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Metabolic Syndrome and New Category 'Pre-Hypertension' in a Japanese Population

Posted on: Tuesday, 9 November 2004, 12:00 CST

Key words: Insulin resistance - Metabolic syndrome - Pre- hypertension

SUMMARY

Objectivera examine whether insulin resistance and metabolic syndrome are associated with prehypertension, a new stage developed by the Joint National Committee on Prevention, Detection, Education and Treatment of High Blood Pressure (JNC-7).

Patients and methods: Subjects included 506 Japanese taking no anti-hypertensive medication. Subjects were divided into three groups according to blood pressure status using the JNC-7 criteria. Normotension (NTN) was defined as a Systolic Blood Pressure (SBP) < 120mmHg and a Diastolic Blood Pressure (DBP) < 80 mmHg, pre- hypertension (PHT) as a SBP 120-139 mmHg or a DBP 80-89 mmHg and hypertension (HTN) as a SBP ≥ 140mmHg or a DBP ≥ 90 mmHg. The metabolic syndrome was defined according to the National Cholesterol Education Program Adult Treatment Panel III as modified for waist circumference criteria by the Regional Office for the Western Pacific Region of WHO. Insulin sensitivity was assessed by plasma glucose and insulin concentrations obtained at fasting or during a 75 g oral glucose tolerance test.

Results: There were no differences with respect to age, gender or glucose intolerance status among the three groups. The mean values of body mass index were similar between NTN and PHT, but were significantly higher in HTN than in other groups. The prevalence of the metabolic syndrome was 9.9% in NTN, 19.2% in PHT and 35.5% in HTN, respectively. The prevalence increased linearly with worsening of blood pressure status (p < 0.0001). An increase in the number of metabolic syndrome components (MS score) was also associated with a progress in blood pressure status. Even in the non-obese persons, the prevalence of the metabolic syndrome and the MS score increased linearly with worsening in blood pressure status. The homeostasis model assessment of insulin resistance (HOMA-R) was significantly higher in PHT and HTN than in NTN and increased significantly with worsening in blood pressure status. Furthermore, the quantitative insulin sensitivity check index (QUICKI) and the insulin sensitivity index proposed by Stumvoll et al. decreased significantly with worsening in blood pressure status.

Conclusions:The metabolic syndrome is prevalent even in the pre- hypertensive stage in a Japanese population and insulin resistance contributes to the underlying mechanisms of these abnormalities.

Introduction

Hypertension is an important risk factor for cardiovascular disease. Recently, the Joint National Committee on Prevention, Detection, Education and Treatment of High Blood Pressure (JNC-7) recommended that subjects with a systolic pressure of 120 to 139mmHg or a diastolic pressure of 80 to 89mmHg are categorized as having 'pre-hypertension' (PHT)1. Those with PHT require health-promoting lifestyle modification2-4, because PHT subjects are at twice the risk of developing hypertension compared with normotensive ones5. In this context, insulin resistance has been proposed as a mechanism in hypertension6-8. But, it is not known whether insulin resistance is involved in Japanese patients with PHT. Furthermore, it is generally believed that individuals with the metabolic syndrome have insulin resistance, which is thought to be primarily due to obesity. The prevalence of the metabolic syndrome may be highly variable among ethnic groups9-11 and most Japanese are less obese than in the Caucasian population. To address these issues, we have carried out a cross- sectional study to examine insulin sensitivity in the PHT patients with or without the metabolic syndrome.

Patients and methods

Subjects

We studied consecutively 506 Japanese patients taking no anti- hypertensive medication. In the present study, we included those patients who underwent a 75 g oral glucose tolerance test (OGTT). Subjects with overt diabetes mellitus or fasting hyperglycaemia ≥ 7.0mmol/L were excluded in the study. Subjects with liver diseases including acute and chronic hepatitis and cirrhosis, chronic infectious diseases, renal failure, endocrine diseases that affect insulin secretion or insulin sensitivity, cancer, or those with a prior gastrectomy were also excluded. Subjects were divided into three groups according to the blood pressure status using the JNC-7 criteria1. Normotension (NTN) was defined as a SBP < 120 mmHg and a DBP < 80 mmHg, prehypertension (PHT) as a SBP 120-139 mmHg or a DBP 80-89 mmHg and hypertension (HTN) as a SBP ≥ 140mmHg or a DBP ≥ 90mHiHg1. This study was performed in accordance with the Helsinki Declaration and written informed consent was obtained from each participant.

Definition of the Metabolic Syndrome

The metabolic syndrome was diagnosed according to the National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III)12 as modified for waist circumference criteria by the Regional Office for the Western Pacific Region of WHO (WPRO)13. The metabolic syndrome was defined as the presence of three or more of the following components: abdominal adiposity (waist circumference ≥ 90 cm in men and ≥ 80 cm in women); hypertriglyceridaemia (≥ 1.69mmol/L); low HDL cholesterol (< 1.04mmol/L in men and < 1.29mmol/L in women); high blood pressure (≥ 130mmHg systolic or ≥ 85mmHg diastolic) and impaired fasting glucose (≥ 6.1 mmol/L).

Oral Glucose Tolerance Test

A 75 g OGTT was performed after an overnight fast. Plasma glucose was determined using a glucose oxidase autoanalyzer. Plasma immunoreactive insulin was measured using an electrochemi- luminescence immunoassay (ECL-IA, Roche-Diagnostic, Basel, Switzerland) which does not cross-react with proinsulin. The area under the response curve for plasma glucose (AUC-G) and insulin (AUC- I) were calculated using the trapezoidal rule.

Evaluation for Insulin Sensitivity

This mathematical index is an accurate and valid technique for the measurement of insulin sensitivity even in relatively lean Japanese individuals17. The cut-off points to define insulin resistance were 75th percentile values of each parameters in non- diabetic population.

Calculation of Glomerular Filtration Rate

Glomerular filtration rate (GFR) was approximated by calculation of creatinine clearance using the Cockcroft-Gault formula18. Significant renal impairment was defined as calculated GFR < 70mL/ min19.

Table 1. Clinical characteristics of subjects

Statistical Analysis

Data are presented as the mean SD. Comparisons between groups were performed using analysis of variance (ANOVA) followed by post- hoc testing with Scheffe's test. Spearman's rank correlation test was performed to examine the relationships between the blood pressure status and other variables. Sensitivity, specificity and likelihood ratio for predicting PHT/HTN were calculated for different numbers (≥ 1, ≥ 2, ≥ 3 and ≥ 4) of the metabolic syndrome components. A p-value less than 0.05 was considered significant.

Results

Table 1 shows the clinical characteristics of the subjects classified as NTN, PHT and HTN. The age and gender were comparable among the three groups. The mean values of BMI were similar between NTN and PHT but were significantly higher in HTN than in the other two groups. The proportions of overweight (BMI ≥ 23 kg/m^sup 2^) and obese subjects (BMI ≥ 25 kg/m^sup 2^) were also significantly higher in HTN than in the other groups. As expected, systolic and diastolic blood pressure increased linearly with worsening in blood pressure status. Fasting plasma glucose was comparable among the three groups, but fasting plasma insulin was significantly higher in HTN than in NTN. The proportions of subjects with glucose intolerance (2-h PG ≥ 11.1 mmol/L) were similar among the three groups. Prevalence of renal impairment was also similar between groups. There were no differences among the three groups with regard to the use of aspirin or nonsteroidal anti- inflammatory drugs (NSAIDs).

The proportion of the metabolic syndrome components is shown in Table 2. The prevalence of the metabolic syndrome was 9.9% in NTN, 19.2% in PHT and 35.5% in HTN, respectively. The prevalence of the metabolic syndrome increased linearly with worsening of blood pressure status (p < 0.0001). An increase in the number of components of metabolic syndrome (MS score) was also associated with a progress in blood pressure status. Additional analysis was done with Spearman's rank correlation test among the three groups by separating non-obese persons (BMI < 25 kg/m^sup 2^) from all patients. Even in the non-obese persons, prevalence of the metabolic syndrome increased linearly with worsening in blood pressure status. The MS score showed a similar pattern. Table 2 also shows insulin sensitivity parameters among the three groups. HOMA-R increased significantly with worsening in blood pressure status. Approximately 27% of PHT and 30% of HTN were in an insulin-resistant state assessed by HOMA-R. QUICKI and ISI-S decreased significantly with worsening in blood pressure status. After exclusion of obese persons, those indexes still showed similar patterns.

Table 2. Metabolic syndrome components and insulin resistance in relation to blood pressure status

Table 3. Characteristics of the study participants with or without the metabolic syndr\ome

Table 3 represents the clinical and metabolic characteristics of the study population by metabolic syndrome status. Overall, 102 subjects (20.2%) had the metabolic syndrome. Persons with the metabolic syndrome were younger and more obese. As expected, SBP and DBP were significantly higher in persons with the metabolic syndrome than in those without. The percentage of patients with a SBP ≥ 120mmHg or a DBP ≥ 80mmHg was also significantly higher in persons with the metabolic syndrome than in those without.

Table 4 represents the sensitivity, specificity and likelihood ratio for predicting PHT/HTN by number of the metabolic syndrome components. There were tradeoffs between sensitivity and specificity. There was a graded relationship between the number of components and the likelihood ratio.

Table 4. Sensitivity, specificity and likelihood ratio of various numbers of the metabolic syndrome components in predicting pre- hypertension/hypertension

Discussion

A new category of 'pre-hypertension' (PHT) was introduced by the JNC-7 Report1. This report also recommended that an intensive targeted strategy must be focused on individuals at high risk for hypertension. In the participants of the Insulin Resistance Atherosclerosis study who were free of hypertension at the baseline, the risk of hypertension was increased in persons with greater insulin resistance20. But, there is little information concerning insulin resistance among patients with borderline hypertension21 or high-normal blood pressure22. To our knowledge, no attempt has been made to evaluate the relationship between PHT and insulin resistance. In the present study, the PHT subjects had significantly higher values of insulin resistance compared with normotensive ones. It has been shown that insulin-resistant hypertensives were more obese than non-insulin-resistant ones8. Indeed in the present study, the mean value of BMI and the proportion of those with obesity were higher in HTN than in both NTN and PHT. By contrast, no difference in the mean value of BMI was seen between NTN and PHT. Thus, it seems likely that a Japanese individual with PHT does not indicate obvious obese. For other factors known to influence insulin sensitivity, age, gender and prevalence of glucose intolerance were also comparable between NTN and PHT These data suggest that insulin resistance is a characteristic feature of PHT in Japanese people independent of obesity. Underlying genetic susceptibility or systemic stress (influenced by urbanization or other environmental factors) may contribute to such a phenotype. This issue needs further investigation.

There are several potential reasons for the common rink between the metabolic syndrome and PHT. Chronic hyperinsulinaemia associated with metabolic syndrome might modulate renal sodium handling, because insulin is thought to affect tubular sodium reabsorption or to increase the expression of sodium-hydrogen exchanger on the renal tubules23. Barbato et al.24 reported that subjects with metabolic syndrome had lower fractional excretion of lithium (FELi; as a validated method to assess renal sodium handling) than those without it and that FELi was inversely correlated with HOMA-R. Although we did not examine FELi, it seems likely that sodium retention could make an important contribution to total blood volume expansion, leading to pre-hypertension or hypertension. In addition, findings from the third National Health and Nutrition Examination Survey (NHANES III) suggested that the metabolic syndrome might be an important factor in the cause of chronic kidney disease25. In the present study, however, the percentage of persons with renal impairment was similar among groups of NTN, PHT and HTN.

This study has several limitations. Firstly, an important question is the validity of the waist circumference criteria from the NCEP ATP III definition when applied across different ethnic group26. For example, some Asians have an excess body fat deposit even when the BMI is within normal limits27. Recently, the Regional Office for the Western Pacific Region of WHO (WPRO) proposed a separate definition for abdominal obesity in Asians: ≥ 90 cm in men and ≥ 80 cm in women13. We used this definition proposed by WPRO, which seems applicable to Japanese people. Secondarily, the validity of simple indices of insulin resistance must be considered. The euglycaemic hyperinsulinaemic clamp technique (Clamp-IR) is the standard method for the measurement of insulin sensitivity, but its invasiveness and high cost have limited its use in clinical practice. To date, clinical researches have chosen HOMA-R or QUICKI as surrogate measures of insulin resistance. Lansang et al.28 reported that HOMA-R is significantly correlated with Clamp-IR in hypertensives (r = -0.64, p < 0.01). Chen et al.29 also reported that QUICKI and Clamp-IR were highly correlated in hypertensives (r = 0.84, p < 0.01). Therefore, these surrogate indexes were applicable to evaluate insulin resistance for use even in subjects with hypertension. In the present study, HOMA-R was significantly higher in PHT compared with NTN. But, it seems likely that the geometric values of HOMA-R in the present study are somewhat low compared to that reported in the white population. Indeed, HOMA-R and QUICKI might be influenced by the degree of compensatory hyperinsulinaemia. Notably, it has been recognized that the compensatory function of the pancreatic beta-cell in Japanese is lower than that observed in Caucasians30. Because Japanese are lean relative to Caucasians, compensatory hyperinsulinaemia is not common in this population. Then, we used a surrogate index of insulin sensitivity based on the 75 g OGTT results. The ISI-S has been compared to Clamp-IR and shown to be a valid measure of insulin resistance in our previous report for Japanese17. Using this index, we confirmed that insulin resistance is increased even in the PHT stage. Finally, prevalence of the metabolic syndrome in the HTN group may be underestimated when compared with the general hypertensive population. In the present study, hypertensive subjects taking anti-hypertensive medication were excluded from the analysis. Additionally, overt diabetes that is frequently associated with hypertension was also excluded. Therefore, true prevalence of the metabolic syndrome among hypertensives would probably be higher in a population-based study in Japan.

In conclusion, the metabolic syndrome is prevalent even in the pre-hypertension stage in a Japanese population and insulin resistance contributes to the underlying mechanism of these abnormalities.

References

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Masao Kanauchi1, Kimiko Kanauchi2, Toshio Hashimoto1 and Yoshihiko Saito1

1 First Department of Internal Medicine, Nara Medical University, Japan

2 Health Support Unit, SHARP Corporation, Japan

Address for correspondence: Dr Masao Kanauchi, First Department of Internal Medicine, Nara Medical University, 840 Shijo-cho, Kashihara, Nara 634-0813, Japan. Tel.: +81-744-223051; Fax: +81-744- 281880; email: kanauchi@nmu-gw.naramed-u.ac.jp

Copyright Librapharm Sep 2004

Source: Current Medical Research and Opinion

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