Urinary oxidized, but not enzymatic vitamin E metabolites are inversely associated with measures of glucose homeostasis in middle-aged healthy individuals

Abstract

Background & aims: Damage induced by lipid peroxidation has been associated with impaired glucose homeostasis. Vitamin E (a-tocopherol, a-TOH) competitively reacts with lipid peroxyl radicals to mitigate oxidative damage, and forms oxidized vitamin E metabolites. Accordingly, we aimed to investigate the associations between a-TOH metabolites (oxidized and enzymatic) in both circulation and urine and measures of glucose homeostasis in the general middle-aged population. Methods: This cross-sectional study was embedded in the population-based Netherlands Epidemiology of Obesity (NEO) Study. a-TOH metabolites in blood (a-TOH and a-CEHC-SO 3) and urine [sulfate (SO 3) and glucuronide (GLU) of both a-TLHQ (oxidized) and a-CEHC (enzymatic)] were quantified by liquid chromatography coupled with tandem mass spectrometry (LC/MSeMS). Measures of glucose homeostasis (HOMA-B, HOMA-IR, Insulinogenic index and Matsuda index) were obtained from fasting and postprandial blood samples. Multivariable linear regression analyses were performed to assess the associations of a-TOH metabolites and measures of glucose homeostasis. Results: We included 498 participants (45% men) with mean (SD) age of 55.8 (6.1) years who did not use glucose-lowering medication. While blood a-TOH was not associated with measures of glucose homeostasis, urinary oxidized metabolites (a-TLHQ-SO 3 /GLU) were associated with HOMA-IR and Matsuda index. For example, a one-SD higher a-TLHQ-SO 3 was associated with 0.92 (95% CI: 0.87, 0.97) fold lower HOMA-IR and 1.06 (1.01, 1.11) fold higher Matsuda index, respectively. Similar results were obtained for the urinary a-TLHQ to a-CEHC ratio as a measure of oxidized-over-enzymatic conversion of a-TOH. Conclusion: Higher urinary levels of oxidized a-TOH metabolites as well as higher oxidized-to-enzymatic a-TOH metabolite ratio, but not circulating a-TOH or enzymatic metabolites, were associated with lower insulin resistance. Rather than circulating a-TOH, estimates of the conversion of a-TOH might be informative in relation to health and disease.

Diet‐Derived Antioxidants Do Not Decrease Risk of Ischemic Stroke: A Mendelian Randomization Study in 1 Million People

“…This hypothesis was supported by a number of our earlier studies in which we investigated the associations of vitamin E and its enzymatic and oxidative metabolites with lifestyle factors and subclinical disease outcomes. 42 , 43 In brief, we showed in these studies that vitamin E concentrations were not correlated with the urinary enzymatic and oxidative vitamin E metabolite levels, and lifestyle factors and subclinical disease outcomes showed different associations with vitamin E concentrations than with their oxidized metabolites.…”

Association of measures of body fat with serum alpha-tocopherol and its metabolites in middle-aged individuals

“…Therefore, we were not able to correct for these factors, but adjusted for other factors related to health consciousness (most notably total energy intake and alcohol consumption) to capture as much confounding as possible in these circumstances. However, we previously published that vitamin E was uncorrelated to the vitamin E metabolites [37] meaning that vitamin E status does not yield differences in vitamin E conversion. Although being validated extensively [27,28,38], self-reported information on lifestyle, used for confounder adjustment, is susceptible to recall bias and/or measurement error.…”

“…After excluding participants with missing data, our study population comprised 511 participants with a mean (SD) age of 55.9 (6.1) years, of whom 53% were women and median (IQR) BMI was 25.4 (23.1, 27.9) kg/m 2 . Women had a higher median [interquartile range] abdominal aSAT and more TBF than men (196 cm 2 [158, 238] aSAT in men, 251 cm 2 [191, 311] aSAT in women; 24% [21,28] TBF in men, 36% [32,40] TBF in women), whereas men exhibited more VAT than women (101 cm 2 [72, 139] VAT in men, 57 cm 2 [37,94] VAT in women). Furthermore, men had higher alcohol consumption than women.…”

Antioxidant Supplementation in Oxidative Stress-Related Diseases: What Have We Learned from Studies on Alpha-Tocopherol?

“…We were particularly interested in the associations between observed levels of α-tocopherol in serum and its metabolomics in urine in relation to behavioral and (subclinical) disease outcomes in a random subsample of 520 individuals. In several studies, the associations between α-tocopherol serum levels and lifestyle factors (such as smoking and alcohol use [ 92 ]), measures of glucose homeostasis [ 93 ], measures of body fat [ 94 ] and lipoprotein (sub)particles [ 95 ] were investigated. Overall, these studies found no associations, or even trends, between circulating α-tocopherol in serum and the different study outcomes.…”

“…These metabolites were measured as sulfated and glucuronidated conjugates of α-tocopherol, the main forms of vitamin E, by mass spectrometry analyses of NEO urine samples. In the NEO study, circulating α-tocopherol did not correlate with its oxidized but with the enzymatic metabolite in urine [ 93 ]. This may suggest that the circulating α-tocopherol level was not a rate-limiting step for the conversion to its oxidized metabolites.…”