Journl of Humn Hypertension (1998) 12, 265 269 1998 Stockton Press. All rights reserved 0950-9240/98 $12.00 ORIGINAL ARTICLE Hypertension, hyperinsulinemi nd obesity in middle-ged Finns with impired glucose tolernce Q Qio, U Rjl nd S Keinänen-Kiuknniemi Deprtment of Public Helth Science nd Generl Prctice, University of Oulu, Oulu University Hospitl, Oulu, Finlnd The im of the study ws to nlyse the dt obtined from 2-yer follow-up study of middle-ged Finnish subjects (n = 183) with previous history of impired glucose tolernce (IGT) in order to elucidte the longitudinl reltionships between hypertension, fsting hyperinsulinemi nd obesity. Hypertension ws defined s either systolic blood pressure (BP) of 160 mm Hg or distolic BP of 95 mm Hg or being on ntihypertensive mediction regrdless of the BP vlue. Multiple logistic regression nlysis djusted for glucose tolernce sttus, serum lipids, exercise behviour nd lcohol consumption shows tht the odds rtios of one unit (mu/l) increse in the bseline fsting insulin concentrtion were 1.13 (95% confidence intervl 1.00 1.28) for the 2-yer incidence of hypertension in subjects with IGT t bseline. Bseline body mss index (BMI) lso predicted the 2-yer incidence of hypertension, with n odds rtio of 1.20 (95% CI 1.02 1.42). BMI correlted positively with fsting insulin level (r = 0.54, P 0.001). It is concluded tht n elevted fsting insulin concentrtion s well s n incresed BMI preceded the onset of hypertension in subjects with IGT. It my suggest cusl reltionship between hypertension nd hyperinsulinemi. Keywords: hypertension; fsting hyperinsulinemi; obesity; impired glucose tolernce Introduction Hypertension, obesity, nd glucose intolernce (impired glucose tolernce nd non-insulin-dependent dibetes) re so commonly ssocited 1 6 s to suggest common pthogenic mechnisms. There is strong belief tht hyperinsulinemi is directly linked to hypertension, 1,2 nd insulin resistnce hs been observed mong len hypertensive ptients. 6 8 However, some studies hve filed to confirm these observtions. 9,10 Most of these studies were crosssectionl in nture, nd cuse nd effect were thus difficult to demonstrte. Longitudinl nd prospective studies on this issue re scrce. One prospective study reveled tht fter djustment for overweight nd body ft distribution, fsting insulin ws n independent risk fctor for hypertension only in subjects with norml body weight nd normoglycemi, 11 wheres nother study showed tht chnges in blood pressure (BP) preceded bnorml glucose tolernce, but not hyperinsulinemi. 4 A study mde on non-obese young dult blck men with the euglycemic hyperinsulinemic clmp technique suggested tht insulin resistnce might precede the onset of estblished essentil hypertension. 12 Correspondence: Qing Qio, Deprtment of Public Helth Science nd Generl Prctice, University of Oulu, Apistie 1, SF-90220, Oulu, Finlnd Received 20 July 1997; revised nd ccepted 23 Jnury 1998 The im of this study ws to nlyse the dt obtined from 2-yer follow-up study of middleged Finnish subjects with impired glucose tolernce (IGT) nd try to elucidte the longitudinl reltionships between hypertension, fsting hyperinsulinemi nd obesity. Subjects nd methods A screening survey for dibetes nd the resons for erly retirement mong the subjects born in 1935 nd living in Oulu, city of 100 000 inhbitnts in northern Finlnd on 1 October 1990, ws conducted from 15 October 1990 to 5 My 1992. In this survey, 207 subjects were defined s hving IGT ccording to 2-h 75 g orl glucose tolernce tests (OGTTs) recommended by the WHO in 1985, 13 ie, 2-h postlod cpillry whole blood glucose vlue of 7.8 to 11.1 mmol/l. A follow-up study of the subjects with bseline IGT ws crried out between 14 Februry nd 9 June 1994, n verge of 2.1 yers (rnge 1.9 to 2.4) fter the initil 2-h OGTTs. Of the 207 IGT subjects, 183 (84 men nd 99 women) corresponding to 88.4% of the originl group prticipted in the retest, two persons hd died, one ws in hospitl due to ctrct, two hd moved nd 19 did not ttend. There were no significnt differences in sex, in nti-hypertensive mediction nd in the men vlues of 2-h OGTT between the prticipnts nd the non-prticipnts. However, higher men fsting insulin level (13.7
266 vs 11.1 mu/l) nd higher men body mss index (BMI) (28.8 vs 27.1) were observed in the non-prticipnts. The detils of the initil survey nd the follow-up study hve been reported previously. 14 16 A postl questionnire concerning the previous history of dibetes, hypertension, nti-hypertensive mediction nd other questions ws sent to ech of the prticipnts, nd the nswers to the questions nd the nti-hypertensive gents used previously were checked during the interviews. Systolic (1st phse of Korotkoff sounds) nd distolic (5th phse) blood pressures were recorded using stndrd mercury sphygmomnometers fter the subjects hd rested for more thn 30 min in the sitting position. A single BP reding ws tken for the subjects with norml BP. A repeted BP mesurement ws mde whenever the first reding ws bove the defined norml limit, nd the second reding ws recorded. For every subject, two BP mesurements were mde seprtely on the dy of interview nd when the subject ws coming in for blood glucose test. The men vlue of the two mesurements ws used in this nlysis. Drug tretment for hypertension ws verified t both the initil survey nd t follow-up. If subject reported tking nti-hypertensive mediction t the initil survey, but not t follow-up, the reson ws investigted by checking the ptient s previous records in the helth centre, nd dignosis of hypertension ws mde on the bsis of the history of the disese. Hypertension ws defined s either systolic BP of 160 mm Hg, or distolic BP of 95 mm Hg, or being on nti-hypertensive mediction regrdless of the BP vlues. 17 The BMI ws clculted by dividing the weight (kg) by the height (m) squred. Chnges in the weight between the initil nd follow-up surveys were clculted by subtrcting the weight t bseline from the weight t follow-up. A positive chnge mens n increse in the weight t follow-up nd negtive chnge mens decrese. The sme principle ws used in clculting the chnges in fsting insulin levels between the two exmintions. A person ws defined s smoker if he/she smoked currently or hd quitted smoking during the follow-up period, but hd smoked for t lest 10 yers before. Exercise behviour ws determined by sking the subjects bout the frequency, intensity nd durtion of exercise tken in their leisure time. A sum vrible with three scles for exercise behviour ws then formed. Physicl inctivity mens tht exercise ws tken once week or less. Moderte ctivity mens tht exercise ws tken twice week or more for hlf n hour or longer t time, but without swet or brethlessness. Vigorous ctivity indictes tht the person did more thn moderte exercise with hevy swet nd brethlessness every time. Alcohol consumption ws ctegorised into three groups ccording to the mount of lcohol consumed within 2-week period, ie, no drink, drinks 56 cl nd 56 cl. Lbortory tests The procedures of lbortory mesurements hve been described in detil elsewhere. 15 In brief, stndrd 75-g OGTT ws mde ccording to the 1985 WHO 13 recommendtion. After fst of 10 12 h, venous blood smple ws drwn between 08.00 10.00 m to obtin fsting vlue nd vlues for serum insulin, totl cholesterol, serum high-density lipoprotein (HDL) cholesterol nd triglycerides. After tht, 75-g glucose lod (Glucodyn/Leirs) ws given to the prticipnts. At 2 h, single cpillry blood smple ws collected for the 2-h vlue. The concentrtion of blood glucose ws determined with the hexokinse-glucose-6-phosphte dehydrogense method (Merck Dignostic, Drmstdt, Germny). The coefficients of vrition (CV) for within-run studies were between 1.7 nd 2.8% depending on the glucose concentrtion. For dy-tody studies, the CV ws 2.8% t the upper end of the reference rnge. The times when the blood smples were tken were registered, nd the 2-h postlod smple ws not ccepted if it hd been drwn more thn 5 min too erly or too lte. The serum smples for insulin nd lipids were deep-frozen ( 74 C) until mesurement. The serum insulin concentrtion ws mesured by rdioimmunossy using Phdeseph Insulin RIA100 (Phrmci Dignostics AB, Uppsl, Sweden), which lso detects proinsulin nd proinsulin conversion products with considerble sensitivity. The cross-rectivity of proinsulin in this ssy is bout 41%. Sttisticl nlysis The sttisticl nlyses were crried out using the SPSS for Windows progrm version 7.5.1. Student s t-tests nd descriptive cross-tbultions were employed to compre the men vlues of selected chrcteristics nd to nlyse the ssocition of the outcome (hypertension vs normotension) with ech ctegoricl vrible. In cse of skewed vribles the geometric mens of insulin concentrtion were presented, bsed on logrithmic trnsformtions. Multiple logistic regression nlyses were performed to investigte the ssocition of hypertension t follow-up (outcome) with bseline fsting insulin level nd bseline BMI in forwrd stepwise mnner seprtely for subjects with normotension t bseline nd for ll of the subjects. Glucose tolernce sttus, sex, BMI, weight chnge during the follow-up, smoking, exercise behviour nd lcohol consumption were djusted in ech regression model. Results Sixteen (18%) of the 91 subjects who were normotensive t bseline hd developed hypertension by follow-up. The highest incidence of hypertension ws seen mong dibetic subjects t follow-up. One dibetic (50%), four (22%) IGT nd 11 (16%) norml glucose tolernce subjects developed hypertension during the follow-up. The bseline chrcteristics of the subjects ccording to the incidence of hypertension t follow-up re presented in Tble 1. Subjects who developed hypertension t follow-up hd
Tble 1 Chrcteristics of the subjects t the initil survey ccording to the incidence of hypertension t follow-up 267 Normotension Hypertension P vlue (n = 75) (n = 16) Sex (%) men 36 50 0.30 women 64 50 Body mss index (kg/m 2 ) b 26.0 (3.0) 28.1 (4.4) 0.02 Increse in weight (kg) b 2.8 (3.5) 3.0 (3.0) 0.82 Fsting insulin (mu/l) c 8.9 (1.6) 11.0 (1.6) 0.04 Increse in fsting insulin c 1.0 (1.3) 1.0 (1.3) 0.86 Fsting blood glucose (mmol/l) 5.2 (0.8) 5.3 (0.8) 0.58 2-h postlod blood glucose (mmol/l) 8.8 (0.8) 9.0 (0.9) 0.49 Totl cholesterol (mmol/l) 5.6 (1.4) 6.2 (1.3) 0.13 HDL-cholesterol (mmol/l) 1.4 (0.4) 1.3 (0.4) 0.26 Triglycerides (mmol/l) 1.1 (0.8) 1.4 (0.8) 0.09 Alcohol drink (cl) per 2 weeks (%) No 69 56 0.64 56 27 38 56 4 6 Smoker (%) No 71 75 0.73 Yes 29 25 Physicl exercise (%) Low 31 60 0.10 Moderte 23 13 Vigorous 47 27 Dt expressed s men (s.d.) except noted. By chi-squre test or by Student s t-test. b Two missing vlues from BMI. c Geometric mens. higher fsting insulin level nd higher BMI t bseline. Tble 2 shows the djusted odds rtios of the ssocition between hypertension nd hyperinsulinemi for subjects normotensive t bseline nd for ll of the IGT subjects. Elevted fsting insulin concentrtion t bseline ws n independent predictor for the incidence of hypertension t follow-up. Elevted bseline BMI ws lso risk for hypertension (Tble 3). The bseline fsting insulin concentrtion ws higher in subjects who developed hypertension compred to subjects who were normotensive, nd the highest fsting insulin level ws seen in obese hypertensive subjects (Tble 4). Tble 2 Adjusted odds rtios for the ssocition between hypertension t follow-up (outcome) nd fsting insulin concentrtion (mu/l) t bseline. The odds rtios corresponding to one unit increse in the fsting insulin level Odds rtios 95% confidence intervl (1) Subjects normotensive t 1.13 1.00 1.28 bseline (n = 91) (2) Normotensive t bseline nd 1.22 1.01 1.47 norml glucose tolernce t follow-up (n = 71) (3) All subjects normotensive or 1.15 1.07 1.25 hypertensive t bseline (n = 183) Sex, 2-h blood glucose, totl cholesterol, HDL-cholesterol, triglycerides, lcohol consumption, nd smoking nd exercise behviour t bseline djusted ech model. Tble 3 Adjusted odds rtios for the ssocition of hypertension t follow-up (outcome) with body mss index (BMI, kg/m 2 )t bseline. The odds rtios corresponding to one unit increse in BMI Odds rtios 95% confidence intervl (1) Subjects normotensive t 1.20 1.02 1.42 bseline (n = 89) (2) All subjects 1.14 1.05 1.24 normotensive or hypertensive t bseline (n = 173) Sex, 2-h blood glucose, totl cholesterol, HDL-cholesterol, triglycerides, lcohol consumption, nd smoking nd exercise behviour t bseline djusted ech model. There re missing vlues from BMI. Tble 4 Geometric men (s.d.) of bseline fsting insulin concentrtion strtified by body mss index (BMI, kg/m 2 ) nd hypertension No. Hypertension Normotension P vlue Normotensive 89 t bseline BMI 27 35 13.9 (1.4) 10.5 (1.4) 0.04 BMI 27 54 8.6 (1.3) 7.9 (1.4) 0.57 All subjects BMI 27 78 13.7 (1.5) 10.6 (1.4) 0.005 BMI 27 95 9.4 (1.4) 7.9 (1.4) 0.03 There re missing vlues from BMI.
268 Discussion In spite of the high respondent rte for this study, the smll smple size nd the short period of followup my obscure the observtion of interest. And, becuse the subjects who did not ttend the followup survey were more obese nd hd higher bseline fsting insulin levels thn the prticipnts, the risk of hypertension nd the observed ssocition between hyperinsulinemi nd hypertension would hve been stronger if ll subjects hd ttended the study. In ddition, becuse wist nd hip circumferences were not mesured t bseline, the ssocition of centrl obesity with hypertension could not be evluted nd djusted for. However, the ssessment of hypertension sttus is quite relible. Firstly, BP ws mesured two times on different dys nd the men of the two mesurements ws used in the dt nlysis. Secondly, we rechecked the disese history from cse records for ll those with inconsistent nswers on nti-hypertensive medictions nd excluded the ptients who took drugs with BP-lowering effect for diseses other thn hypertension. Subjects with IGT provide good opportunity to study the ssocition between hypertension nd hyperinsulinemi, since hyperinsulinemi nd insulin resistnce re bsic chrcteristics of ptients with IGT, 18 20 nd the incidence of IGT is higher in hypertensive ptients. 21 In this study, the incidence of hypertension ws higher in the subjects with dibetes nd IGT compred to the subjects with norml glucose tolernce t follow-up. This suggested the coexistence of hypertension nd glucose intolernce, which hs been observed in mny other studies. 1 6 An independent ssocition of hyperinsulinemi with hypertension hs lso been reported in mny other studies. 5,22 26 However, most of the studies hve been cross-sectionl, nd thus the presence of hyperinsulinemi could be consequence of hypertension or hyperlipidemi rther thn cuse of these disorders. Longitudinl studies to verify the etiologic role of hyperinsulinemi in the development of hypertension re still scrce. Christlieb et l 5 found cusl reltionship between the level of circulting insulin nd distolic BP t the first-yer follow-up of subjects with impired glucose tolernce. Hffner et l 11 observed n independent ssocition in subjects with norml body weight nd normoglycemi. A cusl reltionship between the elevted fsting insulin concentrtion nd the development of hypertension ws found in this study. But, the presence of this ssocition in the generl popultion remins to be demonstrted since the popultion studied here hd previous history of IGT. Insulin resistnce hs been thought to rise the BP by incresing renl sodium retention or stimulting the sympthetic nervous system, or both. 27 But the biologicl plusibility of insulin s hypertensive gent seems slender. 28 An independent ssocition of obesity nd weight gin with hypertension hs been observed in mny cross-sectionl nd prospective studies, 29 31 nd severl studies hve shown tht body ft distribution is more powerful determinnt of BP thn overll mesures of obesity, 32,33 In this study, the incresed BMI preceded the development of hypertension, nd correlted positively with the fsting insulin concentrtion (r = 0.54, P 0.001). 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