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Hypertension. 1998;32:115-122

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(Hypertension. 1998;32:115-122.)
© 1998 American Heart Association, Inc.

Scientific Contributions

Insulin Resistance in Hypertension Is Associated With Body Fat Rather Than Blood Pressure

Ingrid Toft; Kaare H. Bønaa; ; Trond Jenssen

From the Institutes of Clinical (I.T.) and Community (K.H.B.) Medicine, University of Tromsø, and the Department of Internal Medicine, Tromsø University Hospital (T.J.), Tromsø, Norway.


*    Abstract
up arrowTop
 *Abstract
down arrowIntroduction
 down arrowMethods
 down arrowResults
 down arrowDiscussion
 down arrowReferences
 
Abstract—The insulin resistance syndrome has been characterized by hypertension, upper body obesity, insulin resistance, hyperinsulinemia, glucose intolerance, and hypertriglyceridemia. Previous studies are inconsistent regarding the relationship between blood pressure and insulin resistance. We therefore compared the metabolic profile in 60 hypertensive subjects (mean±SD arterial pressure, 116±7 mm Hg) and 60 normotensive subjects (mean arterial pressure, 88±5 mm Hg) matched for age, gender, and body mass index. Hypertensives had significantly higher waist-to-hip ratio than normotensives (P=0.002). The groups did not differ in fasting plasma glucose (0.2 mmol/L, P=0.09), insulin (6 pmol/L, P=0.14), insulin sensitivity index (-0.01 µmol · kg-1 · min-1 · pmol/L-1, P=0.7), and suppression of nonesterified fatty acids during a hyperglycemic clamp (1%, P=0.40). There were significant differences in fasting levels of C-peptide (50 pmol/L, P=0.004) and proinsulin (2 pmol/L, P=0.01), 2-hour postload levels of glucose (0.8 mmol/L, P=0.01) and insulin (84 pmol/L, P=0.01) after oral glucose challenge, and hepatic glucose production during the clamp (2.87 µmol · kg-1 · min-1, P=0.02). These differences were not significant when controlling for waist-to-hip ratio. Body mass index and waist-to-hip ratio were similarly associated with the insulin sensitivity index in the hypertensive (r=-0.59, P=0.0001 and r=-0.32, P=0.05) and normotensive (r=-0.58, P=0.0001 and r=-0.39, P=0.05) groups. Hypertension per se is not associated with insulin resistance. However, even small increments in both body mass index and waist-to-hip ratio, as often seen in hypertension, may lead to impairment in insulin sensitivity, probably mediated through altered lipid metabolism.


Key Words: hypertension, essential • insulin sensitivity • body mass index • waist-to-hip ratio


*    Introduction
up arrowTop
 up arrowAbstract
 *Introduction
down arrowMethods
 down arrowResults
 down arrowDiscussion
 down arrowReferences
 
Hypertension has been associated with insulin resistance, hyperinsulinemia, glucose intolerance, dyslipidemia, and hypofibrinolysis, a condition known as the insulin resistance syndrome.1 2 3 It has been argued that insulin resistance is involved in the pathogenesis of essential hypertension.4 5 6 Compensatory hyperinsulinemia7 8 seen in insulin resistance is suggested to play a causal role in development of hypertension7 9 because hyperinsulinemia has been associated with proliferation of vascular smooth muscle cells,10 increased renin output,11 increased renal sodium retention,12 and increased catecholamine secretion.13 Hyperinsulinemia has also been associated with elevated activity of PAI-1,3 14 an inhibitor of fibrinolysis15 that may predict future risk of myocardial infarction.16 17 Several epidemiological studies support the assumption that the plasma level of insulin is an independent risk factor for cardiovascular disease.7 18 19 20 On the other hand, other studies have not found any evidence that insulin is associated with cardiovascular disease.21 22 23 Chronic insulin infusion in dogs does not raise the blood pressure,24 and patients with insulinoma do not have alterations in blood pressure.25

The inconsistencies in previous reports concerning metabolic derangements in hypertension and cardiovascular disease may be due to confounding factors such as age, gender, body weight, fat distribution, physical activity, diet, and other lifestyle factors. To study the role of insulin resistance and hyperinsulinemia in essential hypertension, we conducted a population-based study of the metabolic profile in 60 persons with long-standing, untreated, mild hypertension and 60 normotensive persons matched on individual basis for gender, age, and BMI.


*    Methods
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 up arrowAbstract
 up arrowIntroduction
 *Methods
down arrowResults
 down arrowDiscussion
 down arrowReferences
 
Participants and Study Design
In 1986 through 1987, 81.3% (n=21826) of the men aged 20 to 61 years and the women aged 20 to 56 years living in Tromsø, Norway, participated in a health survey.26 On the basis of that study, 156 persons with mild hypertension were enrolled in 1988 in a 10-week intervention trial with n-3 polyunsaturated fatty acids.27 In 1991 these persons were invited to be examined at the Clinical Research Unit of the University Hospital of Tromsø for recruitment into the present study. Of the invited persons, 103 volunteered. Each completed a questionnaire about previous and present illnesses, family history, medication, diet, physical activity, and smoking and alcohol habits. A laboratory screening and measurements of blood pressure and body weight were also performed. Fifty-eight subjects were receiving no medication, had cholesterol levels between 6.0 and 8.9 mmol/L, systolic blood pressure <190 mm Hg, and diastolic pressure between 90 and 110 mm Hg on three separate occasions. None were diabetic, had ischemic heart disease, or were receiving antihypertensive drug treatment. These 58 persons participated in the present study together with 2 hypertensive subjects recruited from the primary healthcare services according to identical criteria. Each hypertensive volunteer was matched with a normotensive (diastolic blood pressure <85 mm Hg) participant in the same health survey26 according to gender, age (within ±2 years), and BMI (within ±0.2 kg/m2). The control subjects also had cholesterol levels within the same range as the hypertensive subjects. Each normotensive person completed the same questionnaire as their hypertensive match and had the same clinical and laboratory workup before enrollment into the study.

The study was approved by the Regional Board of Research Ethics, and each person gave written informed consent before participation. All studies were started at 8 AM after an overnight fast. The studies of each matched hypertensive and normotensive pair were performed on the same day in most cases or at a maximum of within 1 week. The participants followed a weight-maintenance diet for 3 days before the experiments and were asked to abstain from alcohol during this period.

Clinical and Laboratory Measurements
Three blood pressure measurements were recorded before the experiments on 2 separate days. The mean of the measurements was used in the analysis. Blood pressure was measured with a mercury sphygmomanometer after the participants had rested for 10 minutes, comfortably seated. Mean arterial pressure was calculated as diastolic pressure plus one third of the pulse pressure. The waist-to-hip ratio was calculated as body circumference at the level midway between the inferior border of the rib cage and superior border of the iliac crest, divided by the maximal circumference of the buttocks.

The blood was arterialized by keeping the subject's hand in a heating device at 65°C28 ; blood was drawn from a cannulated dorsal hand vein without stasis. Fasting blood samples were drawn for determination of lipid profile and fibrinolytic variables. Glucose and insulin kinetics were assessed with an oral glucose tolerance test (1 g dextrose per kg body weight or a maximum of 75 g dextrose). Postload glucose and insulin responses were calculated as arbitrary incremental area units over the 2-hour sampling time. The molar ratio of C-peptide to insulin is an approximate indicator of insulin extraction in the liver29 and was calculated as the molar ratio of incremental area under the C-peptide curve to the incremental area under the insulin curve during the oral glucose tolerance test.

On a separate day, a hyperglycemic clamp (glucose level, 10 mmol/L)30 31 was performed to assess insulin secretion and insulin sensitivity to glucose disposal and to suppression of NEFAs. First-phase insulin release reflects the early insulin peak secreted from the pancreatic ß-cells in response to glucose stimulation and was calculated as the area under the insulin curve over the initial 10 minutes of the hyperglycemic clamp. Second-phase insulin release reflects the ß-cell function under sustained elevated glucose levels and was calculated as the area under the insulin curve from 120 to 180 minutes of the clamp. The efficiency of plasma insulin to induce increased glucose uptake was assessed as the insulin sensitivity index, calculated from the hyperglycemic clamp by dividing mean glucose infusion rate during the last hour of the clamp (µmol · kg-1 · min-1) by average plasma insulin concentration in the same period of time (pmol/L). Suppression of plasma NEFA during physiological insulin stimulation was expressed as percent suppression of NEFA during the third hour of the hyperglycemic clamp, calculated by the formula {([NEFA]-30–0-[NEFA]120–180)/[NEFA]-30–0}x100, where [NEFA]-30–0 is mean baseline concentration at 30 and 0 minutes before initiation of the clamp, and [NEFA]120–180 is mean NEFA concentration at 120 and 180 minutes of the clamp. To estimate the degree of suppression of hepatic glucose production during the hyperglycemic clamp, 46 of the participants also had a primed (30 µCi), continuous (0.30 µCi) infusion of 3-[3H]glucose during the clamp. The rate of appearance (Ra) of glucose in the plasma during the last hour of the clamp was calculated from the plasma 3-[3H]glucose specific activities using the non–steady-state equation of DeBodo et al.32 The difference between exogenous glucose infusion rate (µmol · kg-1 · min-1) and the calculated appearance of glucose in plasma (µmol · kg-1 · min-1) equals the endogenous glucose production rate, which is assumed to be suppressed under clamp conditions.

We also did a euglycemic, hyperinsulinemic clamp30 on 25 normotensive and 25 hypertensive participants on a third day to compare the insulin sensitivity indexes obtained from the two clamp techniques. Pearson correlation coefficient for the insulin sensitivity index calculated by the two clamp techniques was 0.79 (P=0.0001).

Plasma glucose concentrations were analyzed at the bedside with a Yellow Spring Instruments glucose analyzer (2300 Stat Plus). Plasma insulin and C-peptide were measured by radioimmunoassay methods previously published.33 34 Proinsulin was measured with an immunofluorometric method as previously described35 using monoclonal antibodies, one directed against insulin and another against C-peptide (PEP-001 and HUI-001 from Novo Nordisk). Glycosylated hemoglobin A1C levels were measured by a liquid chromatographic procedure (Diamat system, Bio-Rad Laboratories GmbH). Serum cholesterol and triglycerides were measured on a Hitachi 737 Automatic Analyzer with a kit from Boehringer Mannheim. HDL cholesterol levels were determined according to the method described by Burstein et al.36 VLDL cholesterol levels were calculated as 0.46 multiplied by the triglyceride level, and LDL cholesterol levels were calculated as total cholesterol minus the sum of VLDL and HDL cholesterol levels, according to the formula of Friedewald et al.37 Apolipoprotein A1 and B were measured by rate nephelometry, using the Array Protein System (Beckman Instruments Inc). Serum NEFAs were analyzed by using an acyl-CoA oxydase–based colorimetric kit (Wako Nefa C Kit, Wako Chemicals Gmbh).

For assessment of fibrinolysis, we measured PAI-1 activity with a commercial two-stage, indirect enzymatic kit (Spectrolyse, Biopool AB).38 tPA activity was determined according to Wiman et al39 as previously described.40 Plasma fibrinogen was measured with an ACL 3000 Coagulation System manufactured by Instrumentation Laboratory SpA.

Statistical Analysis
All variables were checked with regard to frequency distribution. Skewed distributions were logarithmically transformed when appropriate. For each variable, the difference between the hypertensive and normotensive subjects was calculated as the value obtained in the hypertensive person minus the value in the normotensive person, by taking into account the individual matching. The average difference between the hypertensive and normotensive groups was calculated as the arithmetic mean (95% confidence interval) of the differences for the 60 pairs and was tested for statistical significance by one-sample t test. Associations between continuous variables were examined by computing the Pearson correlation coefficient, and multiple linear regression analyses were used to examine independent relationships. ANCOVA was used to adjust for differences in waist-to-hip ratio. In these analyses, we used each individual's value (n=120) and a dummy variable (0,1) to indicate hypertensive status. Two-factor ANOVA with an interaction term was used to examine whether differences among hypertensives and normotensives depended on gender. Frequency differences in categorical data obtained from the questionnaire were tested with the {chi}2 test. Data are given as mean±SD. P<0.05 was considered statistically significant. The data were analyzed using the SAS software package.41


*    Results
up arrowTop
 up arrowAbstract
 up arrowIntroduction
 up arrowMethods
 *Results
down arrowDiscussion
 down arrowReferences
 
The hypertensive and normotensive groups were similar in age, smoking habits, physical activity, BMI, and cholesterol levels (Table 1Down). Body weights measured on the day of the experiments and at the screening examination 1 year before experiments were similar in both groups (data not shown), indicating that both groups had been weight stable before the experiments. Compared with control subjects, the hypertensive subjects had higher waist-to-hip ratio (P=0.002) (Table 1Down) and higher levels of fasting triglycerides (P=0.01), VLDL cholesterol (P=0.01) (Table 2Down), C-peptide (P=0.004), and proinsulin (P=0.01), as well as 2-hour postload levels of glucose (P=0.011) and insulin (P=0.015) (Table 3Down). Waist-to-hip ratio was significantly and similarly associated with the metabolic variables that differed in the hypertensive and normotensive groups (data not shown). When controlling for waist-to-hip ratio (by ANCOVA with hypertensive status as factor and waist-to-hip ratio as covariate), there were no longer any significant differences between the hypertensive and normotensive subjects in levels of triglycerides (P=0.21), VLDL cholesterol (P=0.21), C-peptide (P=0.42), proinsulin (P=0.15), and postload glucose (P=0.26) and insulin (P=0.46). Inclusion of waist-to-hip ratio in the models gave a significant increase in R2, ie, the overall error variance was lowered.


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  		Table 1. Clinical and Lifestyle Characteristics of Hypertensive and Normotensive Persons Matched for Gender, Age, and BMI


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  		Table 2. Lipid and Hemostatic Variables in Hypertensive and Normotensive Subjects Matched for Gender, Age, and BMI


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  		Table 3. Glucose and Insulin Metabolism in Hypertensive and Normotensive Persons Matched for Gender, Age, and BMI

Subgroup analysis according to gender showed that the hypertensive and normotensive women were similar in waist-to-hip ratio and metabolic variables, whereas the hypertensive and normotensive men differed significantly both in waist-to-hip ratio and the metabolic variables (Table 4Down). There was no statistically significant interaction by 2-factor ANOVA (Table 4Down).


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  		Table 4. Influence of Gender and Blood Pressure Status on Variables That Differed Among Hypertensive (n=60) and Normotensive (n=60) Persons

In the subgroup of participants in whom glucose turnover was measured, the hypertensives (n=23) were found to have a higher endogenous glucose production during the clamp than their normotensive controls (n=23; P=0.02) (Table 3Up). The insulin levels during the clamp were 247±160 and 217±131 pmol/L (P>0.3), and the rates of total glucose appearance were 34.83±12.71 and 33.34±13.64 µmol · kg-1 · min-1 (P>0.30), respectively. Adjustment of the endogenous glucose production rate for differences in insulin levels during the clamp did not influence the results, but standardizing for group differences in waist-to-hip ratio eliminated the differences in endogenous glucose production (adjusted means, 2.34 and 2.10 µmol · kg-1 · min-1, respectively; P=0.3).

The hypertensive and normotensive groups were similar both in insulin sensitivity to glucose disposal and NEFA suppression (Table 3Up). No correlations between blood pressure and insulin sensitivity index, percentage of NEFA suppression, fasting and postload glucose and insulin levels, or proinsulin levels were observed in separate analyses of the 2 groups and in the total study population. The relationships between the insulin sensitivity index and BMI were similar in the hypertensive (r=-0.59, P=0.0001) and normotensive (r=-0.58, P=0.0001) groups (Figure 1Down), and waist-to-hip ratio was also similarly associated with the insulin sensitivity index in the two groups (r=-0.32, P=0.05 and r=-0.39, P=0.05, resepctively; r=Pearson correlation coefficient) (Figure 2Down). BMI (P=0.0001) and waist-to-hip ratio (P=0.05) were independent predictors of insulin sensitivity for glucose disposal when included as predictor variables in a multiple linear regression model together with mean arterial pressure and age (data not shown).



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  		Figure 1. Scatterplots showing associations between BMI and insulin sensitivity index in normotensive (n=60) and hypertensive (n=60) persons matched for age, gender, and BMI. LOGISI indicates log insulin sensitivity index (µmol · kg-1 · min-1 · pmol/L-1). The associations between BMI and insulin sensitivity index are expressed as Pearson correlation coefficients. R2 (by linear regression) was 0.33 in the hypertensive group and 0.37 in the normotensive group.



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  		Figure 2. Scatterplots showing associations between waist-to-hip ratio and insulin sensitivity index in normotensive (n=60) and hypertensive (n=60) persons matched for age, gender, and BMI. LOGISI indicates log insulin sensitivity index (µmol · kg-1 · min-1 · pmol/L-1). The associations between waist-to-hip ratio and insulin sensitivity index are expressed as Pearson correlation coefficients. R2 (by linear regression) was 0.11 in the hypertensive group and 0.14 in the normotensive group.

In pooled analyses of both study groups, fasting and postload glucose levels correlated with mean arterial pressure (r=0.17, P=0.05 and r=0.26, P=0.004), triglycerides (r=0.32, P=0.0003 and r=0.33, P=0.0002), and waist-to-hip ratio (r=0.46, P=0.0001 and r=0.45, P=0.0001). Of these variables, only waist-to-hip ratio showed a statistically significant association with glucose levels when they were included as predictor variables in a multiple linear regression model.

The hypertensive and normotensive groups did not differ in NEFA levels, levels of LDL and HDL cholesterol, apolipoprotein A and B, or fibrinolytic variables such as PAI-1 activity (Table 2Up).


*    Discussion
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 up arrowAbstract
 up arrowIntroduction
 up arrowMethods
 up arrowResults
 *Discussion
down arrowReferences
 
The present population-based study suggests that hypertension per se is not associated with impaired insulin sensitivity or with fasting hyperinsulinemia. Our study also indicates that body fat distribution, as measured by waist-to-hip ratio, may be concerned in the pathogenesis of the metabolic derangements observed in essential hypertension. We studied a fairly large group of stable hypertensive and normotensive subjects recruited from a population health survey26 with a high attendance rate (81.3%), and the two groups were well balanced for potentially confounding factors. A large proportion of all persons who had untreated, stable hypertension after the health survey were screened for recruitment into the present study, and all subjects fulfilling the inclusion criteria participated. The normotensive control subjects were selected from participants from the same population study as the hypertensive subjects, and it is unlikely that the limited number of matching variables (gender, age, and BMI) would result in the selection of a particular subgroup of normotensive persons who did not reflect the distribution of the metabolic variables in the normotensive population as a whole. The generalizability of the present results therefore appears sound.

Our data demonstrate that even if the effect of BMI is well accounted for in studies on insulin sensitivity, small differences in waist-to-hip ratio may still influence the results. The waist-to-hip ratio may have a strong impact on variables associated with insulin sensitivity because accumulation of visceral fat increases the hepatic NEFA flux42 and leads to altered insulin clearance43 and hyperinsulinemia.29 Hyperinsulinemia may downregulate the peripheral insulin receptors.44 45 Increased oxidative NEFA turnover in the liver drives the gluconeogenesis46 and may cause impairment in hepatic sensitivity to insulin.47 Increased nonoxidative NEFA turnover leads to augmented VLDL and triglyceride synthesis.48 49 Higher rates of both nonoxidative50 and oxidative46 NEFA turnover impair insulin sensitivity to glucose disposal. The amounts of visceral fat and total body fat are determinants of the NEFA production rate49 and are therefore closely related to insulin sensitivity. It is crucial to take this into account in the investigation of a possible causal role of insulin or insulin resistance in the pathogenesis of essential hypertension. The assumption that plasma insulin level is associated with raised blood pressure and cardiovascular disease is based on the results of studies7 18 19 20 where either fasting7 18 or postload7 19 20 insulin levels were associated with hypertension7 and coronary heart disease.18 19 20 In these studies, the degree of insulin resistance was defined by hyperinsulinemia and was not measured directly by clamp technique. Other variables, such as waist-to-hip ratio, BMI, or triglyceride and NEFA levels, were either insufficiently7 19 20 or not18 controlled for. The inconsistencies in these studies may be due to variations in lipid metabolism, since hyperinsulinemia during elevated NEFA flux could be the result of reduced hepatic clearance29 43 and not necessarily a compensation for impaired insulin sensitivity.

Only a few clamp studies have been done to assess insulin sensitivity in hypertension.4 5 51 Ferrannini et al4 found a 40% reduction in nonoxidative glucose disposal in 13 young hypertensive subjects compared with controls with comparable BMI and percentage of body fat. Unfortunately, data for waist-to-hip ratio and triglyceride levels were not given. However, the finding of increased lipid oxidation during the clamp in the hypertensive group indicates that there were differences in lipid metabolism that could account for the impairment in insulin sensitivity, rather than elevated blood pressure per se. Pollare et al5 have done extensive clamp studies of 58 lean and 85 obese hypertensive subjects, and they reported that lean and obese hypertensives had a 20% and 40% reduction in glucose disposal rate, respectively. Both the lean and the obese hypertensives, however, had considerably higher serum lipid levels and higher waist-to-hip ratios compared with the control subjects. The measurements of insulin sensitivity were not adjusted for differences in serum lipids. Another clamp study51 showed that obese hypertensive persons had the same degree of insulin resistance as obese normotensive subjects. This observation is in keeping with the present study.

The finding that BMI and waist-to-hip ratio predict insulin sensitivity, whereas blood pressure is not associated with insulin sensitivity, suggests that elevated blood pressure is a bystander in the development of insulin resistance. The important role of increased hepatic NEFA flux due to abdominal fat accumulation in the development of insulin resistance has been demonstrated in a recent Finnish study,52 in which 12% of a nondiabetic population had a mutation of the ß3-adrenergic receptor gene in visceral fat. Persons with this type of mutation have increased abdominal fat deposition and thus elevated NEFA flux to the liver.42 These persons were found to have increased waist-to-hip ratio, higher blood pressure levels, increased insulin response after glucose challenge, and decreased glucose disposal during clamp studies compared with persons without this mutation. A recent prospective study of 4089 subjects53 further illustrates the importance of NEFA in the glucose homeostasis. High concentration of plasma NEFA is reported to be a risk factor for future glucose intolerance independent of age, waist-to-hip ratio, BMI, and fasting or postload insulin levels.

In the present study, the hypertensive subjects tended to have higher glucose levels than the control subjects. An independent relationship between blood pressure and plasma glucose was observed in the Paris Prospective Study.18 It has been speculated that hyperglycemia may have a direct stimulatory effect on the sympathetic nervous system54 or may lead to hypertension through oxidative stress caused by glycation of proteins.55 Our data showed that hypertension was not associated with glucose levels when waist-to-hip ratio was controlled for and that waist-to-hip ratio predicted glucose levels independently of blood pressure. This suggests that the higher glucose levels were related to increased hepatic NEFA turnover and increased hepatic glucose production rather than to elevated blood pressure. The finding that hypertensive subjects who underwent tracer studies did not have completely suppressed hepatic glucose production during hyperglycemic clamp was unexpected. The ongoing endogenous glucose production was not accounted for in the calculation of insulin sensitivity index, since we had these data for a subgroup of the study population only. We may therefore have underestimated the insulin sensitivity index, which means that the hypertensive subjects were even more sensitive to insulin in nonhepatic tissue than stated in the present study.

It has been suggested that insulin precursors may differ from insulin in biological effects and may therefore be more important than insulin in predicting vascular disease.56 In the present study, fasting levels of C-peptide and proinsulin were higher in hypertensive than in normotensive subjects. Since the differences did not persist after adjustment for waist-to-hip ratio, we believe that the levels of C-peptide and proinsulin in the hypertensive group were higher because the efficiency to clear these substances was impaired by raised lipid flux.

In summary, we find that well-matched hypertensive and normotensive persons do not differ in insulin sensitivity and that BMI and waist-to-hip ratio are closely linked to insulin sensitivity, regardless of blood pressure status. We suggest that raised NEFA turnover associated with increments in BMI and waist-to-hip ratio causes the deterioration in insulin sensitivity often observed in hypertension. Increments in BMI and waist-to-hip ratio also increase the tendency to develop hypertension. It seems that there are two parallel mechanisms whereby BMI and waist-to-hip ratio are key factors affecting both blood pressure and insulin sensitivity in a deleterious way.


*    Selected Abbreviations and Acronyms
 
BMI = body mass index
NEFA = nonesterified fatty acid
PAI = plasminogen activator inhibitor
tPA = tissue plasminogen activator


*    Acknowledgments
 
This study was supported by grants from the Norwegian Diabetes Association, Nordic Research Funding, and the Norwegian Research Council. We thank the staff of the General Clinical Research Center and appreciate the technical assistance of Jorunn Eikrem, Åse Lund Bendiksen, and Hege Iversen.


*    Footnotes
 
Reprint requests to Dr Ingrid Toft, Department of Internal Medicine, University Hospital of Tromsø, N-9038 Tromsø, Norway.

Received February 3, 1998; first decision February 18, 1998; accepted February 27, 1998.


*    References
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 up arrowIntroduction
 up arrowMethods
 up arrowResults
 up arrowDiscussion
 *References
 

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