Plasma Uric Acid Level and Its Association With Diabetes Mellitus and Some

AMBBJCAN JOURNAL or EPIDEMIOLOGY VOL 127, No 2Copyright O 1988 by Tbe John* Hopkins University School of Hygiene and Public Health Printed mUSA.All rights reserved

PLASMA URIC ACID LEVEL AND ITS ASSOCIATION WITHDIABETES MELLITUS AND SOME BIOLOGIC PARAMETERS IN A

BHIACIAL POPULATION OF FIJI

JAAKKO TUOMILEHTO,1 PAUL ZIMMET,1 EVA WOLF,1 RICHARD TAYLOR,1

PARSHU RAM,4 AND HILARY KING'

TuomJIehto, J. (Dept of Epidemiology, National Public Health Institute, 00280Helsinki, Finland), P. Zlmmet, E. Wolf, R. Taylor, P. Ram, and H. King. Plasma uricacid level and its association with diabetes mellitus and some biologic parametersIn a biradal population of Fiji. Am J Epidemiol 1988; 127:321-36.

Plasma uric acid was Investigated in a population survey on diabetes andcardiovascular risk factors among Melaneslans and Asian Indians In Fiji In 1980.Plasma uric add levels were elevated In men and women with impaired glucosetolerance in both ethnic groups. The lowest plasma uric add levels were foundIn diabetic patients, especially in diabetic men. Even though obesity was posi-tively associated with plasma uric add, it did not explain the high plasma uricadd level in persons with impaired glucose tolerance. Body mass index had asignificant and independent impact on plasma uric add levels both in nondiabeticand diabetic men and women. The strongest predictor of plasma uric add in themultiple regression analysis In our study populations was plasma creatinlne: Italone explained 9% of the variation in men and 2% In women; and 24% InMetaneslans and 5% In Asian Indians. Our findings suggest a strong renalinvolvement in the balance of plasma uric add and may also reflect certaindietary patterns, such as a high intake of protein, fats, and certain local vegeta-bles. Although the prevalence of hyperurfcemia was high, 27% in both Melanesianmen and women, 22% in Asian Indian men, and 11% In Asian Indian women,dlnical gout was uncommon. Many predictor variables and their interactions wereanalyzed along with the reasons for the high plasma uric add levels in personswith Impaired glucose tolerance and for the low plasma uric add levels in diabeticpatients.

creatrrdne; diabetes mellitus; glucose; hypertension; obesity; rural population;urban population; uric add

Plasma uric acid is the end product of but are influenced by multiple environmen-the purine metabolism and is related to the tal factors. Several studies have been car-purine bases of the nucleic acids; plasma ried out in various populations in order touric acid levels are genetically determined study the distribution of plasma uric acid

Received for publication July 29,1986, and in final ' South Pacific Commission, P. O. Box D5, Noumeaform April 7, 1987. Cedex, New Caledonia.

1 Department of Epidemiology, National Public * Colonial War Memorial Hospital, Suva, Fiji.Health Institute, Mannerheimintie 166, SF-00280 This study was carried out with the support of theHelsinki, Finland. (Reprint requests to Dr. Jaakko World Health Organization, Regional Office for tbeTuomilehto.) Western Pacific, Manila, Philippines, and NTH Grant

1 World Health Organization Collaborating Centre RO1AM26446.for the Epidemiology of Diabetes Mellitus, The Royal The authore are grateful to the Ministry of Health,Southern Memorial Hospital, Caulfield South, 3162, Fiji, for permission and help in undertaking this study.Victoria, Australia.

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322 TUOM1LEHTO ET AL

in different ethnic groups (1-12) and toestablish whether an association exists be-tween plasma uric acid and such diseasesas clinical gout (2, 4, 6, 11, 13), diabetesmellitus (2-4,11,12,14-16), coronary heartdisease (1, 5, 7, 17, 18), and hypertension(1, 5, 7, 8, 12, 17, 19, 20).

Over the last two decades, significanteconomic and environmental changes havetaken place in developing Pacific countriessuch as Fiji. The traditional way of life withits characteristic dietary and exercise pat-terns has changed, particularly in urbanareas, to a modernized Western lifestyle.This change has been accompanied by adramatic rise in the prevalence of chronicdegenerative diseases such as diabetes mel-litus and hypertension (21-23). Whereas 25years ago diabetes mellitus was not a healthproblem in this area, it is now well estab-lished that some developing Pacific coun-tries have a higher prevalence of type 2(non-insulin-dependent) diabetes mellitusthan that found in any Caucasoid popula-tions (22-26). For example, in the adultMicronesian population of the central Pa-cific island republic of Nauru, the preva-lence of diabetes mellitus is 24 per cent (27,28), nearly as high as that found in theAmerican Pima Indians, who have theworld's highest prevalence of this disease(29).

The numbers of cases of myocardial in-farction and stroke have likewise increasedduring the last decade in the Pacific island-ers (30), and the frequency of hypertension,one of the major risk factors for ischemicheart disease, has also increased substan-tially (30, 31).

In the few Pacific islanders who maintaina traditional lifestyle, hypertension and di-abetes mellitus are still rare (28), but hy-peruricemia is found frequently (32-35).Jackson et al. (34) found that in both thosewho lived in a traditional manner and inWesternized Polynesians from WesternSamoa, 40 per cent of the men and 26 percent of the women had hyperuricemia. Thehighest prevalence has been found inNauru, where over 60 per cent of men and

women had elevated plasma uric acid values(32). Prior et al. (11, 35) reported thatalmost half of the Polynesian population ofthe Pukapuka atoll still living in their tra-ditional cultural setting had hyperuricemia.Polynesian people in a different environ-ment have been found to have high plasmauric acid levels, which indicates a stronggenetic influence on plasma uric acid. Theprevalence of hyperuricemia in Melane-sians and in Asian Indians was somewhatless than that found in several Polynesianpopulations (11, 32-35) but higher thanthat in most Caucasoid populations.

In 1967, Cassidy (36) reported that AsianIndians living in Fiji had a much higherprevalence of diabetes than the indigenousMelanesians. The most recent survey in Fiji(23) showed that diabetes prevalence inMelanesians has increased since Cassidy'sstudy, and the difference in diabetes prev-alence between these two ethnic groups hasdecreased but is still pronounced.

The aim of this paper was to study thedistribution of plasma uric acid in the twodistinctly different ethnic groups living inFiji and to establish whether there is anassociation between plasma uric acid levelsand diabetes mellitus, hypertension, obe-sity, plasma cholesterol, and plasma creat-inine levels in Fiji Melanesians and AsianIndians. In our analyses, special attentionwas paid to the variation of plasma uricacid in different categories of glucose intol-erance as defined by the World Health Or-ganization (WHO) classification (37).

BACKGROUND

Fiji is a group of islands located in thesouthwestern Pacific with an estimatedpopulation of 646,500 in 1981, of which 43per cent are indigenous Melanesians and52 per cent are Hindi speaking Asian Indi-ans, who migrated to Fiji at the end of the19th century.

In a survey carried out in 1980, 1,340Melanesians and 1,298 Asian Indians wereselected from Suva, the capital of Fiji,where the population is nearly completelyurbanized, and from the Sigatoka Valley, a

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PLASMA URIC ACID AND GLUCOSE INTOLERANCE IN FIJI 323

relatively isolated rural area, where the Mel-anesians live as subsistence farmers andthe Indians are involved in subsistence andcash crop agriculture. Sampling methods,response rates, and survey procedures aredescribed in more detail elsewhere (23).The participation rates varied from 83 percent to 90 per cent in the urban and ruralsamples of each ethnic group. Blood sam-ples were drawn in the morning, and thesubjects were advised to be in the fastingstate.

MATERIALS AND METHODS

Plasma uric acid concentrations were de-termined by a colorimetric method (38) us-ing a SMAC 20 (Technicon InstrumentCorporation, Tarrytown, NY). Hyperuri-cemia was defined as plasma uric acid levels>0.42 mmol/liter (7.0 mg/100 ml) in menand >0.36 mmol/liter (6.0 mg/100 ml) inwomen (11).

The diagnosis of clinical gout was basedon medical history or the presence of typi-cal podagra affecting the joints of the greattoe or foot and/or typical deformities ofgout-like tophus formation. The reliabilityof this diagnosis is not known. Impairedglucose tolerance was defined according tothe current WHO criteria (37) in personswho were not known to be diabetic and whohad two-hour plasma glucose levels be-tween 7.8 and 11.0 mmol/liter (140-200mg/100 ml). Diabetes melhtus was also de-fined according to WHO criteria (37). Per-sons whose two-hour plasma glucose after75 g of glucose local was 2:11.1 mmol/liter(200 mg/dl), and those known to be diabeticregardless of their glucose values, were con-sidered as having diabetes.

Body mass index was used as a measureof obesity and calculated as weight (kg)/height (m)2. Obesity was defined as a bodymass index of >29.0 kg/m2. The group witha body mass index <29.0 kg/m2 containedsubjects who were about 10 per cent to 15per cent overweight.

Blood pressure was recorded using aHawksley random-zero mercury sphygmo-manometer with the subject seated for at

least 10 minutes. A 14-cm large cuff wasused, but larger cuffs were selected forobese people. Blood pressure was recordedto the closest 2 mmHg, and diastolic bloodpressure was defined as the fifth phase ofKorotkoff sounds. Mean arterial pressurewas calculated as one-third systolic plustwo-thirds diastolic blood pressure of thefirst blood pressure recording. Mean arte-rial pressure was used as a measure of bloodpressure in the multiple regression anal-yses. Hypertension was defined usingWHO criteria (39) as the mean of tworeadings of systolic blood pressure of atleast 160 mmHg or diastolic blood pressureof at least 95 mmHg. Persons treated withdiuretics or other antihypertensives forhigh blood pressure were also classified hy-pertensive regardless of their blood pres-sure values at the survey.

High plasma creatinine levels were de-fined arbitrarily as >105 Mmol/liter (1.19mg/100 ml) in men and >100 /imol/liter(1.13 mg/100 ml) in women. High plasmacholesterol was defined as >6.0 mmol/liter(232 mg/100 ml).

Statistical analysis

Data were collected on standardizedforms and were stored in the computercenter in Melbourne. From there, they weretransferred on computer tape to the com-puter center of the University of Kuopio,Finland, where the statistical analysis wasdone with a Digital Vax-780 computer us-ing the SPSS software package (40). Thestatistical significance of plasma uric acidlevels between different strata of indepen-dent variables with covariance correctionfor confounding factors and independentvariables was tested using the analysis ofcovariance program. Plasma uric acid levelwas used as the dependent variable, andstatistical inferences were based on the Fratio statistics from the analysis of covari-ance models which include the effect ofindependent variables, their interaction,and covariates simultaneously. These pro-cedures were based on the knowledge thatthe relation between the dependent van-

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324 TUOMILEHTO ET AL.

able and the covariates could be assumedto be linear. Persons with a missing obser-vation in any variable in a particular analy-sis of covariance model were omitted in thatanalysis.

The partial impact of several parameterswas estimated and was tested by a multipleleast squares regression analysis with astep-up procedure separately for each sex,ethnic group, and diabetes status group.

RESULTS

Overall, higher plasma uric acid levelswere found in Melanesians (except for ruralmales) than in Asian Indians, and men hadhigher plasma uric acid values than women(table 1). Mean plasma uric acid levels var-ied significantly with age only in Melane-sian women both in the urban and ruralsamples. For all women, after adjusting forbody mass index, the increase with age inthe adjusted mean plasma uric acid levelstill remained significant. The plasma uricacid level in women, adjusted for age andbody mass index, was significantly higherin Melanesians than in Asian Indians (p <0.001).

In all men, the body mass index-adjustedmean plasma uric acid level did not increasewith age, nor were the levels significantlydifferent between Melanesian men andAsian Indian men. The significant (p =0.007) interaction in men between age andethnic origin of mean plasma uric acid lev-els adjusted for body mass index indicatedthat the trend with age in Melanesian andAsian Indian men was different.

Urban Melanesian men and women hada higher prevalence of hyperuricemia thanurban Asian Indians (table 2). The preva-lence of hyperuricemia was higher in urbanMelanesian men than in rural Melanesianmen and significantly higher in both urbanand rural Melanesian women than in urbanand rural Asian Indian women. Very fewpatients, all of whom lived in urban areas,suffered from clinical gout: Only twoMelanesians and six Asian Indians had thedisease, even though Asian Indians gener-

ally had a lower prevalence of hyperuri-cemia.

Of the three categories of diabetes status,the highest plasma uric acid levels werefound in men with impaired glucose toler-ance in all subgroups (table 3). When allmen were analyzed together, diabetic menhad the lowest plasma uric acid levels. Di-abetes status and body mass index wereboth significantly associated with plasmauric acid (p < 0.001) in all men. DiabeticAsian Indian men showed the lowestplasma uric acid levels, which were signifi-cantly lower than those in nondiabeticAsian Indian men in both urban and ruralsamples. Plasma uric acid levels werehigher in men who were obese. This asso-ciation was significant for all men and forthe subgroups of urban Melanesian andrural Asian Indian men.

In all women combined (table 4), theadjusted mean plasma uric acid levels weresignificantly associated with both diabetesstatus (p = 0.035) and body mass index (p< 0.001). The highest plasma uric acid lev-els were found in those women with im-paired glucose tolerance, except in ruralMelanesians. Unlike the men, diabeticwomen did not have significantly lowermean plasma uric acid levels than nondi-abetic women. Obese women with a bodymass index of at least 29.0 (kg/m2) hadhigher plasma uric acid levels than non-obese women. This difference was signifi-cant only in urban Melanesian (p < 0.001)and rural Asian Indian (p = 0.003) women,although a similar trend was seen in ruralMelanesian women and urban Asian Indianwomen.

Obese men and women had higher meanplasma uric acid levels than nonobese sub-jects in all categories of diabetes status,except in men with impaired glucose toler-ance whose mean values were the same(table 5). This indicates that the differencesbetween the three categories of diabetesstatus were not due to differences in bodymass index alone. Furthermore, the rela-tion between plasma uric acid and obesitywas independent of diabetes status, and the

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TA

BL

E 1

Mea

n (±

sta

ndar

d de

viat

ion

(SD

)) p

lasm

a ur

ic a

cid

leve

ls (

mm

ol/li

ter)

in

two

popu

latio

ns, F

iji,

1980

(yea

rs)

20-2

930

-39

40-4

960

-69

60+

Tot

al

Lev

el o

f si

gnif

ican

cebe

twee

n ag

e gr

oups

20-2

930

-39

40-4

950

-69

60+

Tot

al

Lev

el o

f si

gnif

ican

cebe

twee

n ag

e gr

oups

Men

Age

Eth

nic

orig

inC

ovar

iate

: bod

y m

ass

inde

xIn

tera

ctio

n: a

ge-e

thni

c or

igin

n 113

102 82 64 44 396 76 63 49 34 31 242

Mel

anes

ians

(n =

133

1)

Men

(n

- 63

7)

Mea

n ±

SD

03

9 ±

0.0

70

39 ±

0.0

70.

39 ±

0.0

70

39

± 0

.07

0 40

± 0

.08

0.39

± 0

.07

NS

'

0.36

± 0

.07

03

6 ±

0.0

60

36

± 0

.06

0.37

± 0

.06

0.40

± 0

08

0.36

± 0

06

p -

0.07

1

p -

0.07

1N

Sp

< 0

.001

p-0

.00

7

n 143

117

100 62 47 469 69 66 48 31 32 235

Wom

en (

n -

694)

Mea

n ±

SD

Urb

an

03

0 ±

0 0

60

32

± 0

.07

03

3 ±

0.0

70

34

± 0

.06

03

4 ±

0.0

8

03

2 ±

0.0

7

p <

0.0

01

Rur

al

0.30

± 0

.07

03

1 ±

0.0

70

32

± 0

.07

03

4 ±

0.0

60

34

± 0

.06

03

2 ±

0.0

7

p-0

00

3

Ana

iytit

of

cov

anan

ce

n 116

118 61 60 39 383 72 69 36 33 14 213

A*M

>n I

ndin

nn(n

-

1,29

4)

Men

(n

- 69

6)

Mea

n±SD

03

6 ±

0.0

70.

36 ±

0.0

80.

36 ±

0.0

80.

36 ±

0.0

80

33

± 0

.11

0 3

6 ±

0.0

8

NS

03

8 ±

0.0

8037

± 0

.08

03

6 ±

0.0

90

34

±0

06

0.36

± 0

.08

0.36

± 0

.08

NS

Wom

en (

n -

698)

n 171

110 83 70 28 462 76 63 42 42 13 236 W

omen

Age

Eth

nic

orig

inC

ovar

iate

: bo

dy m

ass

inde

xIn

tera

ctio

n: a

ge-e

thni

c or

igin

Mea

n±SD

0.26

± 0

.18

0.28

± 0

.26

0.29

± 0

.08

03

0 ±

0.0

70

32

± 0

.08

0.28

± 0

.17

NS

0.26

± 0

.06

0.28

± 0

.07

0.28

± 0

.07

0.29

± 0

.08

0.29

± 0

.07

0.27

± 0

.07

NS

p-0

.00

2p

< 0

.001

p <

0.0

01N

S

"9 )MA URIC ACID %D GLUCOSE INTOLER/ a 2

* N

S,

not

sign

ific

ant.

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TABLE 2

Prevalence of hyperuncemia* and number of patients with clinical gout m two populations, Fiji, 1980

UrbanRural

Total

UrbanRural

Total

n

401242

643

462235

697

Melanesians(n - 1,340)

Prevalence ofhyperuncemia

(%)

32.416.9

266

26.827 7

271

No ofpatients

withgout

10

1

10

1

n

Men384214

598

Women462238

700

Asian Indians(n-1,298)

Prevalence ofhyperuncemia

(%)

21921.5

217

11597

10 9

No ofpatients

withgout

40

4

20

2

pt

p-0004NSt

p < 0.001p < 0.001

* Hyperuncemia was defined as plasma unc acid levels 0 42 mmol/hter in men and 0 36 mmol/liter in woment Level of significance of prevalence between ethnic groupsX NS, not significant.

TABLE 3

Adjusted* mean plasma unc acid concentration (mmol/hter), by diabetes status, body mass index, and ethnic

origin, in urban and rural men Fiji, 1980

Diabetes statusNormalImpaired glucose toleranceDiabetes

Body maaa index (kg/m1)<2S.O£29.0

Grand mean

Analysis of covananceDiabetes statusBody mass index

CovanatesAgePlasma cholesterolPlasma creatinine

Melanesians

Urban

0.39 (345)t0 40 (32)0.37 (17)

0 38(307)0 41 (87)

0 39(394)

NStp = 0002

NSp-0.002p<0001

Rural

0.36 (223)0.38 (15)0.37 (4)

0 36(209)0 37 (33)

0.36 (242)

NSNS

NSNS

p<0001

Asian

Urban

0 36(289)0.36 (36)0 31 (52)

0 35(356)0 37(21)

0 35 (377)

p<0001NS

p<0001p<0001p<0001

fndiflnw

Rural

0.36 (166)0 39(20)0 32 (27)

0.36 (204)0.42 (8)

0 36 (212)

p - 0 . 0 0 4p - 0 . 0 2 9

p<0001p < 0.001

NS

All monf u l A44VU

0.37 (1,022)0 38 (103)0 33 (100)

0.37 (1,076)0.40 (149)

0 37(1,226)

p<0001p<0001

p<0001p<0001p<0001

* Adjusted for age, plasma cholesterol, and plasma creaUnine.t Number of persons.t NS, not significant.

lowest plasma uric acid levels were seen innonobese diabetic men and women.

Hypertensive men had higher plasmauric acid levels than normotensive men (p< 0.001) irrespective of their diabetes sta-tus after controlling for age, body massindex, ethnic origin, plasma creatinine, andplasma cholesterol by analysis of covari-ance (table 6). Broken down by ethnicgroup, however, hypertension status corre-lated with plasma uric acid in Melanesian

men but not in Asian Indian men. Menwith high plasma creatinine values hadhigher mean plasma uric acid levels thanmen with low plasma creatinine (p < 0.001)irrespective of their diabetes status, hyper-tension status, or ethnic origin. In men whohad high plasma creatinine levels, the dif-ferences in plasma uric acid levels betweenthe three categories of diabetes status werenot large. Only those diabetic men who hadlow plasma creatinine levels had decreased

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PLASMA URIC ACID AND GLUCOSE .INTOLERANCE IN FIJI 327

Adjusted* mean plasma


Body man index (kg/m1)<290£29.0

Grand mean

Analysis of covananceDiabetes statusBody mass index


TABLE 4unc acid concentration (mmol/Uter), by diabetes status,

origin, in urban and rural women, Fiji, 1980

Melanesia™

Urban

0.32 (362)t0.35 (62)0.32 (38)

0 31(267)0.35 (185)

0 32 (452)

p = 0.003p < 0.001

p = 0.048p-0004p<0001

Rural

0.32 (207)0.33(24)0.37 (4)

0.32 (173)0 33 (62)

0 32 (235)

NStNS

NSp-0005p < 0.001

body mass

Asian Indians

Urban

0 28(350)0.29 (52)0.28(56)

0.28(360)0.29 (98)

0 28(458)

NSNS

NSp = 0064p-0044

Rural

0.26 (180)0.31 (26)0.27 (29)

0.27 (209)0.30 (26)

0.27 (236)

p-0001p-0003

NSp < 0.001

NS

index, and ethnic

All women

0.30 (1,089)0.32 (164)0.29 (127)

0 29 (1,009)0 32 (371)

0 30 (1,380)

p-0.036p < 0.001

p = 0009p < 0.001p < 0 0 0 1

* Adjusted for age, plasma cholesterol, and plasma creatininet Number of personst NS, not significant.

TABLE 5

Adjusted* mean plasma uric acid concentration (mmol/Uter), by body mass index and diabetes status, inMelanesian and Asian Indian men and women, Fiji, 1980


Total

Analyiis of covananceDiabetes statusBody mass index


<290

0 37 (9O7)t0 39 (81)0.32 (88)

0 37 (1,076)

Men

p<0001p<0001

p<0001p<0001p<0001

Body mass index

£29 0

0 40(115)0 39(22)0.37 (12)

0 40(149)

(kg/m1)

<290

0 29(840)0.30 (96)0 28 (73)

0 29(1,009)

Women

p = 0035P-C0001

p - 0 0 0 9p < 0.001p<0001

229 0

0.32 (249)0.36 (68)0.31 (54)

0 32(371)

* Adjusted for age, plasma cholesterol, and plasma creatinine.t Number of persons

plasma uric acid levels irrespective of eth-nic origin (interaction between plasma cre-atinine and diabetes status: p = 0.009 forall men, p = 0.029 for Melanesians, and p= 0.059 for Asian Indians).

High plasma creatinine levels were alsoindependently and positively associatedwith plasma uric acid levels in all women(p = 0.001), but broken down by ethnicgroup, the association was statistically sig-nificant only in Melanesians (p < 0.001)

(table 7). The differences in mean plasmauric acid levels between hypertensive andnormotensive Asian Indian women asshown in table 7 were explained by age,body mass index, and plasma cholesterol,which were included as covanates in theanalysis of covariance. Women with im-paired glucose tolerance had the highestplasma uric acid levels (p = 0.066) irre-spective of plasma creatinine level, hyper-tension status, and ethnic origin. Unlike in

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0.41

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men, diabetic women with low plasma cre-atinine did not have especially low meanplasma uric acid levels.

In men, but not in women, plasma cho-lesterol of 6.0 mmol/liter or more contrib-uted significantly (p = 0.024) to plasmauric acid (table 8). The highest plasma uricacid level was found in men with impairedglucose tolerance and high plasma choles-terol. The difference in mean plasma uricacid level between men with impaired glu-cose tolerance from unity was significantlygreater in those with high than in thosewith low plasma cholesterol (p = 0.005).Unlike in men, diabetic women with highplasma cholesterol seemed to have thehighest plasma uric acid levels, but this wasmainly explained by ethnic origin, age, andbody mass index.

We were also able to study the effect ofa vegetarian diet on plasma uric acid levelin 68 Asian Indian men and women whowere vegetarians and in 1,218 Asian Indi-ans who were nonvegetarians. Nearly allMelanesians were nonvegetarians. In gen-eral, vegetarians did not have differentmean plasma uric acid levels (0.30 mmol/liter) compared with nonvegetarians (0.31mmol/liter), but the nonvegetarians withhigh plasma cholesterol had higher plasma

uric acid values (0.35 mmol/liter) after ad-justing for age and body mass index.

Mean plasma uric acid levels were similarin previously and newly diagnosed malediabetic patients, whereas previously diag-nosed female diabetic patients had lowermean plasma uric acid levels than newlydiagnosed diabetic women (table 9).

In the multiple regression analysis fornondiabetic men in both ethnic groups,plasma uric acid had the strongest partialregression on plasma creatinine (table 10).All other variables that were included, ex-cept age in Melanesians, contributed sig-nificantly to the regression model in non-diabetic men. Age was negatively and sig-nificantly associated with plasma uric acidin nondiabetic Asian Indian men. Theregression model explained 18.8 per cent ofthe variation in plasma uric acid in Mel-anesian nondiabetic men and 24.6 per centin Asian Indian nondiabetic men. In Mel-anesian men with impaired glucose toler-ance, plasma uric acid had a significantpartial regression only on plasma choles-terol and age (negative), and the regressionmodel explained 34.0 per cent of the vari-ation in plasma uric acid. In Asian Indianmen with impaired glucose tolerance, theregression model explained 44.6 per cent of

TABLE 8

Mean plasma uric acid concentration (mmol/hter), by diabetes status and plasma cholesterol level, in Melanesmnand Asian Indian men and women combined, Fiji, 1980

Diabetes statusNormalImpaired glucose toleranceDiabetesTotal

Analysis of covananceDiabetes statusPlasma cholesterol

CovanatesAgeBody mass indexEthnic origin

InteractionDiabetes status-plasma cholesterol

Men

< 6 0

0.37 (906)*0.38 (74)0 34(69)0 36(1,049)

p<0001p - 0 0 2 4

p = 0002p<0001

NS

p - 0 0 0 5

Plasma cholesterol

£ 6 0

0 39(51)0.46 (12)0.30 (13)0 39 (76)

(mmol/Uter)

Women

<6.0

0.29 (981)0 32(131)0 30(91)0 29(1,203)

NStNS

p = 0.001p<0001p<0001

NS

£ 6 0

0 31 (47)0.29 (9)0.34 (6)0 31 (62)

* Number of penons.t NS, not significant

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TABLE 9

Adjusted* mean plasma uric acid concentration (mmol/Uter), in combined Melanesian and Asian Indian urbanand rural men and women with impaired glucose tolerance, previously diagnosed diabetes, and newly diagnosed

diabetes, Fiji, 1980

Impaired glucose tolerancePreviously diagnosed diabetesNewly diagnosed diabetes

Men

Rural

0.38 (36)t0 33(12)0.32 (19)

Urban

0.37 (68)0.34 (34)0.34 (38)

Rural

0.32 (50)0.26 (13)0.32 (21)

Women

Urban

0.32 (115)0.29 (40)0.30 (55)

* Adjusted for age and body mass indext Number of persons.

the variation in plasma uric acid; the onlyvariables with a significant and indepen-dent association with plasma uric acid wereplasma creatinine and plasma cholesterol.In diabetic men, the regression models withthe five variables explained less of the var-iation in plasma uric acid: 11.2 per cent inMelanesians and 17.0 per cent in AsianIndians. In Melanesian diabetic men, theonly variables that contributed signifi-cantly to the regression model were plasmacreatinine and body mass index; in AsianIndian diabetic men, plasma cholesteroland mean arterial pressure also contributedto the regression model.

In nondiabetic Melanesian women,plasma uric acid had a positive and signif-icant partial regression on plasma creati-nine, body mass index, plasma cholesterol,and mean arterial pressure (table 10). Innondiabetic Asian Indian women, plasmauric acid had a significant regression onlyon plasma cholesterol. The entire modelexplained 17 per cent of the variation inplasma uric acid in nondiabetic Melanesianwomen and only 2.5 per cent in Asian In-dian women. In both Melanesian and AsianIndian women with impaired glucose tol-erance, plasma uric acid had the strongestpartial regression on plasma creatinine andbody mass index. In Melanesian womenwith impaired glucose tolerance, the regres-sion model explained 34.3 per cent of thevariation in plasma uric acid, and in AsianIndian women with impaired glucose tol-erance, the regression model explained asmuch as 44.5 per cent of the variation inplasma uric acid. In diabetic women,

plasma uric acid had the strongest partialregression on plasma creatinine and bodymass index in both ethnic groups and onmean arterial pressure in Melanesians. Theregression model explained 43.9 per cent ofthe variation in plasma uric acid in Mel-anesian diabetic women and 12.9 per centin Asian Indian diabetic women.

DISCUSSION

The main finding of our study was thatplasma uric acid levels were elevated in menand women with impaired glucose toleranceboth in Melanesians and Asian Indians liv-ing in Fiji. The lowest plasma uric acidlevels were found in diabetic patients.Plasma uric acid levels were clearly de-creased, especially in diabetic men of bothethnic groups.

A negative association of plasma uricacid with overt diabetes was found earlierin several other studies (3, 6, 7, 15-17, 40-43). Our results confirm this finding despitethe methodological differences and the var-ious diagnostic criteria for diabetes mellitusused in these studies. In a prospective studyof 10,000 Israeli men, it was found thatdiabetic men had lower plasma uric acidlevels than "prediabetic" men, who hadhigher levels than nondiabetic men (15,42,43). None of the previously published epi-demiologic studies of plasma uric acid anddiabetes have used the WHO classificationfor impaired glucose tolerance and diabetesmellitus (37). Our study used the WHOcriteria and showed that Melanesian andAsian Indian men and women with im-

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paired glucose tolerance had the highestplasma uric acid levels. An interesting find-ing in our study was that plasma uric acidlevels were clearly reduced in diabetic menof both ethnic groups compared with non-diabetic men, whereas in diabetic womenof both ethnic groups, plasma uric acidlevels were similar to those in nondiabeticwomen. Obesity in diabetic women wasmore prevalent (43 per cent) than in dia-betic men (12 per cent), but controlling forbody mass index did not remove the differ-ence between men and women in this re-spect.

Both absolute and relative weight havebeen shown to be positively associated withplasma uric acid in clinical and in popula-tion studies (12, 34, 44). Yano et al. (12)claimed that obesity is the most commonand important predictor of plasma uricacid, but their study, as all earlier studies,did not include plasma creatinine in thedata analysis. Our study confirmed thatbody mass index had a significant and in-dependent impact on plasma uric acid lev-els in nondiabetic and diabetic men andwomen and in those with impaired glucosetolerance.

Obesity is known to be associated withearly stages of type 2 diabetes and oftenprecedes it (43-45). It has been claimedthat obesity is responsible for high plasmauric acid in newly diagnosed diabetics andin prediabetics (12, 43). In our study, how-ever, controlling for obesity (and simulta-neously for several other factors) did notremove the significant positive associationof mean plasma uric acid levels with im-paired glucose tolerance (in men andwomen) and the negative association withovert diabetes (in men). Thus, obesity alonecannot explain the high plasma uric acidlevels in persons with impaired glucose tol-erance in our study.

Weight loss may result in a reduction inplasma uric acid (46). It is known that inmany diabetic patients, body weight fallsafter the onset of the disease. Our findingssuggest that reduced plasma uric acid levels

reflect changes in body weight: Nonobesediabetic men and women had the lowestplasma uric acid levels. Furthermore, thedifference in plasma uric acid levels be-tween men with impaired glucose toleranceand men with diabetes was 0.04 mmol/liter;the prevalence of obesity was also different:21 per cent for men with impaired glucosetolerance and 12 per cent for diabetic men.In women, plasma uric acid level was onlyslightly lower in diabetic women comparedwith those with impaired glucose tolerance,and the prevalence of obesity was not dif-ferent (43 per cent and 41 per cent, respec-tively) between these two subgroups.

Using a multivariate analysis in whichseveral confounding and modifying factorswere taken into account, we tried to explainthe variation in the overall plasma uric acidlevel and particularly the differences inplasma uric acid levels between personswith diabetes, impaired glucose tolerance,or normal glucose tolerance. Parametersknown to be possibly associated withplasma uric acid such as age, body massindex, blood pressure, plasma creatinine,and plasma cholesterol were included in theanalyses of our present study.

We found a positive association betweenplasma uric acid and plasma cholesterol inour study population, but its partial corre-lation after controlling for plasma creati-nine and body mass index was relativelyweak. In diabetic men and women and inmen with impaired glucose tolerance,plasma cholesterol did not contribute in-dependently to plasma uric acid. In bothMelanesian and Asian Indian nondiabeticmen and women, the association betweenplasma cholesterol and plasma uric acidwas significant, but it explained only about2 per cent of the variation in plasma uricacid. Several other studies in Caucasoid (3,7, 8, 17), black American (7), and Japanese(12) populations have reported no signifi-cant association between plasma uric acidand plasma cholesterol. Two large popula-tion studies (6, 44) found a significant andpositive correlation between plasma choles-

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terol and plasma uric acid after controllingfor several other variables. In those studies,plasma cholesterol explained only a smallpart of the variation in plasma uric acid,similar to the finding in our study.

We found a significant intercorrelationbetween plasma uric acid, impaired glucosetolerance, and plasma cholesterol in menbut not in women. It has been suggestedthat persons with impaired glucose toler-ance have higher plasma cholesterol levelsthan those with a normal glucose tolerance,possibly because they eat more saturatedfats and less fiber, drink more alcohol, andare more obese. All these factors might alsoinfluence plasma uric acid levels in thepopulation (12, 44).

The strongest predictor of plasma uricacid in our study population was plasmacreatinine; it explained independently 9 percent of the variation in men and 2 per centin women, and 24 per cent in Melanesiansand 5 per cent in Asian Indians. Our find-ings suggest a strong renal involvement inthe balance of plasma uric acid. Unfortu-nately, most previous epidemiologic studiesdid not include plasma creatinine in theiranalyses. In a study of elderly untreatedhypertensive patients (47), plasma uric acidwas significantly correlated with only bodyweight and plasma creatinine. Diuretictreatment resulted in a significant increasein plasma creatinine and plasma uric acidlevels. An increase in plasma creatinine wasalso associated with an increase in plasmauric acid in patients treated with a placebo,even though the mean plasma uric acidlevel did not change significantly in theplacebo group. In the present study, we didnot find a difference in plasma uric acidlevels between untreated hypertensive pa-tients and those treated with diuretics.

High plasma uric acid levels can becaused either by an overproduction of uricacid due to an increased breakdown of nu-cleic acids or by a decreased rate of excre-tion due to increased retention associatedwith kidney disease. About two thirds ofthe daily uric acid excretion occurs throughthe kidneys, and only one third is excreted

through the gastrointestinal tract (48).Normally, uric acid is totally filtered in therenal glomeruli and nearly completely reab-sorbed in the proximal tubuli. Only 5 percent to 10 per cent is then secreted in thedistal tubuli, and a further reabsorption ofsecreted uric acid takes place at a distalpost-secretory site (49, 50).

Glucose is also filtered by the renal glo-meruli and reabsorbed in the proximal tu-bules. It has been shown that hypergly-cemia enhances uric acid excretion by pos-sibly impairing tubular reabsorption of uricacid (51, 52). This assumes that the kidneysare operating normally. In our study, dia-betic men with normal plasma creatininehad the lowest mean plasma uric acid lev-els, supporting the above-described hypoth-esis.

There are many reasons for renal damagein the general population; therefore, we ex-pected to find high plasma uric acid levelsboth in diabetic patients and in thosewith impaired glucose tolerance, and evenin those with normal glucose tolerance.Diabetes and hypertension, both knownto be associated with renal complications,seemed to have a synergistic effect, as seenby the increase in plasma uric acid levels,especially when plasma creatinine was alsoelevated.

In Melanesian men, a slight trend in theincrease in mean plasma uric acid levelswith age was seen, whereas in Asian Indianmen, the reverse was found. This was pos-sible because of the higher frequency ofdiabetes mellitus in older Asian Indians orbecause Asian Indian men with highplasma uric acid levels more frequently dieat an earlier age.

In women, but not in men, plasma uricacid levels increased with age, and overall,Melanesians had higher mean plasma uricacid levels than Asian Indians. The preva-lence of hyperuricemia (>0.42 mmol/literin men and >0.36 mmol/liter in women)was 27 per cent both in Melanesian menand women; in Asian Indians, the preva-lence was 22 per cent in men and 11 percent in women.

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There appears to be a high prevalence ofprimary hyperuricemia in indigenous Pa-cific populations (32T35). In spite of this,the frequency of gout is known to be low orgout is completely absent, as in the Polyne-sian populations of the Cook Islands (53),of Funafuti (33), and of Western Samoa(34). In our study, the frequency of goutwas low in Melanesians, although thisgroup had a higher prevalence of hyperuri-cemia than Asian Indians. However, across-sectional study is likely to underesti-mate the real frequency of gout, if clinicallydemonstrable attacks are short-lived.

REFERENCES

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Plasma Uric Acid Level and Its Association With Diabetes Mellitus and Some