Effect of vitamin E supplementation on HDL function by haptoglobin genotype in type 1 diabetes: results from the HapE randomized crossover pilot trial

Abstract

Aims Haptoglobin (Hp) genotype 2-2 increases cardiovascular diabetes complications. In type 2 diabetes, α-tocopherol was shown to lower cardiovascular risk in Hp 2-2, potentially through HDL function improvements. Similar type 1 diabetes data are lacking. We conducted a randomized, cross-over pilot of α-tocopherol supplementation on HDL function (i.e. cholesterol efflux (CE) and HDL-associated lipid peroxides (LP)) and lipoprotein subfractions in type 1 diabetes. Methods Hp genotype was assessed in members of two Allegheny County, PA type 1 diabetes registries and the CACTI cohort; 30 were randomly selected within Hp genotype, and 28 Hp 1-1, 31 Hp 2-1 and 30 Hp 2-2 were allocated to daily α-tocopherol or placebo for 8 weeks with a 4-week wash-out. Results Baseline CE decreased with the number of Hp 2 alleles (p-trend=0.003). There were no differences in LP or lipoprotein subfractions. In intention-to-treat analysis stratified by Hp, α-tocopherol increased CE in Hp 2-2 (beta=0.79, p=0.03) and LP in Hp 1 allele carriers (betaHp 1-1=0.18, p=0.05 and betaHp 2-1 =0.21, p=0.07); reduced HDL particle size (beta=−0.07, p=0.03) in Hp 1-1 carriers; increased LDL particle concentration in Hp 1-1 and decreased it in Hp 2-2 carriers. However, no significant interactions were observed by Hp. Conclusions In this type 1 diabetes study, HDL function worsened with the number of Hp 2 alleles. α-tocopherol improved HDL function in Hp 2-2 carriers and appeared to adversely affect lipid peroxides and lipoprotein subfractions among Hp 1 allele carriers. As no significant interactions were observed, findings require replication in larger studies.

Glycaemic control modifies the haptoglobin 2 allele‐conferred susceptibility to coronary artery disease in Type 1 diabetes

“…In Type 2 diabetes, clinical trial evidence points to a reduction in cardiovascular events with vitamin E supplementation among Hp 2‐2 carriers . Similar trial evidence does not exist in Type 1 diabetes, although in a small intervention trial, vitamin E appeared to improve HDL‐mediated reverse cholesterol transport, a proposed mechanism by which Hp relates to CAD, among Hp 2‐2 carriers . In conclusion, while the present findings require validation in further cohorts, the effects of the genetic polymorphism in the Hp gene raises new avenues regarding cardiovascular disease prevention in Type 1 diabetes, particularly for those with residual risk, despite better glycaemic control.…”

The Haptoglobin genotype predicts cardio-renal mortality in type 1 diabetes

“…To this point, three clinical trials in type 2 diabetes have suggested that supplementation with vitamin E reduces the increased cardiovascular susceptibility associated with the HP 2-2 genotype (33–35), potentially by ameliorating the noted HDL dysfunction (5) in this population subgroup. We have similarly shown in type 1 diabetes, that HDL-mediated cholesterol efflux appeared to worsen incrementally with the number of HP 2 alleles in a small type 1 diabetes intervention trial, while the daily administration of 400 IU α-tocopherol was shown to improve cholesterol efflux in the genetically susceptible HP 2-2 group (30). Given the lack of robust clinical trial data, however, no conclusions can be currently drawn on whether α-tocopherol supplementation may lower the incidence of cardiovascular disease in type 1 diabetes.…”

“…Thus, the ability of the HP 2-2 – hemoglobin complex to structurally and functionally modify HDL, leading to impaired reverse cholesterol function (27–30), is thought as one of the pathways by which HP 2-2 increases the incidence of CAD in diabetes. In addition, the greater likelihood that the HP 2-2 – hemoglobin complex is cleared from the kidneys rather than by the usual CD163 monocyte/macrophage receptor, may lead to a concomitant increase in iron accumulation in renal proximal tubule cells, oxidative stress, and hypertrophy (1, 31).…”

Link of dietary patterns with metabolic syndrome: analysis of the National Health and Nutrition Examination Survey

“…These findings are in agreement with earlier studies reported salutary effects of dietary fiber, 29 vitamin A, 30 vitamin B12, 7, 30 niacin, 31 magnesium 32 and copper 9 on the rate of MetS. Possible mechanisms may partially be explained by improvement of insulin resistance and glucose intolerance 33 by folate, vitamin A, -E, -B6, -B12, thiamine, magnesium and copper; improvement of endothelial function 33, 34 by magnesium, folate, niacin and vitamin E; decrease in blood pressure 34, 35 by niacin, thiamine, riboflavin, vitamin B12, Iron and magnesium; increased HDL and decreased oxidative stress 36, 37 by niacin, vitamin E, magnesium and copper; and decrease in triglycerides 38 by vitamin E, and magnesium, altogether translate to lower likelihood of MetS components and eventually lower likelihood of MetS.…”