hp 2-2 diabetic mice; P < 0.0006, n = 15 comparing Hp 1-1 vs. Hp 2-2 type 1 diabetic individuals; P < 0.001, n = 30 comparing Hp 1-1 vs. Hp 2-2 type 2 diabetic individuals). Efflux is expressed as the percentage of that obtained for Hp 1-1 diabetic mice, type 1 diabetic, and type 2 diabetic individuals, respectively.
Mentions: We assessed the ability of serum from Hp 1-1 or Hp 2-2 diabetic mice or humans with type 1 or type 2 diabetes to promote cholesterol efflux from macrophages in vitro. We found a significant 30–40% decrease in HDL function in Hp 2-2 diabetes compared with Hp 1-1 diabetes (Fig. 4). No differences were found between Hp 1-1 and Hp 2-2 in the absence of diabetes or between Hp 1-1 with and without diabetes (data not shown) (26).

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