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A population-based study of the association between betel-quid chewing and the metabolic syndrome in men^1,2,3

¹ From the Institute of Preventive Medicine, College of Public Health, National Taiwan University, Taipei, Taiwan (AM-FY, L-SC, C-CH, and TH-HC); the Taiwan Association of Medical Screening. Taipei, Taiwan (AM-FY, L-SC, H-MW, C-CH, and TH-HC); the Health Bureau of Keelung City, Keelung City, Taiwan (Y-HC); the Graduate Institute of Epidemiology, College of Public Health, National Taiwan University, Taipei, Taiwan (H-MW); the Center for Diabetes & Metabolic Medicine, Queen Mary School of Medicine & Dentistry, Royal London Hospital, London, United Kingdom (BJB)

² Supported by the National Science Council (NSC 91-2320-B002-171; NSC 91-2320-B002-172).

³ Address reprint requests to TH-H Chen, Institute of Preventive Medicine, College of Public Health, Room 521, No. 17, Hsu-Chow Road, National Taiwan University, Taipei, Taiwan. E-mail: stony{at}episerv.cph.ntu.edu.tw.

	ABSTRACT

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Background: Betel-quid chewing, an established risk factor for oropharyngeal malignancy, is associated with hyperglycemia and obesity. Associations with other characteristics of the metabolic syndrome have not been reported.

Objective: This study examined associations between betel-quid chewing and the metabolic syndrome, allowing for recognized risk factors and exploring dose-response effects in a population-based study.

Design: Age-specific prevalence rates of the metabolic syndrome were examined in betel-quid chewing and nonchewing men (n = 19 839) recruited into the Keelung Community-based Integrated Screening program in 2001–2003. The independent effect of betel-quid chewing on metabolic syndrome risk was examined by using multiple logistic regression with control for well-recognized risk factors (eg, education, physical activity, and dietary factors) and dose-response effects were examined by using trend tests.

Results: The age-adjusted prevalence of the metabolic syndrome was highest in current chewers (25.13%), next highest in ex-chewers (22.04%), and lowest in nonchewers (15.73%) (P < 0.0001). Odds ratios (95% CIs) for the metabolic syndrome were 1.38 (1.19, 1.60) and 1.78 (1.53, 2.08) in ex-chewers and current chewers, respectively, adjusted for other significant correlates such as a family history of hypertension and diabetes mellitus. Meaningful odds ratios for the metabolic syndrome components ranged from 1.24 for hyperglycemia (95% CI: 1.09, 1.64) to 1.90 (95% CI: 1.66, 2.19) for hypertriacylglycerolemia. Increasing odds ratios for the metabolic syndrome with higher consumption of betel quid (whether by rate of use, duration of use, or cumulative exposure) suggest dose-response effects.

Conclusions: After adjustment for well-established risk factors, our study showed independent predictive dose-response effects of betel-quid chewing for the metabolic syndrome and its components in a population-based study of men with a 15% prevalence of betel-nut chewing.

Key Words: Metabolic syndrome • betel quid • Areca catechu • chewing • dose-response effect • community-based integrated screening • risk factors

	INTRODUCTION

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Although chewing betel quid, containing Areca catechu palm nuts, is a recognized risk factor for oral premalignancy and cancer, few studies have focused on associations between betel-quid chewing and chronic diseases, even though it is the fourth most common addictive habit worldwide (1). Betel-quid chewing has been shown to be associated with the development of obesity and hyperglycemia in mice (2) and with hyperglycemia and type 2 diabetes, epidemiologically, in humans (3, 4).

Furthermore, betel-quid chewing has been reported to be associated with increased waist size and weight, recognized features of the metabolic syndrome, in British South Asians (5). A review of the literature shows many reported physiologic and metabolic effects of betel-quid consumption (4). Arecal alkaloids, the major psychoactive components of Areca catechu nuts, chewed alone in Piper betle (betel) leaf-wrapped quids or, as in Taiwan, with sliced inflorescence of Piper betle (Lao-Hwa) (1), are competitive inhibitors of -aminobutyrate receptors with widespread effects because -aminobutyrate receptors are found in the brain, cardiovascular system, lungs, gut, and pancreatic islets. Areca catechu nut (commonly called "betel nut") alkaloids activate the sympathetic nervous system (even at low doses), increase adrenal medullary catecholamine secretion, and at high doses can increase blood pressure. These are properties that could be expected to increase the risk of ischemic heart disease, although only one report suggests an association of acute coronary events with betel-quid chewing (6).

Betel-quid chewers are reported to be at increased risk of developing type 2 diabetes. Thus, it is important to establish whether there may also be associations between the betel habit (the chewing of Areca catechu nuts), used by 600 million people worldwide (1, 7), and the development of the metabolic syndrome because, with or without overt diabetes, it is strongly associated with the development of atherosclerotic disease. The aims of the present study, therefore, were 1) to assess whether betel-quid chewers have higher prevalence rates of the metabolic syndrome than do nonchewers, after control for other recognized risk factors for the metabolic syndrome, in a population-based study, and 2) to determine whether there was evidence of dose-response effects for the risk of the metabolic syndrome, or any of its component features, associated with the duration of betel-quid chewing, the rate of use, cumulative exposure, and the duration of time after quitting betel-quid chewing (quitting-years).

	SUBJECTS AND METHODS

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Subjects
Subjects were participants in the Keelung Community-based Integrated Screening (KCIS) program, a screening program targeting 5 neoplastic diseases (cervical, colorectal, liver, oropharyngeal, and breast cancers) and 3 nonneoplastic chronic diseases (diabetes mellitus, hypertension, and hyperlipidemia) that began recruitment in 1999 in Keelung, Taiwan. Details of the study design, implementation, and preliminary results have been described in full elsewhere (8). In brief, the invited population of the KCIS program was derived from 217 884 people aged 30–79 y resident in Keelung in 1999. Because the Pap smear screening program was a major screening target at that time, we initially invited women who had no history of having Pap smear or who had not undergone a Pap smear for 3 y and used this invitation as an incentive to invite their husbands and other relatives to attend a series of screenings integrated within the KCIS program. The overall attendance rate for women invited to attend the Pap smear screening was 80%. The total number of participants had reached 61 653 by the end of 2003 (28.3% of the total population). A comparison of attendant with nonattendant subjects with respect to age, sex, and education showed that the old and the less-educated women were more likely to attend the KCIS than were the men, the young, or the highly educated and it became necessary to control for age and education in multivariate analysis (see below) for the men only.

Because the measurement of HDL cholesterol only began in 2001, only those subjects screened between 1 January 2001 and 31 December 2003 were included in the present subgroup analyses, which allowed the use of consistent criteria for the presence of the metabolic syndrome as defined by using modified National Cholesterol Education Panel Adult Treatment Panel III (NCEP ATP III) criteria (see below) (9). A total of 53 948 subjects (20 111 men and 33 837 women) participated in the KCIS program between 2001 and 2003 after having given informed consent. After the exclusion of 569 subjects without adequate records for betel chewing, the prevalence of betel nut chewers (including both ex- and current chewers) was 15.1% in men and 0.8% in women. In view of the low prevalence of betel chewing in women, data analysis was limited to 19 839 men.

Data collection
Questionnaire data on demographic features, dietary habits (intakes of meat, vegetables, fruit, beans, fish, seafood, milk, and coffee), lifestyle (betel-quid chewing, smoking, drinking, and physical activity), personal and family disease history (diabetes mellitus, hypertension, cardiovascular and cerebrovascular disease, hyperlipidemia, and stroke), and data relating to cancer risks, was obtained by one-to-one interviews conducted by specially trained public health nurses or volunteer workers. Physical activity was defined as nonoccupational exercise, and information was collected on the number of sessions per week and categorized as none, 1–3 times/wk, or 4 times/wk in the following analysis. Data on the diet during the previous 6 mo (including seafood, meat, fish, fried oil, bean or egg products, fruit and vegetables, milk, soda, and coffee) was also obtained. Food modes and standard dishes or containers of each food were displayed to assist in estimates of portion sizes for food consumed per meal. The frequency of consumption was then categorized into 5 groups: never or seldom, 1–2 times/wk, 3–4 times/wk, 5–6 times/wk, and 7 times/wk. Note that the intake of meat and vegetables was recorded in days. Physical measurements, including reclining blood pressure after 5 min of rest, were then recorded. Fasting blood samples were drawn at recruitment and repeated yearly, ie, both during the 3-y study period and during follow-up. Anthropometric measurements were made by trained staff; height was measured with a stadiometer, waist and hip circumferences (to 0.1 cm) were measured with a standard tape measure, and weight (to 0.1 kg) was measured with standardized weight scales. Waist size was measured midway between the inferior margin of the rib cage and the iliac crest horizontally, and hip circumference was measured as the maximum horizontal circumference around the buttocks. The serum biomarkers measured included fasting glucose, aspartate transaminase, alanine transaminase, triacylglycerol, total cholesterol, and LDL- and HDL-cholesterol concentrations.

The definition of the metabolic syndrome used was based on NCEP ATP III criteria (9), adjusted for waist size in Asian subjects (10). Metabolic syndrome was defined as present when subjects met 3 of the following criteria: 1) central obesity (waist circumference 90 cm for men and 80 cm for women), 2) hypertriacylglycerolemia (150 mg/dL), 3) an abnormally low HDL-cholesterol concentration (<40 mg/dL for men and <50 mg/dL for women), 4) elevated blood pressure (130 mm Hg systolic or 85 mm Hg diastolic), or 5) an elevated fasting glucose concentration (110 mg/dL).

Statistical analysis
Comparisons of demographic features, lifestyle and dietary factors, and family history across current-, ex-, and non–betel quid chewers were made by using chi-square and analysis of variance tests for categorical and continuous variables, respectively. Multiple logistic regression analysis was used to obtain adjusted odds ratios (ORs) and their 95% CIs for the presence of the metabolic syndrome in relation to betel quid use (classified as current chewer, ex-chewer, or nonchewer). Analysis for trend was used to investigate dose-response effects of the duration of betel-quid chewing, of rate of use, of cumulative exposure (quid-days), and of quitting years. To determine whether the risk of the metabolic syndrome decreased with time after quitting in ex-chewers by cumulative exposure to previous betel chewing, after control for risk factors that were significantly correlated with the metabolic syndrome, cumulative exposure was categorized into 4 groups: <10 000, 10 000–32 000, >32 000–79 000, and 79 000 quid-days. All statistical analyses were carried out by using SAS software (version 8.0; SAS Institute Inc, Cary, NC).

	RESULTS

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The distribution of demographic, lifestyle, and dietary factors among betel-quid chewers and nonchewers is shown in Table 1. Chewers were younger, less educated, and more likely to report manual labor or service jobs as their occupation than were the nonchewers. As far as the lifestyle factors were concerned, less physical activity and an increased prevalence of smoking and drinking alcohol were found in betel nut chewers (P < 0.001). Chewers also ate more meat, beans, and coffee and less vegetables than did nonchewers. There were no significant differences in any other lifestyle variable between chewers and nonchewers. Chewers had more second-degree relatives with diabetes and hypertension, but the rates of cardiovascular disease in second-degree relatives did not differ significantly between chewers and nonchewers.

Table 2

Table 3

Table 4

Table 5

	DISCUSSION

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No comparably large population-based study appears to have been conducted that addressed the relation of betel-quid chewing to each of the components currently defining the metabolic syndrome in humans, although relations with increased glycemia, waist circumference, and weight have been reported (3–5). Our findings may have been confounded by the use of simple grading to assess lifestyle factors or by the lack of data on risk factors such as vitamin D deficiency (12). However, our findings are supported by earlier work in the CD1 mouse (2), in which a significant proportion of young adult animals fed high doses of betel quid for 5 d later developed central obesity (a doubling of body weight), permanent hyperglycemia, and histologic changes in pancreatic islets indistinguishable from those of human type 2 diabetes. Several mechanisms could account for these findings. These mechanisms included increased sympathetic activity due to Arecal alkaloids or damage to DNA by carcinogenic nitroso adducts of Arecal alkaloids (1), because many similarly conformed nitrosamines are diabetogenic in animals (13–15) and some, such as streptozotocin, are diabetogenic in humans (16). Other unidentified substances, including non-arecal nitroso compounds in Lao-Hwa betel-quid chews or in the Taiwanese diet, could also be contributory.

In view of the findings in mice, it was surprising that the association between betel-quid chewing and hyperglycemia (110 mg/dL) was smaller than for the metabolic syndrome components such as hypertriacylglycerolemia. This may have been due to the criterion for diagnosis of the metabolic syndrome being based on fasting glucose concentrations, because both impaired glucose tolerance (IGT) and type 2 diabetes (determined by oral-glucose-tolerance test) can occur with fasting normoglycemia—overlap between impaired fasting glucose (IFG; 100–126 mg/dL) and IGT (normal fasting glucose but elevated 2-h glucose) being found in only 21% of Taiwanese subjects (17). If the diagnosis of glucose intolerance had been based on IFG, 66.6% of the subjects found to have IGT with abnormal cardiovascular disease profiles would have gone undetected. Subjects with IFG have abnormal ß cell function (18), which suggests that the effects of betel chewing on insulin release, or secretion, may differ from the effects on insulin resistance. Additional reports of marked contrasts between the findings on fasting blood sugar and on the basis of hemoglobin A_1c and 2-h oral-glucose-tolerance tests, support this argument (19). Thus, nonidentification of subjects with IGT in this study may have led to underestimates of the association of betel-quid chewing with hyperglycemia. The marked association of hypertriacylglycerolemia with betel chewing may reflect a particular sensitivity of adipose tissue, its hormonal axis or autonomic nerve supply, to betel-quid chewing toxicity.

The history of metabolic syndrome in first- and second-degree relatives was included in analysis because family aggregation of the metabolic syndrome could be conferred by both genetic factors and shared environmental and lifestyle factors. However, limiting family history to first-degree relatives did not affect the findings.

A major strength of the present cross-sectional study was that it was population-based and large enough to enable us to examine associations between betel-quid chewing and the components of the metabolic syndrome after adjusting for a constellation of risk factors known to increase the prevalence of the metabolic syndrome and to look for the dose-response effects found that support the possibility of a causal relation between betel consumption and the metabolic syndrome suggested by studies in the CD1 mouse (2). Although these findings suggest that betel-quid chewing contributes to the development of the metabolic syndrome and hence to the burden of diabetes and vascular disease causality, causality cannot be demonstrated in cross-sectional studies such as this. The contribution of the betel habit to human disease should, therefore, be assessed by further prospective studies. Confirmation of causality would enhance the importance of primary prevention and cessation programs for this habit, already important health targets in user populations for the reduction of cancer risks (3, 6), and might reduce the burden of metabolic syndrome–related disease in the 600 million people currently chewing betel nut worldwide (1).

In conclusion, significant associations were shown between betel nut (Areca catechu) chewing and metabolic syndrome risk in a male population with a 15.1% prevalence of betel-quid chewing, which matched experimental findings in mice. Dose-response effects of betel use (eg, on the duration of use, rate of use, cumulative exposure, and quitting years) in relation to the risk of the metabolic syndrome support this finding. However, prospective studies are required to confirm these findings because betel-quid chewing cessation programs, already being developed to reduce the incidence of oropharyngeal cancer, could lead to a reduction in metabolic syndrome–related disease in the 10% of the world population (600 million people) currently chewing betel quid.

	ACKNOWLEDGMENTS

 
We are indebted to our colleagues in the Bureau of Health in Keelung City for implementing the Keelung Community-based Integrated Screening program, which provided the screening results for participants that formed the basis of the current study. The manuscript is identified as KCIS no. 13.

AM-FY helped with the data retrieval, data analysis, and writing of the draft. Y-HC assisted with the data collection and interpretation of results. L-SC, H-MW, and C-CH participated in the data retrieval, data management, and interpretation of results. BJB contributed to the concepts investigated, writing of the draft, interpretation of the results, and the writing of the manuscript. TH-HC synthesized the analyses and headed the writing of the manuscript. All authors approved the final version of the text. None of the authors had a conflict of interest.

	REFERENCES

TOP ABSTRACT INTRODUCTION SUBJECTS AND METHODS RESULTS DISCUSSION REFERENCES

 

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