Correction of HDL Dysfunction in Individuals With Diabetes and the Haptoglobin 2-2 Genotype

• Published in: Diabetes (New York, N.Y.) Vol. 57; no. 10; pp. 2794 - 2800
• Main Authors: ASLEH, Rabea, BLUM, Shany, ABASSI, Zaid, LEVY, Andrew P, KALET-LITMAN, Shiri, ALSHIEK, Jonia, MILLER-LOTAN, Rachel, ASAF, Roy, ROCK, Wasseem, AVIRAM, Michael, MILMAN, Uzi, SHAPIRA, Chen
• Format: Journal Article
• Language: English
• Published: Alexandria, VA American Diabetes Association 01.10.2008
• Subjects: Animals; Antioxidants - pharmacology; Antioxidants - therapeutic use; Biological and medical sciences; Cardiovascular diseases; Care and treatment; Clinical trials; Complications; Complications and side effects; Development and progression; Diabetes; Diabetes mellitus; Diabetes Mellitus, Type 2 - drug therapy; Diabetes Mellitus, Type 2 - genetics; Diabetes Mellitus, Type 2 - metabolism; Diabetes. Impaired glucose tolerance; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Etiopathogenesis. Screening. Investigations. Target tissue resistance; Genotype; Genotype & phenotype; Haptoglobin; Haptoglobins - genetics; Haptoglobins - metabolism; Heart attacks; High density lipoproteins; Humans; Hypotheses; Lipids; Lipoproteins, HDL - chemistry; Lipoproteins, HDL - metabolism; Medical sciences; Mice; Models, Biological; Oxidation-Reduction - drug effects; Oxidative stress; Physiological aspects; Polymorphism; Precision medicine; Proteins; Public health; Research design; Vitamin E; Vitamin E - pharmacology; Vitamin E - therapeutic use; Israel; Endocrinopathy; Human; Genotype; Dysfunction; Diabetes mellitus
• ISSN: 0012-1797; 1939-327X
• DOI: 10.2337/db08-0450

Correction of HDL Dysfunction in Individuals With Diabetes and the Haptoglobin 2-2 Genotype Rabea Asleh 1 , Shany Blum 1 , Shiri Kalet-Litman 1 , Jonia Alshiek 1 , Rachel Miller-Lotan 1 , Roy Asaf 1 , Wasseem Rock 2 , Michael Aviram 2 , Uzi Milman 3 4 , Chen Shapira 5 6 , Zaid Abassi 7 and Andrew P. Levy 1 1 Department of Anatomy and Cell Biology, Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel 2 Lipid Research Laboratory, Rambam Medical Center, Haifa, Israel 3 Clinical Research Unit, Clalit Health Services, Haifa and Western Galilee, Israel 4 Department of Family Medicine, Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel 5 Clalit Health Services, Haifa and Western Galilee, Israel 6 Lady Davis Carmel Medical Center, Haifa, Israel 7 Department of Physiology and Biophysics, Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel Corresponding author: Andrew P. Levy, alevy{at}tx.technion.ac.il 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. Footnotes Published ahead of print at http://diabetes.diabetesjournals.org on 3 July 2008. Clinical trial reg. no. NCT00314379, clinicaltrials.gov . Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.org/licenses/by-nc-nd/3.0/ for details. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Accepted June 26, 2008. Received April 2, 2008. DIABETES