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

被引:113
作者
Asleh, Rabea [1 ]
Blum, Shany [1 ]
Kalet-Litman, Shiri [1 ]
Alshiek, Jonia [1 ]
Miller-Lotan, Rachel [1 ]
Asaf, Roy [1 ]
Rock, Wasseem [2 ]
Aviram, Michael [2 ]
Milman, Uzi [3 ,4 ,5 ]
Shapira, Chen [6 ]
Abassi, Zaid [7 ]
Levy, Andrew P. [1 ]
机构
[1] Technion Israel Inst Technol, Rappaport Fac Med, Dept Anat & Cell Biol, Haifa, Israel
[2] Rambam Med Ctr, Lipid Res Lab, Haifa, Israel
[3] Clalit Hlth Serv, Clin Res Unit, Haifa, Israel
[4] Clalit Hlth Serv, Clin Res Unit, Western Galilee, Israel
[5] Technion Israel Inst Technol, Rappaport Fac Med, Dept Family Med, Haifa, Israel
[6] Lady Davies Carmel Med Ctr, Haifa, Israel
[7] Technion Israel Inst Technol, Rappaport Fac Med, Dept Physiol & Biophys, Haifa, Israel
基金
以色列科学基金会;
关键词
D O I
10.2337/db08-0450
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
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.
引用
收藏
页码:2794 / 2800
页数:7
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