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Clinical Chemistry 43: 1066-1071, 1997;
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(Clinical Chemistry. 1997;43:1066-1071.)
© 1997 American Association for Clinical Chemistry, Inc.

Articles

Reference values for retinol, tocopherol, and main carotenoids in serum of control and insulin-dependent diabetic Spanish subjects

Begoña Olmedillaa, Fernando Granado, Enrique Gil-Martinez, Inmaculada Blanco and Enrique Rojas-Hidalgo

a Author for correspondence. Fax +34-1-373 76 67 or +34-1-373 05 35;


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
To establish reference ranges for use in clinical and epidemiological studies, we determined concentrations of retinol, {alpha}-tocopherol, ß-carotene, {alpha}-carotene, ß-cryptoxanthin, lutein, zeaxanthin, and lycopene in 450 Spanish control subjects and 123 Spanish patients with insulin-dependent diabetes mellitus (IDDM). Results were grouped according to sex, and samples were collected throughout the year. Concentrations of retinol were significantly lower and ß-carotene and {alpha}-carotene were higher in women than in men, both in controls and IDDM subjects, whereas ß-cryptoxanthin concentrations were higher only in control women. Conditional logistic regression analysis showed that retinol, ß-carotene, and lycopene were the variables associated with diabetes. In comparison with other populations, our controls showed, in general, ordinary concentrations of retinol, comparatively low ß-carotene and high ß-cryptoxanthin concentrations, and a relatively high {alpha}-tocopherol/cholesterol ratio.


Key Words: indexing terms: nutritional status • ß-cryptoxanthin • lutein • zeaxanthin • lycopene • vitamins • antioxidants


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
Carotenoids, retinol, and tocopherol are among the most widely studied compounds in various populations, for both serum concentrations and dietary intake (1)(2)(3)(4)(5)(6)(7)(8), because of their inverse relationship with the development of several diseases, e.g., cancer, cardiovascular disease, and cataracts (9)(10)(11)(12).

Several factors have been described as influencing serum concentrations of carotenoids, and to a lesser extent, the concentrations of tocopherol and retinol: sex, age, dietary intake, smoking and drinking habits, and seasonality (1)(2)(13)(14)(15)(16). In the literature, a great variability is evident in carotenoid serum concentrations from various populations (1)(2)(3)(4)(17)(18), a fact that has made it difficult to establish consensus cutoff points for application to different populations and for interpretation of carotenoid concentration in the context of disease prevention.

Subjects with insulin-dependent diabetes mellitus (IDDM) are among the groups at risk of having low vitamin concentrations (19)(20). Despite the large amount of literature dealing with the role of dietary composition in control of diabetes mellitus, relatively few studies deal with the effects of the disease on micronutrient status in these patients. Those that do are inconclusive (21)(22).

The present study was designed to establish reference values for these compounds in our population for use in comparisons with other control populations, for interpreting values in different clinical conditions, and for application in diet and in health and disease epidemiological studies. In addition, study of the fat-soluble antioxidant status in IDDM patients should allow us to assess, in the future, the possible relation of antioxidants to the development of late complications of diabetes.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
subjects
Recruited as control subjects were 450 free-living, apparently healthy people from Madrid, ages 5–79 years (median: males 32 years, females 32.5 years). They had ordinary eating habits, with none on a special diet or taking vitamin or carotenoid supplements. Their cholesterol and triglyceride concentrations fell within normal reference ranges. Groups were established according to sex (210 males and 240 females), and serum samples were taken and averaged throughout the year (spring–summer and autumn–winter), given that seasonality may influence the concentrations of several of the analytes being investigated (16).

Also recruited were 123 insulin-dependent diabetics, ages 13 to 84 years (median: males 27.5 years, females 27 years). Groups were established according to sex (60 males and 63 females) and sample collection was evenly distributed throughout the year.

The age distributions and proportions of smokers were similar in both groups. Blood samples were collected after an overnight fast and centrifuged at 630g for 10 min; the serum was removed and stored at -24 °C until analyzed (within 5 months). The procedures used were in accordance with the ethical standards of the Ethical Committee of Clinical Investigation of Clìnica Puerta de Hierro.

sample preparation and chromatography
The HPLC method and sample preparation used in this study were slightly modified from those previously described (18). Briefly, 800 µL of ethanol containing retinyl acetate (0.4 mg/L) and tocopheryl acetate (0.1 g/L) as internal standards was added to 800 µL of serum. After vortex-mixing for 45 s, we extracted the sera twice with hexane (2 mL, stabilized with 0.1 g/L butylated hydroxytoluene), vortex-mixing the extracts for 3 and 2 min, respectively. The organic phases were removed, pooled, and evaporated under nitrogen atmosphere, reconstituted with 300 µL of an equivolume solution of tetrahydrofuran:ethanol, and injected (7.5 µL) onto the HPLC system.

The chromatographic system consisted of a Spheri-5-RP-18 or Spheri-5-ODS (5 µm) column (Applied Biosystems, San Jose, CA) used with gradient elution at 1.8 mL/min from ammonium acetate, 0.2 g/L in acetonitrile:dichloromethane:methanol (85:15 by vol), for 5 min to ammonium acetate, 0.2 g/L in acetonitrile:methanol (70:20:10 by vol), for 20 min.

The following compounds were analyzed: carotenoids (lutein, zeaxanthin, ß-cryptoxanthin, lycopene, {alpha}-carotene, and ß-carotene), {alpha}-tocopherol, and retinol. Other identified compounds included {gamma}-tocopherol, retinyl palmitate, {alpha}-cryptoxanthin, phytoene, phytofluene, cantaxanthin, and isomers of ß-carotene and lycopene.

A Model 490 programmable multiwavelength detector and Model 996 photodiode array detector with a Millenium data station were used (all from Waters Associates, Milford, MA). Carotenoids were detected at 450 nm, retinol and retinyl acetate at 313 nm, and tocopherol and tocopheryl acetate at 294 nm.

The precision of the analytical methods used was evaluated periodically through our participation in the Quality Assurance Program conducted by the National Institute of Standards and Technology (NIST; Gaithersburg, MD).

statistical methods
Statistical comparisons between the results for males and females, in both the control and the diabetic groups, were carried out with nonparametric methods (Mann–Whitney U-test). Control and diabetic groups were compared by using conditional logistic regression analysis.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Table 1 shows the median values and the 5th, 25th, 75th, and 95th percentiles for control and diabetic groups, according to sex. Significant sex-related differences were found for retinol (higher in males), both in the controls (P = 0.001) and the diabetic group (P = 0.01), whereas females had higher concentrations of ß-carotene (control, P = 0.001; IDDM, P = 0.008) and {alpha}-carotene (control, P = 0.001; IDDM, P = 0.018). ß-Cryptoxanthin concentrations were also higher in females but only in the control group (P = 0.001). Lutein was statistically higher in diabetic females (P = 0.037) than in diabetic males, whereas the vitamin E/cholesterol ratio was significantly higher (P = 0.022) only in the control group males.


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  		Table 1. Reference values (µmol/L) for retinol, {alpha}-tocopherol, and main carotenoids in serum of Spanish subjects (450 controls and 123 IDDM patients).

Statistically significant differences between controls and diabetics were observed for retinol (P = 0.001) and ß-carotene (P = 0.001), in both sexes. In addition, control and diabetic males had significantly different concentrations of {alpha}-tocopherol (P = 0.001) and ß-cryptoxanthin and lycopene (P = 0.05).

The highest correlation coefficients (r = 0.63–0.74) were obtained for lutein vs zeaxanthin and for ß-carotene vs {alpha}-carotene, regardless sex or group. Correlations (r = 0.01–0.1) were very low between retinol and each of the provitamin carotenoids (ß-carotene, {alpha}-carotene, ß-cryptoxanthin). Retinol and {alpha}-tocopherol showed correlations of r = 0.31–0.52 in all cases except in IDDM women (r = 0.01). {alpha}-Tocopherol showed correlation coefficients of 0.32–0.44 with lutein and zeaxanthin (except for lutein in diabetic men, r = 0.09).

High correlation coefficients were also observed (in IDDM women only) between ß-cryptoxanthin and zeaxanthin (r = 0.54) and between ß-carotene and ß-cryptoxanthin (r = 0.59) or zeaxanthin (r = 0.51). Finally, IDDM men showed a correlation between lycopene and {alpha}-carotene (r = 0.58).

Conditional logistic regression analysis (including all analytes and age) between control and diabetic groups, selected retinol, ß-carotene, and lycopene as the variables most significantly different between these groups. When the analysis was carried out according to sex, the entry order (ß coefficient) in the equation was retinol (males: -0.076 ± 0.01, P <0.0001; females: -0.085 ± 0.01, P <0.0001) and ß-carotene (males: 0.033 ± 0.02, P = 0.066; females: 0.024 ± 0.01, P = 0.012) in both sexes, followed by lycopene only in males (0.021 ± 0.01, P = 0.046).


   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
To correctly interpret the serum concentrations of fat-soluble vitamin-related compounds, establish reference ranges, and detect groups at risk in a population, one must know the distribution of each analyte in control subjects as well as validate the methodology used. Through our participation for several years in the Fat-Soluble Vitamin Quality Assurance Program conducted by NIST, we have determined that the accuracy and precision of our analytical methods for retinol, {alpha}-tocopherol, and ß-carotene have been within acceptable values (performance rated as 1 or 2, meaning within 1 or 2 SD of the assigned NIST values).

As reported by other authors [23–26] using the described methodology, one can identify in all sera not only the above-quantified compounds, but also the following compounds: {alpha}-cryptoxanthin, cis-ß-carotene (13-cis), cis-lycopene (at least three isomers), cis-lutein/zeaxanthin; {gamma}-tocopherol, 2,3-anhydrolutein, {xi}-carotene, and three ketocarotenoids [24]; several unidentified peaks are also visible. Other compounds not always present, or that need to be concentrated in the sample for detection, include cantaxanthin, {gamma}-carotene, phytoene, phytofluene, retinyl palmitate, and echinenone.

When determining these compounds, the presence of interfering substances can lead to overestimation of the concentration of a given compound. This depends not only on the analytical method used but also on the relative concentrations of the analyte and the interferent. In our control groups, we have observed possible interferences between {alpha}-tocopherol and normal concentrations of ß-cryptoxanthin on the downslope of the {alpha}-tocopherol peak that, given the absorbance of ß-cryptoxanthin at 294 nm, can lead to overestimation of {alpha}-tocopherol when quantified by peak area. Khachik et al. [27] described a lack of interference between {gamma}-tocopherol and ß-cryptoxanthin, despite the coincidence of the peaks; this may be due to the low concentration of ß-cryptoxanthin.

reference values in control populations
Table 2 summarizes data reported for studies from different countries, when sample size was >100 subjects and results were differentiated by sex. For vitamins A and E, for which accepted "normal" ranges exist, 7 of the 10 populations in Table 2 have mean or median values in the upper part of the reference range for retinol. A consistent sex-dependent effect (males higher than females) in retinol concentrations was seen in all the populations listed, as well as in the diabetic group in this study.


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  		Table 2. Median or mean (*) carotenoid, retinol, and {alpha}-tocopherol concentrations (µmol/L) in serum [7, 2, 30, 34] or plasma [1, 28, 29, 31, 32, 33, 35] in different populations.

With regard to {alpha}-tocopherol, the mean values observed in all populations fall within a narrower range than for retinol and is the same for both sexes. The carotenoids, however, show differences of two- to fivefold in the values reported, as well as variability in the values reported for a given country; this may reflect differences between and within populations/countries, seasonality, and interlaboratory analytical variability.

As was the case for our controls, higher concentrations of provitamin A carotenoids in women than in men (Table 2Up ) are also reported in other populations, regardless of dietary habits (17). For lutein/zeaxanthin and lycopene (nonprovitamin A carotenoids), other studies reported no differences in either among control groups.

iddm group vs control group
IDDM subjects seem to behave in a different way. Although retinol is consistently higher in our IDDM males than in the IDDM females, both sexes have lower concentrations than their sex-matched controls, as has been observed previously (36)(37)(38). This appears to be associated with low concentrations of retinol-binding protein and (or) reduced mobilization of vitamin A from the liver in IDDM patients (36). Results reported for vitamin E are confusing, having been stated as higher or similar in diabetes patients in comparison with controls, possibly because of inclusion of hyperlipemic subjects or inhomogeneity of the sample (or both) (22)(39); when normalized with respect to cholesterol concentrations, the {alpha}-tocopherol concentrations in diabetics were not different from those of normolipemic controls (40).

Sex-related differences for retinol and provitamin carotenoids are similar to those observed in controls, except for ß-cryptoxanthin, although lutein is distinctly present. Total lycopene concentrations differed only between control males and IDDM males, as was also seen in the conditional logistic regression analysis. Moreover, lycopene is the only carotenoid that seems to be affected by the duration of diabetes (41). However, the difference is only quantitative and not qualitative, the profile of lycopene isomers in IDDM subjects being the same as in our controls and also described in other studies (26).

correlations among analytes
Regardless of sex and diabetic condition of the subjects, we obtained high correlation coefficients (r >0.6, P <0.0001) between {alpha}- and ß-carotene as well as between lutein and zeaxanthin, and the correlations were very similar to those described earlier (35). This may be due to their simultaneous occurrence in several vegetables and fruits—although this explanation is not equally reflected in the case of lutein and ß-carotene, both of which are invariably present in green vegetables. A similar correlation between lycopene and ß-carotene has been described by Ascherio et al. (35), who, on finding no correlation with dietary intake, suggested a metabolic or absorptive link.

As would be expected, the lowest correlations were obtained between retinol and each of the provitamin carotenoids, agreeing with those reported by others (9)(35). Nevertheless, as described by Gey et al. (9), retinol and {alpha}-tocopherol showed correlation coefficients, except in IDDM females, of between 0.31 and 0.52 (P <0.0001 in controls; P <0.02 in IDDM males), slightly higher than previously described (30).

In summary, considering the possible implication in disease prevention of several compounds analyzed in this study, IDDM subjects can be considered as an at-risk group for low-retinol status, a situation specifically linked to diabetes. That concentrations of ß-carotene and lycopene are higher in the patients than in the controls also shows a strong association of these compounds with diabetes. On the other hand, the {alpha}-tocopherol/cholesterol ratio is as high as in IDDM as in controls and is not affected by the disease. From these data, we conclude that IDDM subjects, although classically considered as a group at risk for cardiovascular disease, do not differ from matched controls with regard to antioxidant status, a poor antioxidant status being associated with a high risk for several chronic and degenerative diseases. The normal concentrations of retinol, relatively high {alpha}-tocopherol/cholesterol ratio, and comparatively low ß-carotene status shown by our control group in comparison with other populations could be compensated or influenced, in part, by higher concentrations of other carotenoids (i.e., ß-cryptoxanthin).


   Acknowledgments
 
This work has been partially funded by a grant from Fondo de Investigaciones Sanitarias (FIS no. 92/0720), Spain. We acknowledge Pilar Martìnez and Teresa Motilla for their efforts in recruitment of volunteers and blood drawing and Isabel Millàn for her statistical advice and work. We are also in debt to Marta Messmann for preparing the manuscript. Several carotenoid standards were a gift from Hoffmann-La Roche (Basle, Switzerland).


   Footnotes
 
Servicio de Nutriciòn, Clìnica Puerta de Hierro, 28035 Madrid, Spain.

This work was presented in part at the conference, Retinoids: new trends in research and clinical applications, held in Genoa, Italy, October 4–7, 1993.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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