This Article Abstract Full Text (PDF) All Versions of this Article: 43/6/1324    most recent 01.HYP.0000128019.19363.f9v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Saad, M. F. Articles by Haffner, S. M. Search for Related Content PubMed PubMed Citation Articles by Saad, M. F. Articles by Haffner, S. M. Pubmed/NCBI databases Compound via MeSH Substance via MeSH Medline Plus Health Information High Blood Pressure Related Collections Clinical Studies Obesity Glucose intolerance

(Hypertension. 2004;43:1324.)
© 2004 American Heart Association, Inc.

Scientific Contributions

Insulin Resistance and Hypertension

The Insulin Resistance Atherosclerosis Study

Mohammed F. Saad; Marian Rewers; Joseph Selby; George Howard; Sujata Jinagouda; Salwa Fahmi; Dan Zaccaro; Richard N. Bergman; Peter J. Savage; Steven M. Haffner

From the Department of Medicine (M.F.S., S.J., S.F.), UCLA School of Medicine, Los Angeles, Calif; the Department of Preventive Medicine and Biometrics (M.R.), University of Colorado, Denver; the Division of Research (J.S.), Kaiser Permanente, Oakland, Calif; the Department of Public Health Sciences (G.H., D.Z.), Wake Forest University Medical School, Winston-Salem, NC; the Department of Physiology and Biophysics (R.N.B.), University of Southern California, Los Angeles; the Division of Epidemiology and Clinical Applications (P.J.S.), National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, Md; and the Department of Medicine (S.M.H.), University of Texas at San Antonio.

Correspondence to Mohammed F. Saad, MD, Division of Clinical Epidemiology, UCLA Medical School, 924 Westwood Blvd, Suite 335 (Mail Box 15), Los Angeles, CA 90024. E-mail msaad{at}mednet.ucla.edu

	Abstract

Top Abstract Introduction Subjects and Methods Results Discussion References

 
The association between insulin resistance and insulinemia and hypertension is controversial. We examined the relation between insulin resistance and hypertension in 564 non-Hispanic whites (NHW), 505 Hispanics (H), and 413 African Americans (AA) who participated in the Insulin Resistance Atherosclerosis Study (IRAS). Insulin sensitivity was measured with a frequently sampled intravenous glucose tolerance test with minimal model analysis. The prevalence of hypertension was 32.5%, 49.4%, and 32.3% in NHW, AA, and H, respectively (P<0.001). When subjects without diabetes in all ethnic groups were combined, age, male sex, race (AA), body mass index (BMI), and insulin resistance, but not fasting insulin, were significantly associated with hypertension. When each ethnic group was analyzed separately, insulin resistance was significantly associated with hypertension in NHW and H, but not AA. After excluding subjects taking antihypertensive medications, male sex, BMI, fasting glucose, and insulin resistance, but not fasting insulin, were significant determinants of blood pressure. When the 3 ethnic groups were analyzed separately, insulin resistance was significantly associated with blood pressure in H, but not NHW, or AA. Neither insulin resistance nor fasting insulin was significantly associated with hypertension or blood pressure in subjects with diabetes of the 3 ethnic groups after adjusting for age, sex, BMI, and waist. In conclusion, insulin resistance, but not insulinemia, was related to hypertension and blood pressure in subjects without diabetes, but ethnic differences in these relations appear to exist. Neither insulin resistance nor insulinemia was related to hypertension or blood pressure in patients with type 2 diabetes in the 3 ethnic groups.

Key Words: insulin resistance • insulin • hypertension • blood pressure • diabetes

	Introduction

Top Abstract Introduction Subjects and Methods Results Discussion References

 
In 1966, Welborn and colleagues¹ described hyperinsulinemia in normoglycemic patients with hypertension and suggested that these subjects could be insulin resistant. Two decades later, Ferrannini et al² confirmed this observation by showing that lean white hypertensive patients had lower insulin-mediated glucose disposal than normal controls. It has been hypothesized, therefore, that insulin and/or insulin resistance could contribute to the pathogenesis of hypertension.³ Insulin was shown to stimulate the sympathetic nervous system, increase renal sodium retention, modulate cation transport, and induce vascular smooth muscle hypertrophy (reviewed in Reference ⁴). It is plausible that insulin resistance through the concomitant compensatory hyperinsulinemia could contribute to the pathogenesis of hypertension by one or more of these mechanisms. Nonetheless, acute insulin infusion was found to have a vasodilator hypotensive rather than a hypertensive effect.^5,6 To reconcile these discrepant observations, it was proposed that insulin resistance might lead to hypertension because of diminished insulin-induced vasodilation and an imbalance between its pressor and depressor effects.⁷

Although a large number of studies examined the relation between insulinemia and hypertension and/or blood pressure (BP), the results have been inconsistent with some reporting strong and others weak, or no association.^8–19 A smaller number of studies measured insulin resistance directly, mostly in small groups of subjects with still conflicting results.^20–27 Herein, we describe the relation between insulin resistance and hypertension in a large triethnic population that participated in the Insulin Resistance Atherosclerosis Study (IRAS). Insulin sensitivity was measured directly with the insulin-modified frequently sampled intravenous glucose tolerance test (FSIGT) with minimal model analysis (MINMOD) in 1482 subjects.

	Subjects and Methods

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Subjects
Details of subject recruitment and study protocol were described.²⁸ In brief, the IRAS included 1625 subjects who were studied at 4 clinical centers at Oakland and Los Angeles, Calif; San Luis, Co; and San Antonio, Tex. Clinical centers in California enrolled non-Hispanic whites (NHW) and African-Americans (AA) from Kaiser Permanente, a nonprofit health maintenance organization. Those in San Antonio, Tex, and San Luis Valley, Co, studied NHW and Hispanics (H) recruited from two ongoing population-based studies (San Antonio Heart Study and the San Luis Valley Diabetes Study), respectively.

The study aimed to include equal numbers of subjects in different categories of glucose tolerance (normal glucose tolerance [NGT], impaired glucose tolerance [IGT], and type 2 diabetes) according to the 1985 World Health Organization criteria. Therefore, subjects with IGT and type 2 diabetes were oversampled. Insulin-treated patients with diabetes and those with a fasting glucose >16.7 mmol/L were excluded. The final IRAS cohort included 721 men and 904 women aged 40 to 69 years; 614 NHW, 548 H, and 464 AA. There were 720 subjects (44%) with NGT, 369 (23%) with IGT, and 537 (33%) with type 2 diabetes. The current analysis includes 1482 subjects in whom insulin sensitivity was measured.

The IRAS examination required 2 visits, 1 week apart. Participants were asked to fast for 12 hours before each visit and to abstain from heavy exercise and alcohol for 24 hours and from smoking the morning of each visit. An oral glucose tolerance test (OGTT) was performed with a 75-g glucose load in the first visit. An insulin-modified FSIGT was done in the second visit for the determination of the insulin sensitivity index (S_I) with the computer program MINMOD.²⁹ An injection of insulin was used to ensure adequate plasma insulin levels for the accurate computation of insulin resistance across a broad range of glucose tolerance.^30–32

BP was measured during each visit with a mercury sphygmomanometer before the OGTT and the FSIGT. A standardized protocol in which the appropriate cuff size was used depending on the arm circumference was followed. Three measurements were taken 5 minutes apart in the right arm in the sitting position after 5 minutes of rest. The average of the second and third measurements was taken as the participant’s BP during each visit. The average BP of the two visits is used in this analysis. Mean BP (MBP) was calculated as 0.33xsystolic BP (SBP)+0.66xdiastolic BP (DBP). Hypertension was defined as SBP 140 mm Hg or DBP 90 mm Hg or as taking antihypertensive medications. Body mass index (weight [kg]/height [m²]) is used as a measure of overall adiposity and minimum waist circumference as an index of body fat distribution.

Statistical Analysis
Data are expressed as means±SE or as means with 95% confidence interval (Cl). Insulin levels and S_I values were log-transformed to normalize the distribution. The log of S_I+1 was used in the analysis because of the existence of zero S_I values. Statistical analyses were performed with programs of SPSS, Inc. One-way ANOVA and ² tests were used to compare continuous and categorical variables, respectively, among the 3 ethnic groups. Two-way ANOVA was used to evaluate the effects of ethnicity and hypertension on different variables. The sample size provided more than 90% to detect differences in fasting and 2-hour insulin concentrations and S_I in the subjects without diabetes by race and hypertension status at a significance level of 0.05. For the subjects with diabetes, the sample size provided <60% power to detect significant differences in these variables. The Tukey method was used for multiple comparisons. Logistic regression analysis was used to evaluate the relation between different variables and hypertension. Linear regression and/or Pearson product moment correlations were used to evaluate the relation between BP and different variables. The sample size of subjects without diabetes provided 80% power to detect a correlation coefficient of 0.11 in the 3 ethnic groups combined (0.16 in whites, 0.22 in AA, and 0.18 in H) at a significance level of 0.05. The sample size of subjects with diabetes provided 80% power to detect a correlation coefficient of 0.18 in the 3 ethnic groups combined (0.29 in whites, 0.37 in AA, and 0.28 in H) at a significance level of 0.05.

	Results

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Glucose Intolerance, Obesity, and Hypertension
The prevalence of hypertension was 32.5% in NHW, 49.4% in AA, and 32.3% in H (P<0.001). Hypertension was more common in subjects with type 2 diabetes, followed by IGT, and then NGT in each ethnic group (Figure 1). Controlling for age and sex, both overall and central adiposity were significantly associated with hypertension in individuals without diabetes in the 3 ethnic groups. In subjects with diabetes, hypertension was significantly associated with BMI in NHW (P=0.01) and H (P=0.04) but not in AA, after adjusting for age and sex. The prevalence of hypertension tended to increase with the waist circumference in subjects with diabetes controlling for age and sex, but the association was statistically significant only in H (P=0.01). Logistic regression analysis of subjects with and without diabetes combined showed that race, age, BMI (or waist circumference), and glycemia were significantly associated with hypertension. Adjusting for age, sex, BMI, and glycemia, the prevalence of hypertension was higher in AA than in NHW (odds ratio: 2.35; 95% CI: 1.67 to 3.30) and H (odds ratio 2.96; CI: 1.82 to 4.81), but there was no difference between H and NHW. An increase in 2-hour plasma glucose of 1 mmol/L was associated with a 5% increase in the likelihood of having hypertension (CI 2.7 to 7.1%), controlling for the other variables.

View larger version (29K): [in this window] [in a new window]   Figure 1. The prevalence of hypertension across the spectrum of glucose tolerance in the 3 ethnic groups. P<0.001 in each.

Insulinemia, Insulin Resistance, and Hypertension in Subjects Without Diabetes
Hypertensive subjects without diabetes were older and had significantly higher BMI, waist circumference, and fasting and 2-hour post-load plasma glucose and insulin concentrations and lower S_I than their normotensive counterparts (Table 1). After adjusting for age, sex, BMI, and waist, differences in fasting insulinemia between hypertensive and normotensive subjects remained significant only in H and those in S_I in NHW and H. The prevalence of hypertension increased with fasting insulinemia. This association was significant in NHW and Hispanics (P<0.01 for linear trend), but not in AA (P=0.16). After adjusting for age, sex, BMI, and waist, insulinemia was significantly associated with hypertension only in H (P=0.001). Similarly, the prevalence of hypertension was higher at lower S_I values in all ethnic groups (P<0.05 in each), but this association remained significant only in H (P=0.02) after controlling for age, sex, BMI, and waist (Figure 2).

View this table: [in this window] [in a new window]   TABLE 1. Characteristics of Hypertensive and Nonhypertensive Subjects Without Diabetes

View larger version (27K): [in this window] [in a new window]   Figure 2. The prevalence of hypertension by quartiles of fasting insulin (upper panels) and SI (lower panels) before (left) and after (right) adjusting for age, sex, BMI, and minimum waist in subjects without diabetes in the 3 ethnic groups. The symbols correspond to the median value in each quartile.

When subjects without diabetes of all ethnic groups were combined, logistic regression analysis showed that age, race (AA), BMI (or waist), and S_I were significantly associated with hypertension (Table 2). Fasting insulin was significantly associated with hypertension only when S_I was not included in the logistic regression models. The interaction term between S_I and ethnicity was not statistically significant (P=0.94), but when each ethnic group was analyzed separately, insulin resistance was significantly associated with hypertension in NHW and H, but not AA (Figure 3).

View this table: [in this window] [in a new window]   TABLE 2. Logistic Regression Analysis Showing Variables Associated with Hypertension in Subjects Without Diabetes (n=1003)

View larger version (11K): [in this window] [in a new window]   Figure 3. The odds ratio (with 95% CI) for having hypertension in relation to a 2-fold increase in insulin resistance adjusting for age, sex, BMI, and glycemia in all subjects without diabetes and in the 3 ethnic groups analyzed separately.

Insulinemia, Insulin Resistance, and Blood Pressure in Subjects Without Diabetes
Because some antihypertensive drugs can affect insulin sensitivity, the relation of insulinemia and insulin resistance with BP was examined in subjects without diabetes not receiving medications (n=773). SBP, DBP, and MBP correlated significantly with fasting insulin and S_I before and after adjusting for age, sex, BMI, and waist (Table 3). When each ethnic group was considered separately, SBP, DBP, and MBP correlated significantly with fasting insulin and S_I in NHW and H, but not in AA before and after adjusting for age, sex, BMI, and waist (Figure 4). Linear regression showed that age, male sex, BMI (or waist), fasting glucose, and S_I were significant determinants of MBP (Table 4). When both S_I and fasting insulin were included in the same model, S_I but not insulin was significantly associated with MBP. The interaction term between S_I and ethnicity was not statistically significant (P=0.78), but when each ethnic group was analyzed separately, S_I was significantly associated with MBP in H, but not in NHW or AA (Figure 4). Figure 5 shows the estimated change in MBP in relation to insulin sensitivity as predicted from a linear regression equation, adjusting for age, sex, BMI, and waist.

View this table: [in this window] [in a new window]   TABLE 3. Correlation Between Blood Pressure and Insulinemia and Insulin Resistance in Subjects Without Diabetes Not Receiving Antihypertensive Medications

View larger version (40K): [in this window] [in a new window]   Figure 4. The relation between each of fasting insulinemia (upper panels) and SI (lower panels) and MBP in the 3 ethnic groups after adjusting for age, sex, BMI, and minimum waist. The regression lines between fasting insulin and MBP in the 3 ethnic groups were not different in the slope (P=0.0792) or the intercept (P=0.642). Likewise, the regression lines between SI and MBP in the 3 ethnic groups were not different in the slope (P=0.435) or the intercept (P=0.675).

View this table: [in this window] [in a new window]   TABLE 4. Linear Regression Analysis of Determinants of Mean Blood Pressure in Subjects Without Diabetes Not Receiving Antihypertensive Medications (n=669)

View larger version (17K): [in this window] [in a new window]   Figure 5. The relation between MBP and SI in the 3 ethnic groups as predicted from regression equations that included age, sex, BMI, and waist in subjects without diabetes not receiving antihypertensive medications in the 3 ethnic groups analyzed separately (the means of age, BMI, and waist and male sex were used).

Insulinemia, Insulin Resistance, and Hypertension in Subjects With Diabetes
Hypertensive subjects with diabetes were older and more obese and had higher fasting glucose than their normotensive counterparts. There was no significant difference, however, between normotensive and hypertensive subjects in waist, 2-hour post-load glucose, insulinemia, or S_I (Table 5). Hypertension was not related to fasting insulinemia or S_I in any of the 3 ethnic groups, before and after adjusting for age, sex, BMI, and waist. When all subjects with diabetes were combined, logistic regression showed that age, race (AA), and BMI, but not insulinemia or S_I were significantly associated with hypertension (Table 6).

View this table: [in this window] [in a new window]   TABLE 5. Characteristics of Hypertensive and Nonhypertensive Subjects With Diabetes

View this table: [in this window] [in a new window]   TABLE 6. Logistic Regression Analysis Showing Variables Associated With Hypertension in Subjects With Diabetes (n=479)

	Discussion

Top Abstract Introduction Subjects and Methods Results Discussion References

 
The association between insulin resistance and insulinemia and hypertension is controversial. Whereas some studies reported that insulin resistance and/or hyperinsulinemia were strongly related to hypertension, others show only a weak or even no association.^7–27 Our data add some insights and show that insulin resistance is at most a modest determinant of hypertension and BP. This effect was not mediated by insulinemia, which was significantly related to hypertension only when S_I was not included in the regression models. In addition, neither insulin resistance nor insulinemia was significantly related to hypertension or BP in patients with diabetes after controlling for age, sex, and obesity.

Our data show that an increase in insulin resistance from the lowest to the highest quartile of the distribution in NHW and H was associated with a 70% higher likelihood of having hypertension, an effect that was similar to a 10-year increase in age. It is to be noted, however, that several antihypertensive medications could worsen insulin resistance³³ and that we could not estimate the effect of drugs because of the cross-sectional nature of the study. Furthermore, the number of hypertensive subjects (7%) not receiving medications was too small to allow analyzing their data separately. Nonetheless, S_I was weakly associated with BP in Hispanic and NHW subjects without diabetes not receiving antihypertensive medications, explaining 2% to 4% of its variance. Figure 5 shows that a decrease in S_I of 2 U (equivalent to change from 20 to 80 percentile of the population) was associated with a 1.2-mm Hg increase in MBP in NHW and H.

The relation between insulinemia and/or insulin resistance and BP appears to vary among ethnic groups. Nearly all studies showing a strong association between insulin and BP were conducted among NHW. Studies in African Americans,^10,19,26 Hispanics,¹⁶ Nauruans, Pima Indians,^15,25 and Asian Indians¹⁸ showed a weak or no association. Even among NHW, the association between insulinemia and BP was inconsistent with some studies reporting a weak or insignificant relationship.^17,19 Similarly, when insulin resistance was directly measured, the findings were discrepant. Pooled European data showed a weak but significant association between insulin resistance and BP.⁷ Saad et al²⁵ found insulin resistance and BP to be related in NHW, but not in AA or Pima Indians. Falkner et al²⁶ described insulin resistance in young hypertensive AA men. Mattiasson et al²⁷ showed that insulin resistance and BP were related only in postmenopausal NHW women with IGT, but not in those with NGT. Our data unfortunately add to the confusion. We found S_I to be related to hypertension and BP in H and NHW without diabetes, but not in AA.

The mechanism through which insulin resistance is associated with hypertension and BP is not known. It is thought that insulin resistance could cause hypertension through compensatory hyperinsulinemia.³ Insulin has been shown to stimulate the sympathetic nervous system, increase renal sodium retention, modulate cation transport, and induce hypertrophy of vascular smooth muscle (reviewed in 4). Our data do not support this notion, however, because insulin was not independently related to hypertension or BP. In addition, acute insulin infusion was found to have a vasodilator hypotensive and not a hypertensive effect.^5,6 It has been known for years that insulin could lower BP substantially in patients with diabetes with autonomic neuropathy.³⁴ Moreover, administration of insulin to individuals without³⁵ and with³⁶ diabetes does not cause a rise in BP in absence of hypoglycemia. It is plausible, however, that it is the resistance to the vasodilator effect of insulin that could lead to a rise in BP. In addition, insulin resistance has been associated with impaired endothelium-dependent vasodilatation,³⁷ which could contribute to increased BP.

Alternatively, the association between insulin resistance and hypertension may not be causal. Instead, they may be linked indirectly through mechanisms of an inherited or acquired nature. A possible link is through the sympathetic nervous system. Enhanced adrenergic tone may lead to increased insulin resistance on the one hand and a rise in BP on the other. Ethnic or racial differences in sympathetic nervous system activity might explain the differences in the relation of insulin resistance to BP. Increased levels of inflammatory markers such as tumor necrosis factor- could contribute to both insulin resistance and endothelial dysfunction³⁷ and underlie the link between insulin resistance and hypertension. A further possibility is that a cellular or structural defect, genetic or acquired, may constitute the link between insulin resistance and BP. Reduced activity of sodium-potassium ATPase, decreased intracellular magnesium, and increased sodium-lithium countertransport have been proposed as possible links. Racial differences in ion regulation have been described and could account for the observed variation in the relation of insulin resistance to BP.³⁸

Our data show that neither insulin resistance nor insulinemia was related to hypertension in patients with diabetes of any ethnic group. This is in agreement with those of Bonora et al³⁹ who found no difference in insulin sensitivity between normotensive and hypertensive patients with diabetes. Laakso et al⁴⁰ reported similar data in obese subjects with diabetes, but found lean hypertensive patients with diabetes more insulin resistant than normotensive counterparts. This latter study included only, however, a small number of lean subjects with diabetes (11 hypertensive and 6 normotensive). Thus, insulin resistance does not appear to be a feature of hypertension in subjects with type 2 diabetes.

Perspectives
The current study shows that insulin resistance, but not insulinemia, was weakly but significantly related to hypertension and BP in subjects without diabetes. This weak association argues against a major role for insulin resistance in the regulation of blood pressure or pathogenesis of hypertension. This is especially true in individuals with type 2 diabetes in whom neither insulin resistance nor insulinemia were related to hypertension or BP.

	Acknowledgments

 
This study was supported by National Heart, Lung, and Blood Institute grants U01-HL47887, U01-HL47889, U01-HL47892, and U01-HL47902.

Received March 15, 2004; first decision March 16, 2004; accepted March 24, 2004.

	References

Top Abstract Introduction Subjects and Methods Results Discussion References

 

1. Welborn TA, Breckenridge A, Rubinstein AH, Dollery CT, Fraser TR. Serum insulin in essential hypertension and in peripheral vascular disease. Lancet. 1966; 1: 1336–1337.[CrossRef][Medline] [Order article via Infotrieve]
2. Ferrannini E, Buzzigoli G, Bonadonna R, Giorico MA, Oleggini M, Graziadei L, Pedrinelli R, Brandi L, Bevilacqua S. Insulin resistance in essential hypertension. N Engl J Med. 1987; 317: 350–357.[Abstract]
3. Reaven GM, Hoffman BB. A role for insulin in the aetiology and course of hypertension. Lancet. 1987; 2: 435–436.[CrossRef][Medline] [Order article via Infotrieve]
4. Reaven GM, Lithell H, Landsberg L. Hypertension and associated metabolic abnormalities–the role of insulin resistance and the sympathoadrenal system. N Engl J Med. 1996; 334: 374–381.[Free Full Text]
5. Creager MA, Liang C-S, Coffman JD. Beta adrenergic-mediated vasodilator response to insulin in the human forearm. J Pharmacol Exp Ther. 1985; 235: 709–714.[Abstract/Free Full Text]
6. Laakso M, Edelman SV, Brechtel G, Baron AD. Decreased effect of insulin to stimulate skeletal muscle blood flow in obese men: a novel mechanism for insulin resistance. J Clin Invest. 1990; 85: 1844–1852.[Medline] [Order article via Infotrieve]
7. Ferrannini E, Natali A, Capaldo B, Lehtovira M, Jacob S, Yki-Järvinen H, for the European Group for the Study of Insulin Resistance (EGIR). Insulin resistance, hyperinsulinemia, and blood pressure. Role of age and obesity. Hypertension. 1997; 30: 1144–1149.[Abstract/Free Full Text]
8. Manicardi V, Camellini L, Bellodi G, Coscelli C, Ferrannini E. Evidence for an association of high blood pressure and hyperinsulinemia in obese men. J Clin Endocrinol Metab. 1986; 62: 1302–1304.[Abstract]
9. Rose HG, Yalow RS, Schweitzer E. Insulin as a potential factor influencing blood pressure in amputees. Hypertension. 1986; 8: 793–800.[Abstract/Free Full Text]
10. Mbanya J-CN, Thomas TH, Wilkinson R, Alberti KGMM, Taylor R. Hypertension and hyperinsulinemia: a relation in diabetes but not essential hypertension. Lancet. 1988; 1: 733–734.[Medline] [Order article via Infotrieve]
11. Verdecchia P, Gatteschi C, Benemio G, Guerrieri M, Porcellati C. Hyperinsulinemia and hypertension in diabetes. Lancet. 1988; 2: 242–244.
12. Zavaroni I, Mazza S, Dall’Aglio E, Gasparini P, Passseri M, Reaven GM. Prevalence of hyperinsulinemia in patients with high blood pressure. J Int Med. 1992; 231: 235–240.[Medline] [Order article via Infotrieve]
13. Muscelli EOA, Saad MJA, Contijo JAR. Insulinemia and blood pressure responses to oral glucose load in primary hypertensive patients. Cardiology. 1991; 79: 14–19.[Medline] [Order article via Infotrieve]
14. Bonora E, Zavaroni I, Alpi O, Pezzarossa A, Bruschi F, Dall’Aglio E, Guerra L, Coscelli C, Butturini U. Relationship between blood pressure and plasma insulin in non-obese and obese non-diabetic subjects. Diabetologia. 1987; 30: 719–723.[CrossRef][Medline] [Order article via Infotrieve]
15. Saad MF, Knowler WC, Pettitt DJ, Nelson RG, Mott DM, Bennett PH. Insulin and hypertension: relationship to obesity and glucose intolerance in Pima Indians. Diabetes. 1990; 39: 1430–1435.[Abstract]
16. Haffner SM, Fong D, Hazuda HP, Pugh JA, Patterson JK. Hyperinsulinemia, upper body adiposity, and cardiovascular risk factors in non-diabetics. Metabolism. 1988; 37: 338–345.[CrossRef][Medline] [Order article via Infotrieve]
17. Folsom AR, Burke GL, Ballew C, Jacobs DR Jr., Haskell WL, Donahue RP, Liu K, Hilner JE. Relation of body fatness and its distribution to cardiovascular risk factors in young blacks and whites; the role of insulin. Am J Epidemiol. 1989; 130: 911–924.[Abstract/Free Full Text]
18. Nagi DK, Hendra TJ, Ryle AJ, Cooper TM, Temple RC, Clark PMS, Eschneider AE, Hales CN, Yudkin JS. The relationship of concentrations of insulin, intact proinsulin and 32–33 split proinsulin with cardiovascular risk factors in type 2 (non-insulin-dependent) diabetic subjects. Diabetologia. 1990; 33: 532–537.[CrossRef][Medline] [Order article via Infotrieve]
19. Manolio TA, Savage PJ, Burke GL, Liu K, Wagenknecht LE, Sidney S, Jacobs DR Jr., Roseman JM, Donahue RP, Oberman A. Association of fasting insulin with blood pressure and lipids in young adults: The CARDIA study. Arteriosclerosis. 1990; 10: 430–436.[Abstract/Free Full Text]
20. Pollare T, Lithell H, Berne C. Insulin resistance is a characteristic feature of primary hypertension independent of obesity. Metabolism. 1990; 39: 167–174.[Medline] [Order article via Infotrieve]
21. Swislocki ALM, Hoffman BB, Reaven GM. Insulin resistance, glucose intolerance and hyperinsulinemia in patients with hypertension. Am J Hypertens. 1989; 2: 419–423.[Medline] [Order article via Infotrieve]
22. Shen D-C, Sheih S-M, Fuh MM-T, Wu D-A, Chen Y-DI, Reaven GM. Resistance to insulin-stimulated glucose-uptake in patients with hypertension. J Clin Endocrinol Metab. 1988; 66: 580–583.[Abstract]
23. Cepaldo B, Lembo G, Napoli R, Rendina V, Albano G, Sacc L, Trimarco B. Skeletal muscle is a primary site of insulin resistance in essential hypertension. Metabolism. 1991; 40: 1320–1322.[CrossRef][Medline] [Order article via Infotrieve]
24. Natali A, Santoro D, Palombo C, Cerri M, Ghione S, Ferrannini E. Impaired insulin action on skeletal muscle metabolism in essential hypertension. Hypertension. 1991; 17: 170–178.[Abstract/Free Full Text]
25. Saad MF, Lillioja S, Nyomba BL, Castillo C, Ferraro R, DeGregorio M, Ravussin E, Knowler WC, Bennett PH, Howard BV, Bogardus C. Racial differences in the relation between blood pressure and insulin resistance. N Engl J Med. 1991; 324: 733–739.[Abstract]
26. Falkner B, Hulman S, Tannenbaum J, Kushner H. Insulin resistance and blood pressure in young black men. Hypertension. 1990; 16: 706–711.[Abstract/Free Full Text]
27. Mattiasson I, Berntorp K, Lindgarde F. Insulin resistance and Na+/K(+)-ATPase in hypertensive women: a difference in mechanism depending on the level of glucose tolerance. Clin Sci (Lond). 1992; 82: 105–111.[Medline] [Order article via Infotrieve]
28. Wagenknecht LE, Mayer EJ, Rewers M, Haffner SM, Selby J, Borok GM, Henkin L, Howard G, Savage PJ, Saad MF, Bergman RN, Hamman R. The Insulin Resistance Atherosclerosis Study (IRAS): objectives, design, and recruitment results. Ann Epidemiol. 1995; 5: 464–471.[CrossRef][Medline] [Order article via Infotrieve]
29. Pacini G, Bergman RN. MINMOD: a computer program to calculate insulin sensitivity and pancreatic responsitivity from the frequently sampled intravenous glucose tolerance test. Comput Methods Programs Biomed. 1986; 23: 113–122.[CrossRef][Medline] [Order article via Infotrieve]
30. Welch S, Gebhart SSP, Bergman RN, Phillips LS. Minimal model analysis of intravenous glucose tolerance derived insulin sensitivity in diabetic subjects. J Clin Endocrinol Metab. 1990; 71: 1508–1518.[Abstract]
31. Saad MF, Anderson RL, Laws A, Watanabe R, Kades WW, Chen Y-DI, Sands RE, Savage PJ, Bergman RN. A comparison between the minimal model and the glucose clamp techniques in the assessment of insulin sensitivity across the spectrum of glucose tolerance. Diabetes. 1994; 43: 1114–1121.[Abstract]
32. Coates PA, Luzio SD; Brunel P, Owens DR. Comparison of estimates of insulin sensitivity from minimal model analysis of the insulin-modified frequently sampled intravenous glucose tolerance test and the isoglycemic hyperinsulinemic clamp in subjects with NIDDM. Diabetes. 1995; 44: 631–635.[Abstract]
33. Pollare T, Lithell H, Berne CN. A comparison of the effects of hydrochlorothiazide and captopril on glucose and lipid metabolism in patients with hypertension. N Engl J Med. 1989; 321: 868–873.[Abstract]
34. Page M McB, Watkins PJ. Provocation of postural hypotension by insulin in diabetic autonomic neuropathy. Diabetes. 1976; 25: 90–95.[Abstract]
35. Heise T, Magnusson K, Heinemann L, Sawicki PT. Insulin resistance and the effect of insulin on blood pressure in essential hypertension. Hypertension. 1998; 32: 243–248.[Abstract/Free Full Text]
36. Genev NM, Lau IT, Willey KA, Molyneaux LM, Xu ZR, Zilkens RR, Wyndham RN, Yue DK. Does insulin therapy have a hypertensive effect in type 2 diabetes. J Cardiovascular Pharmacol. 1998; 32: 39–41.[CrossRef][Medline] [Order article via Infotrieve]
37. Wheatcroft SB, Williams IL, Shah AM, Kearney MT. Pathophysiological implications of insulin resistance on vascular endothelial function. Diabet Med. 2003; 20: 255–268.[CrossRef][Medline] [Order article via Infotrieve]
38. Aviv A, Gardner J. Racial difference in ion regulation and their possible links to hypertension in Blacks. Hypertension. 1989; 14: 584–589.[Free Full Text]
39. Bonora E, Bonadonna RC, Del Prato S, Gulli G, Solini A, Matsuda M, DeFronzo RA. In vivo glucose metabolism in obese and type 2 diabetic subjects with or without hypertension. Diabetes. 1993; 42: 764–772.[Abstract]
40. Laakso M, Sarlund H, Mykkanen L. Essential hypertension and insulin resistance in non-insulin-dependent diabetes. Eur J Clin Invest. 1989; 19: 518–526.[Medline] [Order article via Infotrieve]

This article has been cited by other articles:

				G. Nijpels, W. Boorsma, J. M. Dekker, F. Hoeksema, P. J. Kostense, L. M. Bouter, and R. J. Heine Absence of an Acute Insulin Response Predicts Onset of Type 2 Diabetes in a Caucasian Population with Impaired Glucose Tolerance J. Clin. Endocrinol. Metab., July 1, 2008; 93(7): 2633 - 2638. [Abstract] [Full Text] [PDF]

				J.-P. Despres, I. Lemieux, J. Bergeron, P. Pibarot, P. Mathieu, E. Larose, J. Rodes-Cabau, O. F. Bertrand, and P. Poirier Abdominal Obesity and the Metabolic Syndrome: Contribution to Global Cardiometabolic Risk Arterioscler. Thromb. Vasc. Biol., June 1, 2008; 28(6): 1039 - 1049. [Abstract] [Full Text] [PDF]

				P. Cirillo, W. Sato, S. Reungjui, M. Heinig, M. Gersch, Y. Sautin, T. Nakagawa, and R. J. Johnson Uric Acid, the Metabolic Syndrome, and Renal Disease J. Am. Soc. Nephrol., December 1, 2006; 17(12_suppl_3): S165 - S168. [Abstract] [Full Text] [PDF]

				T. Tillin, N. G. Forouhi, P. M. McKeigue, and N. Chaturvedi The Role of Diabetes and Components of the Metabolic Syndrome in Stroke and Coronary Heart Disease Mortality in U.K. White and African-Caribbean Populations. Diabetes Care, September 1, 2006; 29(9): 2127 - 2129. [Full Text] [PDF]

				E. Ferrannini Insulin and Blood Pressure: Connected on a Circumference? Hypertension, March 1, 2005; 45(3): 347 - 348. [Full Text] [PDF]

This Article Abstract Full Text (PDF) All Versions of this Article: 43/6/1324    most recent 01.HYP.0000128019.19363.f9v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Saad, M. F. Articles by Haffner, S. M. Search for Related Content PubMed PubMed Citation Articles by Saad, M. F. Articles by Haffner, S. M. Pubmed/NCBI databases Compound via MeSH Substance via MeSH Medline Plus Health Information High Blood Pressure Related Collections Clinical Studies Obesity Glucose intolerance