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American Journal of Clinical Nutrition, Vol. 82, No. 3, 685-693, September 2005
© 2005 American Society for Clinical Nutrition

ORIGINAL RESEARCH COMMUNICATION

Diabetes mellitus and serum carotenoids: findings of a population-based study in Queensland, Australia1,2,3

Terry Coyne, Torukiri I Ibiebele, Peter D Baade, Annette Dobson, Christine McClintock, Sophie Dunn, Dympna Leonard and Jonathan Shaw

1 From the School of Population Health, University of Queensland, Brisbane, Australia (TC and AD); the Epidemiology Services Unit, Health Information Branch, Queensland Health, Brisbane, Australia (TC, TII, and CM); the Viertel Center for Research in Cancer Control, Queensland Cancer Fund, Brisbane, Australia (PDB); Oxfam, Oxford (SD) Tropical Public Health Unit, Queensland Health, Cairns, Australia (DL); and the International Diabetes Institute, Melbourne, Australia (JS)

2 Supported by the Australian Department of Health and Ageing, state and territory governments, and pharmaceutical companies: Eli Lilly (Aust) Pty Ltd, Janssen - Cilag (Aust) Pty Ltd, Knoll Australia Pty Ltd, Merck Lipha s.a. Alphapharm Pty Ltd, Merck Sharp & Dohme (Aust), Pharmacia and Upjohn Pty Ltd, Roche Diagnostics, Servier Laboratories (Aust) Pty Ltd, SmithKline Beecham International, BioRad Laboratories Pty Ltd and HITECH Pathology Pty Ltd; Qantas Airways Ltd and the Australian Kidney Foundation. The Queensland phase of the study was partially funded by Queensland Health.

3 Reprints not available. Address correspondence to T Coyne, School of Population Health, The University of Queensland, Public Health Building, Herston 4029, Queensland, Australia. E-mail: t.coyne{at}sph.uq.edu.au.


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 SUBJECTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Background: Epidemiologic evidence suggests that serum carotenoids are potent antioxidants and may play a protective role in the development of chronic diseases including cancers, cardiovascular disease, and inflammatory diseases. The role of these antioxidants in the pathogenesis of diabetes mellitus remains unclear.

Objective: This study examined data from a cross-sectional survey to investigate the association between serum carotenoids and type 2 diabetes.

Design: Study participants were adults aged ≥25 y (n = 1597) from 6 randomly selected cities and towns in Queensland, Australia. Study examinations conducted between October and December 2000 included fasting plasma glucose, an oral-glucose-tolerance test, and measurement of the serum concentrations of 5 carotenoid compounds.

Results: Mean 2-h postload plasma glucose and fasting insulin concentrations decreased significantly with increasing quintiles of the 5 serum carotenoids—{alpha}-carotene, ß-carotene, ß-cryptoxanthin, lutein/zeaxanthin, and lycopene. Geometric mean concentrations for all serum carotenoids decreased (all decreases were significant except that of lycopene) with declining glucose tolerance status. ß-Carotene had the greatest decrease, to geometric means of 0.59, 0.50, and 0.42 µmol/L in persons with normal glucose tolerance, impaired glucose metabolism, and type 2 diabetes, respectively (P < 0.01 for linear trend), after control for potential confounders.

Conclusions: Serum carotenoids are inversely associated with type 2 diabetes and impaired glucose metabolism. Randomized trials of diets high in carotenoid-rich vegetables and fruit are needed to confirm these results and those from other observational studies. Such evidence would have very important implications for the prevention of diabetes.

Key Words: Type 2 diabetes • diabetes mellitus • impaired glucose tolerance • serum carotenoids • {alpha}-carotene • ß-carotene • ß-cryptoxanthin • lutein/zeaxanthin • lycopene • antioxidant vitamins • diet • cross-sectional surveys • health surveys • nutrition


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
SUBJECTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Carotenoids are a wide range of compounds derived solely from plants; the major ones found in serum are {alpha}-carotene, ß-carotene, ß-cryptoxanthin, lutein/zeaxanthin, and lycopene. Considerable epidemiologic evidence exists that some carotenoids are potent antioxidants and may play a protective role against the development of chronic diseases such as atherosclerosis (1, 2), stroke (3), certain cancers (4), and inflammatory diseases (5). Although obesity and physical inactivity are known to be major risk factors for type 2 diabetes, evidence suggests that oxidative stress also may contribute to the pathophysiology of type 2 diabetes (6). Multiple factors have been associated with increased oxidative stress in diabetes mellitus. These factors include glucose autoxidation that results in the production of free radicals, an increase in protein glycation (glucooxidation), and a decrease in antioxidant defenses. Enhanced oxidative stress is considered an underlying condition that is responsible for some of the complications of diabetes (7).

Serum or dietary vitamin A, E, and C concentrations have been hypothesized to be lower in persons with impaired glucose tolerance (IGT) or with type 2 diabetes than in those who have normal glucose tolerance (8, 9); nevertheless, there is conflicting evidence concerning these relations (10, 11). Several cross-sectional epidemiologic studies have reported an inverse relation between serum carotenoids and diabetes status (12–15), and yet intervention studies providing supplements of antioxidant vitamins have shown conflicting results (7, 16). In this study, we investigated the relations between the major serum carotenoids—{alpha}-carotene, ß-carotene, ß-cryptoxanthin, lutein/zeaxanthin, and lycopene—and type 2 diabetes status in a cross-sectional population-based study in Queensland, Australia.


   SUBJECTS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 SUBJECTS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Subjects
The study was conducted between October and December 2000 as part of a national study, the Australian Diabetes, Obesity and Lifestyle Study (AusDiab), to determine the prevalence of diabetes and associated cardiovascular disease risk factors among adults aged ≥25 y (17). Six urban sites (cities and towns) were randomly selected from census collector districts (CDs) in Queensland. The CDs were selected and with probability proportional to size. Noninstitutionalized adults aged ≥25 y who were residing in private dwellings were included in the survey if they had resided full-time at the address for ≥6 mo before the survey. Persons with physical or intellectual disabilities that precluded participation in the study were not included.

Trained interviewers conducted house-to-house interviews, and eligible participants were invited to attend a biomedical examination that included collection of blood samples, blood pressure measurements, and anthropometric measurements and the administration of standardized questionnaires related to diet as well as sociodemographic, lifestyle, and health-related characteristics. Details of the sampling framework and overall study design have been published elsewhere (18). A total of 1634 persons in Queensland completed the physical examination. Although the overall response rate in the study was low ({approx}50% of those invited and 30% of those estimated to be eligible), the internal validity and quality control of the data collection were high (18).

All respondents gave written informed consent to participate in the survey on arrival at the testing site.The study was approved by the International Diabetes Institute and The University of Queensland ethics committees.

Methods
Study participants arrived for the examination after having fasted for ≥12 h. Blood pressure measurements were taken by using a Dinamap sphygmomanometer (Critikon, Tampa, FL). Blood was drawn for fasting glucose and insulin determinations. Participants not taking hypoglycemic medication completed a 2-h oral-glucose-tolerance test (OGTT) after consuming a 75-g glucose drink. Fasting and 2-h glucose were measured enzymatically (glucose oxidase) on an Olympus AU600 analyzer (Olympus Optical Co, Tokyo, Japan). Insulin analysis was conducted for all participants aged >35 (n = 1303) by using the Human Insulin Specific RIA Kit (catalog #HI-14K; Linco Research Inc, St Charles, MO).

The lipids total and HDL cholesterol and triacylglycerol were measured enzymatically on an Olympus AU 600. LDL cholesterol was calculated from the equation of Friedewald et al (19):

(1)
Glucose, insulin, and lipid determinations were carried out as part of the AusDiab study.

Blood was drawn for the carotenoid determinations at the time of the 2-h OGTT or, for those subjects who did not take the OGTT, 2 h after the fasting sample. Serum samples were meticulously handled and protected from light at each stage of processing to prevent deterioration and degradation (20). The serum was pipetted, frozen, packed in dry ice, shipped to the laboratory in Brisbane, and analyzed within 3 wk of collection. The 5 serum carotenoids were assayed simultaneously according to the HPLC procedure described by Talwar et al (21). Reported intrabatch CVs obtained by using this method were 6.5%, 7.6%, 7.3%, 6.9%, and 9.0%, and interbatch (analyzed after storage at –70 °C for 8 wk) CVs were 13%, 9.6%, 8.7%, 8.5%, and 11%, respectively, for {alpha}-carotene, ß-carotene, ß-cryptoxanthin, lutein/zeaxanthin, and lycopene (21). Complete data for serum carotenoids and plasma glucose were available for 1597 adults.

The diagnostic criteria for the presence of diabetes, IGT, and impaired fasting glucose were based on values for venous plasma glucose concentration (fasting and 2-h measurements) outlined in the World Health Organization report on the diagnosis and classification of diabetes mellitus (22) and are summarized in Table 1Go. Participants were also classified as having diabetes if they were receiving treatment for diabetes in the form of tablets or insulin at the time of the study.


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  		TABLE 1 Classification of glucose tolerance status according to fasting plasma glucose values and 2-h plasma glucose values obtained during a 75-g oral-glucose-tolerance test1

 
Of those diagnosed with diabetes, 2.5% were classified as having type 1 diabetes and were excluded from the analysis. Participants were defined as having type 1 diabetes if insulin treatment had been started within 2 y of diagnosis and, for those aged ≥40 y when diagnosed, if their current BMI was <27. For the purpose of this analysis, diabetes status was categorized as normal glucose tolerance, impaired glucose metabolism (IGM)—calculated as IGM = IGT and impaired fasting glucose combined—and type 2 diabetes.

Demographic and lifestyle variables were collected by using standardized questionnaires and were categorized as follows. Age was divided into 10-y age groups. Educational status was categorized as secondary school or less, trade certificate or bachelor's degree, and postgraduate qualification. Body mass index (BMI; in kg/m2) was categorized as obese (BMI ≥ 30), overweight (BMI ≥ 25 to <30), and normal-weight (BMI < 25) (23). Because only 18 participants were classified as underweight (BMI < 18.5), they were grouped with the normal-weight group.

Smoking status was categorized as current smoker (at least daily), former smoker (less than daily for at least the last 3 mo, but used to smoke daily), and nonsmoker (smoked < 100 cigarettes over lifetime) (24). Alcohol consumption was categorized as none, ≤60 standard drinks/mo, or >60 standard drinks/mo (24). Physical activity beneficial to health was categorized as sufficiently active (>150 min physical activity time in the previous week), insufficiently active but not sedentary (<150 min physical activity time in the previous week), and sedentary (no participation in physical activity in the previous week). Physical activity time was calculated as the sum of the time spent walking or performing moderate activity plus double the time spent in vigorous activity (to reflect its greater intensity) (25). Vitamin supplement use during the previous 24 h was categorized as yes for respondents who indicated that they took any vitamin or mineral supplements on the previous day and no for respondents who indicated they did not do so.

Plasma lipids were categorized by using the criteria for abnormal lipid concentrations that were based on recommendations from the National Heart Foundation (26) and the Australian Diabetes Society (27). The presence or absence of hypertension was determined for each participant in accordance with World Health Organization guidelines (28).

Intakes of vegetables and fruit were approximated by asking 2 questions. Participants were asked, "How many serves [ie, servings] of vegetables do you usually eat each day? Including fresh, frozen or tinned vegetables (a serve = 1/2 cup [ie, 75 g] cooked vegetables or 1 cup [ie, {approx}130 g] salad vegetables)." Usual consumption of fruit was assessed by the question, "How many serves of fruit do you usually eat each day? Including fresh, frozen, or canned fruit (a serve = 1 medium piece or 2 small pieces of fruit or 1 cup [ie, 150 g] diced pieces of fruit.)." Participants were categorized into 3 groups (ie, ≤ 1 serving, 2–3 servings, and ≥4 servings) according to their responses to both questions.

Statistical analysis
Data were analyzed by using the survey commands in STATA statistical software (version 8; Stata Corp, College Station, TX; 29). These commands take into account the complex survey design in the calculation of estimates, variance, SEs, and CIs. Pearson's chi-square statistic was used to assess the relation between diabetes status and selected categorical variables. Student's t test was used to compare differences in means between 2 groups; analysis of variance was used to assess overall differences in means between serum carotenoids and the variables with >2 groups.

Mean fasting plasma glucose, 2-h postload glucose, and plasma insulin concentrations were estimated for quintiles of each serum carotenoid after adjustment for age, and P for trend was calculated by using multiple linear regression. Distributions of serum carotenoids were skewed and therefore were natural logarithmically transformed to better approximate the normal distribution for regression analyses. Associations between serum carotenoids as dependent variables and diabetes status (as an ordinal variable) were assessed by using multiple linear regression analysis, and P for trend was estimated. The adjust command in STATA was used to provide adjusted predictions of mean serum carotenoid concentrations for each level of diabetes status. Results are reported as back-transformed geometric means. Analysis was performed separately for each serum carotenoid, after adjustment for the potential confounders age; sex; BMI; physical activity; education; vitamin use; smoking status; alcohol intake; systolic and diastolic blood pressures; total, HDL, and LDL cholesterol; and triacylglycerol. The confounders were put into the model simultaneously as categorical variables. Because of missing values, the sample size is not the same for all analyses.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 SUBJECTS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
The prevalence of diabetes and IGM according to demographic and health-related characteristics is shown in Table 2Go. There was no significant difference in diabetes status between males and females. Significant differences in diabetes status were evident for subjects by age, BMI, physical activity status, total and HDL cholesterol, triacylglycerol, and systolic blood pressure.


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  		TABLE 2 The prevalence of type 2 diabetes and impaired glucose metabolism by demographic and health-related characteristics for adults aged ≥25 y in the 2000 Queensland AusDiab study1

 
The relations between the 5 serum carotenoids and the various sociodemographic, anthropometric, and health-related variables are shown in Table 3Go. Although there were significant differences in mean serum carotenoids within many of these categories, age group, BMI, alcohol intake, and HDL and LDL cholesterol had significant relations with all the serum carotenoids. Apart from educational status, all the other variables in Table 3Go were related to some but not all carotenoids.


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  		TABLE 3 Geometric mean (and 95% CI) concentrations of serum carotenoids by selected variables for adults aged ≥25 y in the 2000 Queensland AusDiab study1

 
The mean fasting plasma glucose, 2-h postload glucose, and fasting insulin by quintiles of each serum carotenoid are shown in Table 4Go. The median of each of the carotenoids is provided for each quintile. Mean 2-h postload glucose and fasting insulin concentrations decreased significantly with increasing quintiles of each serum carotenoid (P for trend < 0.05). Fasting glucose concentrations also decreased significantly with increasing quintiles of {alpha}-carotene and ß-carotene (P < 0.01).


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  		TABLE 4 Age-adjusted mean fasting plasma glucose, 2-h postload plasma glucose, and fasting insulin by quintile (Q) of serum carotenoids for adults in the 2000 Queensland AusDiab study1

 
After adjustment for the potential confounders age; sex; BMI; physical activity; educational status; smoking; alcohol intake; vitamin use; total, HDL, and LDL cholesterol; triacylglycerol; and systolic and diastolic blood pressures, significant linear trends in serum carotenoid concentrations (except lycopene) by diabetes status were evident (Table 5Go). ß-Carotene showed the most decline; its geometric means were 0.59, 0.50, and 0.42 µmol/L in persons with normal glucose tolerance, IGM, and type 2 diabetes, respectively (P < 0.01 for linear trend).


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  		TABLE 5 Adjusted geometric mean (and 95% CI) concentrations of serum carotenoids by diabetes status for adults aged ≥25 y who participated in the 2000 Queensland AusDiab study1

 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 SUBJECTS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
The data from the current population study suggest that serum carotenoids are associated with diabetes status. Our study showed an increasing trend in 2-h postload plasma glucose and fasting insulin concentrations with decreasing quintiles of all of the carotenoids tested. A decreasing trend in fasting plasma glucose concentrations was observed with increasing quintiles of {alpha}-carotene and ß-carotene. In addition, serum carotenoid concentrations showed a linear decrease with the degree of glucose tolerance abnormality. This decrease was significant for all of the carotenoids except lycopene. These findings are consistent with data reported by Ford et al (12) from the third National Health and Nutrition Examination Survey (NHANES III; 12). In NHANES III, Ford et al reported a significant linear decrease in ß-carotene and lycopene in persons with IGT and in persons with newly diagnosed diabetes compared with persons with normal glucose concentrations, after adjustment for confounding factors similar to those in our study. The association between serum carotenoid concentrations and diabetes status observed in our study was also consistent with associations reported in studies from several other countries (13–15, 30, 31).

Because of the cross-sectional design of our study, however, it is not possible to draw inferences as to whether the lower serum carotenoid concentrations found in participants with diabetes are the result of increased utilization of these antioxidants due to the oxidative stress effects of the disease or whether the low concentrations are involved in the pathogenesis of the disease and reflect low intakes of carotenoid-rich vegetables and fruit. It has been postulated that the lower serum carotenoid concentrations found in this study may be due to the oxidative stress effects of IGM. Research has shown that oxidative stress, an imbalance in which the production of free radicals overwhelms the body's antioxidant defenses, is involved in the causation and progression of type 2 diabetes (32). There currently is considerable evidence that hyperglycemia, hyperinsulinemia, and insulin resistance result in greater reactive oxygen species production that contributes to oxidative stress in diabetes (33), and that this greater reactive oxygen species production may be beyond the capacity of the antioxidant defense mechanisms (34). Oxidative stress and free radical activity have been reported to be involved in the pathogenesis of type 1 diabetes (35), as well as in the development of complications associated with type 2 diabetes (36, 37). It is postulated that the oxidative stress associated with diabetes is responsible for the reduced carotenoid concentrations found in this study, which suggests that glucose intolerance is influencing the carotenoid concentrations, rather than the low carotenoid concentrations being causally related to diabetes status.

It has also been suggested that the oxidative stress observed in persons with glucose impairment is due to lower antioxidant concentrations. Facchini et al (38) suggested that insulin-mediated glucose disposal in healthy persons is significantly related to lipid hydroperoxide concentrations and fat-soluble antioxidant vitamins. Their work showed that nondiabetic subjects with insulin resistance had high plasma lipid peroxidation values well before the development of IGT or type 2 diabetes. They observed significant inverse associations between steady state plasma glucose values and {alpha}-carotene, ß-carotene, lutein, {alpha}-tocopherol, and {delta}-tocopherol in 36 healthy nondiabetic volunteers. Facchini et al also observed that the higher the steady state plasma glucose, the more insulin resistant the person. They hypothesized that insulin resistance can result in greater lipid peroxidation, which is accompanied by a decrease in plasma antioxidant concentrations. Conversely, lipid peroxidation is accelerated by low antioxidant activity, which could impair insulin action and result in diabetes (38). Thus it is possible that oxidative stress is a result of low antioxidant concentrations in persons who already have IGM and type 2 diabetes.

Several studies have shown a relation between vegetable or carotenoid intake and diabetes status (9, 14, 31). Suzuki et al (15) found a significantly lower odds ratio for high glycated hemoglobin (Hb A1c) among those with the highest intakes of carrots and pumpkin than among those with low intakes. The large EPIC-Norfolk study found that persons with higher intakes of vegetables and fruit have higher serum carotenoid concentrations and lower risk of type 2 diabetes than do those with lower intakes (39). Montonen et al (9) reported that, in older adults, ß-cryptoxanthin intake was inversely associated with reduced risk of type 2 diabetes. Ylönen et al (13) reported advantageous associations with both dietary and plasma carotenoids and glucose status among males but not among females in the Botnia Dietary Study.

Serum carotenoids are considered reliable markers of vegetable and fruit intake, and our study did find significant associations between the approximated vegetable and fruit intakes and serum concentrations of {alpha}-carotene, ß-carotene, ß-cryptoxanthin, and lutein/zeaxanthin (40). We did not, however, find a significant association between glucose intolerance and self-reported vegetable and fruit intake or dietary ß-carotene intake (not shown). This lack of association may have been due to the crudeness of our methods for estimating vegetable and fruit intakes.

We recognize that residual confounding may have occurred in our study because of suboptimal measurements of several factors. For instance, concentrations of carotenoids (except lycopene) in our study were significantly lower among smokers, which is consistent with other studies (12). However, there may be residual confounding because of our simple categorization of smoking. This could have enhanced the magnitude of the association between serum carotenoids and glucose status, but it is not likely to explain most of the association.

Whereas our findings and data from other studies suggest a probable association between several carotenoids and diabetes, they do not establish a causal relation. In a clinical trial among US male health professionals, Liu et al (16) found no difference in the incidence of diabetes between the group receiving ß-carotene supplements and the control group. Liu et al concluded, however, that the results of their trial of ß-carotene supplementation "should not be interpreted as refuting the findings of observational studies that suggest that increased intake of vegetables rich in carotenoids and other antioxidants may decrease the risk of type 2 diabetes" (16).

Diabetes is increasing in most countries of the world today and will continue to increase (41). As populations continue to age and as overweight and obesity continue to escalate, especially among children, diabetes will become an increasing burden on the health system. Lifestyle interventions have shown a dramatic reduction in risk of diabetes among those with IGT (42, 43). However, strategies for both primary and secondary prevention will be necessary to reduce the burden of diabetes in future years and generations in both developed and developing countries. Clinical trials based on diets high in carotenoid-rich vegetables and fruit may provide important insight in relation not only to the prevention of complications of diabetes, but also to reducing the risk of developing the disease, especially among those with IGT.


   ACKNOWLEDGMENTS
 
TC was responsible for the concept and conduct of the study and preparing the manuscript. TII performed the statistical analysis and writing the results section. PDB and AD provided technical assistance on the data analysis. JS, SD, and CM provided details regarding the study methods. DL gave technical assistance on writing and interpretation. None of the authors had a personal or financial conflict of interest.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 SUBJECTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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Received for publication December 8, 2004. Accepted for publication June 3, 2005.




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