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Homeostasis Model Assessment of Insulin Resistance, Quantitative Insulin Sensitivity Check Index, and Oral Glucose Insulin Sensitivity Index in Nonobese, Nondiabetic Subjects with High-Normal Blood Pressure

First Department of Internal Medicine (M.K., S.Y., Y.S.), Nara Medical University, Nara 634-0813, Japan; and Medical Center for Employers’ Health (K.K.), SHARP Corporation, Shinjo 639-2198, Japan

Address all correspondence and requests for reprints to: Dr. Masao Kanauchi, First Department of Internal Medicine, Nara Medical University, 840, Shijo-cho, Kashihara, Nara 634-0813, Japan. E-mail: kanauchi{at}nmu-gw.naramed-u.ac.jp.

	Abstract

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To investigate the relationships between high-normal blood pressure (BP) and insulin resistance, we examined insulin sensitivity in 306 nonobese and nondiabetic Japanese subjects with various BP categories (optimal BP, normal BP, high-normal BP, and hypertension). Insulin sensitivity was measured from fasting plasma glucose and insulin values and those during a 75-g oral glucose tolerance test by five formulas: the homeostasis model assessment of insulin resistance (HOMA-R), the quantitative insulin sensitivity check index (QUICKI), the oral glucose insulin sensitivity (OGIS) index, and two insulin sensitivity indexes (ISI-composite and ISI-stumvoll). The HOMA-R was significantly higher, and the QUICKI was significantly lower in subjects with hypertension than in subjects with optimal BP. Both HOMA-R and QUICKI values showed that high-normal BP patients had a higher (but not significant) degree of insulin resistance than optimal BP patients. The OGIS index was significantly lower in subjects with high-normal BP or hypertension than in subjects with optimal BP. The ISI-composite was significantly lower in subjects with high-normal BP or hypertension than in subjects with optimal BP, and it was also significantly lower in subjects with hypertension than in subjects with normal BP. The ISI-stumvoll was significantly lower in subjects with high-normal BP or hypertension than in subjects with optimal BP. The OGIS index, ISI-composite, and ISI-stumvoll significantly decreased with increasing severity of BP status among the normotensive groups (optimal BP, normal BP, and high-normal BP). These findings indicate that insulin resistance is present even in the high-normal BP categories of nonobese and nondiabetic Japanese individuals.

	Introduction

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SEVERAL STUDIES HAVE shown that insulin resistance is related to essential hypertension (1, 2, 3, 4) and even to borderline hypertension (5). Recently, normal blood pressure (BP) was subdivided into three categories: optimal, normal, and high-normal BP (6). High-normal BP has been shown to be a strong predictor of hypertension (7) and an increased risk factor for type 2 diabetes mellitus (8). To our knowledge, the relationship between insulin resistance and high-normal BP has not been evaluated. Various methods have been used to evaluate insulin resistance and sensitivity (9). The homeostasis model assessment of insulin resistance (HOMA-R) (10), the quantitative insulin sensitivity check index (QUICKI) (11), the oral glucose insulin sensitivity (OGIS) index (12), and other indices using an oral glucose tolerance test (OGTT; Refs. 13 and 14) have been reported to be useful estimates of insulin resistance and sensitivity. The aim of this study was to examine the relationship between the severity of BP status and insulin resistance in nonobese and nondiabetic subjects.

	Subjects and Methods

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Subjects

We studied 306 nonobese and nondiabetic Japanese subjects. Subjects were excluded if they were obese [body mass index (BMI) 30 kg/m²] or had diabetes (fasting plasma glucose 126 mg/dl or 2-h plasma glucose 200 mg/dl). BP was measured with a standard mercury sphygmomanometer after the subjects had rested at least 10 min. Systolic BP (SBP) was recorded at the appearance of sounds, and diastolic BP (DBP) was recorded at the disappearance of sounds (V-phase Korotkov). Hypertension was defined as a SBP of at least 140 mm Hg or a DBP of at least 90 mm Hg; high-normal BP was defined as a SBP of 130–139 mm Hg or a DBP of 85–89 mm Hg; normal BP was defined as a SBP of 120–129 mm Hg and a DBP of 80–84 mm Hg; and optimal BP was defined as a SBP below 120 mm Hg and a DBP below 80 mm Hg (6). No subject was currently receiving any antihypertensive drugs. This study was performed in accordance with the Helsinki Declaration, and written informed consent was obtained from each participant.

OGTT

A standard 75-g OGTT was performed after a 10-h overnight fast. Plasma samples were obtained at 0, 30, 60, 90, 120, and 180 min after glucose loading. Plasma glucose was determined using a glucose oxidase autoanalyzer, and plasma immunoreactive insulin was measured by an enzyme immunoassay (Entym Insulin Test, Roche, Basel, Switzerland). The plasma glucose response and total insulin secretion were evaluated from the area under the response curve (AUC) for plasma glucose and insulin (3-h glucose AUC and 3-h insulin AUC) calculated from the fasting, 30-, 60-, 90-, 120-, and 180-min plasma concentrations using the trapezoid rule.

Evaluation for insulin resistance/sensitivity

The HOMA-R was used to calculate an index from the product of the fasting concentrations of plasma insulin (microunits per milliliter) and plasma glucose (millimoles per liter) divided by 22.5 (10). The QUICKI proposed by Katz et al. (11) was calculated as follows: 1 / [log (fasting plasma insulin) + log (fasting plasma glucose)].

Insulin sensitivity was also evaluated by three different formulas using 75-g OGTT values. The OGIS index proposed by Mari et al. (12) was calculated as follows: Cl_OGTT = p4 x {[p1 D₀ - V(G₁₈₀ - G₁₂₀) / 60] / G₁₂₀ + p3 / G₀} / [I₁₂₀ - I₀ + p2]; B = [p5 (G₁₂₀ - G_CLAMP) + 1] x Cl_OGTT; and OGIS index = 0.5 x {B + square root of [B² + 4 x p5 x p6 x (G₁₂₀ - G_CLAMP) x Cl_OGTT]}, in which p1, p2, p3, p4, p5, and p6 are parameters (289, 270, 14,000, 440, 0.000637, and 117, respectively), D₀ is an oral glucose dose (expressed in grams per square meter), V represents the total glucose distribution volume (assumed a value of 10 liter/m²), and G_CLAMP is 90 mg/dl.

The insulin sensitivity index (ISI) proposed by Matsuda and DeFronzo (13) was calculated as follows: ISI-composite = 10,000 / square root of [(mean plasma insulin x mean plasma glucose during OGTT) x (fasting plasma glucose x fasting plasma insulin)].

The ISI proposed by Stumvoll et al. (ISI-stumvoll;14) was calculated as follows: ISI-stumvoll = 0.226 - (0.0032 x BMI) - (0.0000645 x I₁₂₀) - (0.00375 x G₉₀).

Statistical analysis

Data are presented as the mean ± SD. Comparisons between groups were performed using ANOVA followed by post hoc testing with Scheffé’s test. Correlation among three normotensive groups (optimal, normal, and high-normal BP) was tested with Spearman’s nonparametric test. A P value less than 0.05 was considered significant.

	Results

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Clinical and metabolic characteristics among groups of subjects with optimal BP, normal BP, high-normal BP, and hypertension are shown in Table 1. No significant differences were seen among groups with respect to mean age, BMI, total cholesterol, triglycerides, high-density lipoprotein-cholesterol, or fasting plasma glucose. Fasting plasma insulin was significantly higher in subjects with hypertension than in subjects with optimal or normal BP. The 2-h plasma glucose was significantly higher in subjects with hypertension than in subjects with optimal BP, and the 2-h plasma insulin was significantly higher in subjects with high-normal BP or hypertension than in subjects with optimal or normal BP. The 3-h glucose AUC was significantly higher in subjects with high-normal BP or hypertension than in subjects with optimal BP, and the 3-h insulin AUC was most prominent in subjects with high-normal BP.

	Discussion

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In this study, we used several estimates for insulin resistance and sensitivity. The HOMA-R and QUICKI have been reported to be useful and easy estimates of insulin sensitivity (10, 11). However, some limitations of these tests must be considered. The HOMA-R and QUICKI are indirect methods that depend on fasting plasma insulin values. Clearly, the Japanese population is lean relative to other populations, and compensatory hyperinsulinemia is not common in this people. Therefore, fasting plasma insulin may be less informative in the Japanese subjects. Indeed, in our study, both HOMA-R and QUICKI values showed a lower (but not significant) degree of insulin sensitivity in high-normal BP patients compared with optimal BP patients. Then, we used three alternative indices of insulin sensitivity based on the 75-g OGTT results. Previous studies have suggested that these alternative indices may provide a reasonable index of insulin sensitivity (9, 11, 12, 13, 14). The euglycemic hyperinsulinemic clamp technique is the standard method measuring insulin sensitivity, but its invasiveness and high cost have limited its use in clinical practice. We have previously demonstrated that insulin sensitivity indices based on the OGTT significantly correlated with the M-value measured by the glucose clamp technique (18); ISI-composite (r = 0.450; P < 0.001) and ISI-stumvoll (r = 0.641; P < 0.001) are significantly correlated with the M-value, but HOMA-R shows weaker correlation (r = -0.227; P = 0.0468). When we applied the data of QUICKI and OGIS index to the study population of a previous report (18), we found that the OGIS index correlated significantly with the M-value (r = 0.566; P < 0.001), but QUICKI weakly did (r = 0.309; P = 0.0063). Therefore, our data suggest that the ISI-stumvoll, OGIS index, and ISI-composite are valid measurements of insulin resistance in Japanese subjects. In the present study, these three values were significantly lower in subjects with high-normal BP compared with subjects with optimal BP. In conclusion, insulin resistance is prominent even in nonobese and nondiabetic Japanese individuals with high-normal BP.

	Footnotes

 
Abbreviations: AUC, Area under the response curve; BMI, body mass index; BP, blood pressure; DBP, diastolic BP; HOMA-R, homeostasis model assessment of insulin resistance; ISI, insulin sensitivity index; ISI-stumvoll, ISI proposed by Stumvoll; OGIS, oral glucose insulin sensitivity; OGTT, oral glucose tolerance test; QUICKI, quantitative insulin sensitivity check index; SBP, systolic BP.

Received October 23, 2002.

Accepted March 28, 2003.

	References

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1. Ferrannini E, Natali A, Capaldo B, Lehtovirta M, Jacob S, Yki-Jarvinen H 1997 Insulin resistance, hyperinsulinemia, and blood pressure. Hypertension 30:1144–1149[Abstract/Free Full Text]
2. Pollare T, Lithell H, Berne C 1990 Insulin resistance is a characteristic feature of primary hypertension independent of obesity. Metabolism 39:167–174[Medline]
3. Natali A, Santoro D, Palombo C, Cerri M, Ghione S, Ferrannini E 1991 Impaired insulin action on skeletal muscle metabolism in essential hypertension. Hypertension 17:170–178[Abstract/Free Full Text]
4. Lind L, Berne C, Lithell H 1995 Prevalence of insulin resistance in essential hypertension. J Hypertens 13:1457–1462[Medline]
5. Masuo K, Mikami H, Ogihara T, Tuck ML 1996 Do reduced insulin sensitivity and dyslipidemia exist in borderline hypertensive patients? J Hypertens 9:566–569
6. 1999 World Health Organization-International Society of Hypertension guidelines for the management of hypertension. Guidelines Subcommittee. J Hypertens 17:151–183
7. Leitschuh M, Cupples LA, Kannel W, Gagnon D, Chobanian A 1991 High-normal blood pressure progression to hypertension in the Framingham Heart Study. Hypertension 17:22–27[Abstract/Free Full Text]
8. Hayashi T, Tsumura K, Suematsu C, Endo G, Fujii S, Okada K 1999 High-normal blood pressure, hypertension, and the risk of type 2 diabetes in Japanese men. Diabetes Care 22:1683–1687[Abstract/Free Full Text]
9. Albareda M, Rodriguez-Espinosa J, Murugo M, de Leiva A, Corcoy R 2000 Assessment of insulin sensitivity and ß-cell function from measurements in the fasting state and during an oral glucose tolerance test. Diabetologia 43:1507–1511[CrossRef][Medline]
10. Matthews DR, Hosker JP, Rudenski AS, Naylor BA, Treacher DF, Turner RC 1985 Homeostasis model assessment. Diabetologia 28:412–419[CrossRef][Medline]
11. Katz A, Nambi SS, Mather K, Baron AD, Follmann DA, Sullivan G, Quon MJ 2000 Quantitative insulin sensitivity check index. A simple, accurate method for assessing insulin sensitivity in humans. J Clin Endocrinol Metab 85:2402–2410[Abstract/Free Full Text]
12. Mari A, Pacini G, Murphy E, Ludvik B, Nolan J 2001 A model-based method for assessing insulin sensitivity from the oral glucose tolerance test. Diabetes Care 24:539–548[Abstract/Free Full Text]
13. Matsuda M, DeFronzo R 1999 Insulin sensitivity indices obtained from oral glucose tolerance testing. Diabetes Care 22:1462–1470[Abstract/Free Full Text]
14. Stumvoll M, Mitrakou A, Pimenta W, Jenssen T, Yki-Jarvinen H, Van Haeften T, Renn W, Gerich J 2000 Use of oral glucose tolerance test to assess insulin release and insulin sensitivity. Diabetes Care 23:295–301[Abstract]
15. Eriksson KF, Lindgarde F 1991 Contribution of estimated insulin resistance and glucose intolerance to essential hypertension. J Intern Med 229(Suppl 2):75–83
16. Morales PA, Mitchell BD, Valdez RA, Hazuda HP, Stern MP, Haffner SM 1993 Incidence of NIDDM and impaired glucose tolerance in hypertensive subjects. Diabetes 42:154–161[Abstract]
17. Rocchini AP 1991 Insulin resistance and blood pressure regulation in obese and nonobese subjects. Hypertension 17:837–842[Abstract/Free Full Text]
18. Kanauchi M, Tsujimoto N, Hashimoto T 2002 Validation of simple indices to assess insulin sensitivity based on the oral glucose tolerance test in the Japanese population. Diabetes Res Clin Pract 55:229–235[CrossRef][Medline]

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