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(Hypertension. 1997;30:1144-1149.)
© 1997 American Heart Association, Inc.

Articles

Insulin Resistance, Hyperinsulinemia, and Blood Pressure

Role of Age and Obesity

Ele Ferrannini; Andrea Natali; Brunella Capaldo; Mikko Lehtovirta; Stefan Jacob; Hannele Yki-Järvinen for the European Group for the Study of Insulin Resistance (EGIR)

From the Metabolism Unit, CNR Institute of Clinical Physiology, and the Department of Internal Medicine, University of Pisa, Italy (E.F.); other affiliations are shown in the Appendix.

Correspondence to Dr E. Ferrannini, CNR Institute of Clinical Physiology, Via Savi, 8, I-56126 Pisa, Italy.

	Abstract

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Abstract In population surveys, blood pressure and plasma insulin concentration are related variables, but the association is confounded by age and obesity. Whether insulin resistance is independently associated with higher blood pressure in normal subjects is debated. We analyzed the database of the European Group for the Study of Insulin Resistance, made up of nondiabetic men and women from 20 centers, in whom insulin sensitivity was measured by the euglycemic insulin clamp. After excluding subjects aged 70 years, those with severe obesity (body mass index [BMI] >40 kg · m^-2), and those with abnormal blood pressure values (140/90 mm Hg), 333 cases (ages 18 to 70 years; BMI, 18.4 to 39.8 kg · m^-2) were available for analysis. In univariate analysis, both systolic and diastolic blood pressures were inversely related to insulin sensitivity, with r values of 0.18 (P<.005) and 0.34 (P<.0001), respectively. In a multivariate model simultaneously accounting for sex, age, BMI, and fasting insulin, systolic and diastolic blood pressures were still inversely related to insulin sensitivity (partial r, 0.15 and 0.19; P<.01 for both). In this model, age was positively related to blood pressure levels independently of insulin sensitivity, whereas BMI was not. The predicted impact on blood pressure of a decrease in insulin sensitivity of 10 µmol · min^-1 · kg^-1 was +1.4 mm Hg, similar to that associated with a 10-year difference in age. Although insulin levels and insulin action were reciprocally interrelated, diastolic blood pressure varied as a simultaneous function of both. In normotensive, nondiabetic Europeans, insulin sensitivity and age are significant, mutually independent correlates of blood pressure, whereas body mass is not. The relation of blood pressure to both insulin action and circulating insulin levels is compatible with distinct influences on blood pressure by insulin resistance and compensatory hyperinsulinemia.

Key Words: arterial blood pressure • insulin • insulin resistance • insulin action • obesity

	Introduction

Top Abstract Introduction Methods Results Discussion Appendix 1 References

 
Since the initial report of disproportionately high plasma insulin concentrations in response to glucose ingestion in patients with essential hypertension,¹ numerous population-based and cohort studies have reported cross-sectional^{2 3 4 5 6 7} and longitudinal^{8 9} associations between measures of arterial blood pressure (systolic, diastolic, or mean) and plasma insulin level (fasting or postglucose). Covariance of blood pressure and plasma insulin has also been shown in normotensive, nondiabetic subjects within the physiological domain of the two variables.¹⁰ These observations have raised the possibility that insulin—like salt intake, alcohol consumption, obesity, and aging—may be a determinant of blood pressure variability and may possibly contribute to the pathogenesis of essential hypertension.

On the other hand, some investigators^{11 12 13 14} have challenged the significance of the association between blood pressure and plasma insulin on the grounds that (1) it is often weak; (2) it depends on the characteristics of the study population (ie, population-based survey versus hospital sample, ethnicity, inclusion criteria with respect to blood pressure, and glucose tolerance); and (3) it is strongly confounded by age and obesity.

A number of case-control studies have addressed the issue by measuring insulin sensitivity directly (most often by the euglycemic insulin clamp technique). The results of these studies have been entirely consistent in showing that lower insulin sensitivity is associated with higher blood pressure in nondiabetic individuals^{15 16} as well as in patients with non–insulin-dependent diabetes.¹⁷ Circulating insulin concentrations are only a surrogate measure of insulin action; thus, full concordance of results obtained by direct measurements may become partially inconsistent when using crude estimates of insulin action. This explanation may, however, be insufficient. In fact, insulin can influence blood pressure in a number of ways. By enhancing renal sodium reabsorption¹⁸ and stimulating the sympathetic nervous system,¹⁹ hyperinsulinemia has the potential to raise or maintain elevated blood pressure. On the other hand, in humans acute insulin administration is associated with a certain degree of vasodilatation.¹⁹ Therefore, a given blood pressure response to insulin is likely to be the net balance between pressor and depressor actions. In virtually all in vivo circumstances, insulin resistance in humans is incomplete (or pathway specific).²⁰ This implies that compensatory hyperinsulinemia, generated by resistance of glucose metabolism to insulin action, may act unopposed on sensitive pathways (eg, sodium reabsorption). Consequently, in metabolically resistant subjects the actual blood pressure levels will depend on which pressor or depressor action of insulin is resistant or sensitive. Conceivably, then, both the degree of insulin sensitivity and the level of hyperinsulinemia may affect blood pressure through separate pathways.

Large series in which both plasma insulin and insulin sensitivity have been related to blood pressure in normotensive nondiabetic subjects are lacking. In the present work, we have assessed the relationship between blood pressure and insulin action by retrospective analysis of the database of the European Group for the Study of Insulin Resistance (EGIR). This database, collected at 20 European centers, includes data from 1146 healthy white men and women, ranging in age from 18 to 85 years, in whom insulin action was determined by the euglycemic insulin clamp technique.

The analysis of a subgroup of this population sample for which blood pressure data were available made it possible to address the following questions: (1) which blood pressure, systolic or diastolic, is related to which aspect of insulin—action, concentration, or both; (2) to what extent do age and obesity explain the association; and (3) what is the quantitative impact of insulin sensitivity or plasma insulin concentration on blood pressure levels in comparison with age and obesity.

	Methods

Top Abstract Introduction Methods Results Discussion Appendix 1 References

 
Subjects
Twenty clinical research centers in Europe (3 in Finland, 1 in Sweden, 1 in the United Kingdom, 1 in Denmark, 4 in Germany, 1 in Switzerland, 7 in Italy, 1 in Yugoslavia, and 1 in Greece) contributed each between 21 and 122 cases. These centers agreed to provide their available clamp studies (whatever the original purpose of these studies) on the condition that the study subjects met the following criteria: (1) no clinical or laboratory evidence of cardiac, renal, liver, or endocrine disease; (2) a fasting plasma glucose concentration <6.7 mmol/L and normal glucose tolerance by American Diabetes Association criteria²¹ ; (3) normal blood pressure (see below for criteria); (4) no recent change (10%) in body weight; and (5) no current medication. Of the 1146 cases in the entire database, blood pressure data were available in 508 cases from 13 centers (3 in Finland, 1 in the United Kingdom, 4 in Germany, 4 in Italy, and 1 in Serbia), each contributing between 20 and 106 cases. For the main analysis included here, additional selection criteria were (1) age 70 years; (2) body mass index (BMI) <40 kg · m^-2; and (3) normal blood pressure according to the JNC-V (systolic <140 and diastolic <90 mm Hg).²² Of the 333 subjects (221 women and 112 men) who met these conditions, 35% were recruited in northern Europe (Finland and the United Kingdom), 24% in central Europe (Germany), and 41% in southern Europe (Italy and Serbia). At each center, the protocol was reviewed and approved by the local ethics committee, and informed consent was obtained from all subjects before their participation.

Protocol
The minimum information required for each case was age, anthropometric variables, and fasting and steady-state (final 40 minutes of a 2-hour insulin clamp; see below) plasma glucose and insulin measurements. Height was measured to the nearest centimeter and weight to the nearest kilogram. BMI was calculated as the weight divided by the square of height. The waist-to-hip circumference ratio (WHR) was determined (in a subset of 121 men and 57 women) by measuring the waist circumference at the narrowest part of the torso and the hip circumference in a horizontal plane at the level of the maximal extension of the buttocks. Arterial blood pressure was measured at least twice (at 5- to 10-minute intervals) by mercury sphygmomanometry after the patients had been in the supine position for at least 20 minutes. The mean of all readings was used.

Insulin action was measured in all subjects by the euglycemic insulin clamp technique²³ using an insulin infusion rate of 7 pmol · min^-1 · kg^-1 (1 mU · min^-1 · kg^-1). Briefly, polyethylene cannulas were inserted into an antecubital vein (for the infusion of glucose and insulin) and retrogradely into a wrist vein after being heated at 60°C in a hot box or heating pad (for intermittent blood sampling of arterialized venous blood). At time zero, a primed-constant infusion of regular insulin was begun and continued for 120 minutes. Four minutes into the insulin infusion, an exogenous glucose infusion was started and adjusted every 5 to 10 minutes to maintain plasma glucose within 10% of its baseline value. Blood samples were obtained at timed intervals in the fasting state and during the clamp study for the measurement of plasma glucose and insulin levels.

Analytical Procedures
Plasma glucose was measured by the glucose oxidase method. Plasma insulin concentrations were measured by radioimmunoassay.

Data Analysis
Insulin sensitivity was expressed as the whole-body glucose disposal rate during the last 40 minutes (80 to 120 minutes) of euglycemic hyperinsulinemia (M value). Changes in glucose concentration in its body pool were taken into account by assuming a distribution volume for glucose of 250 mL · kg^-1. Whole-body glucose disposal was normalized per kilogram of body weight. With the insulin dose used in the present studies, endogenous glucose output has been previously shown to be fully suppressed in old as well as young subjects.^{23 24} In addition, in a subgroup of subjects (n=56) endogenous glucose production was directly measured by using a constant infusion of [³H]glucose and applying the principles of the dilution theory at steady state.²⁵ In these subjects, mean endogenous glucose production during the final 40 minutes of the clamp study was not different from zero (0.69±2.6 [SD] µmol · min^-1 · kg^-1), and there was no difference between subjects with BMI 25 kg · m^-2 (-1.1±0.8 µmol · min^-1 · kg^-1, n=22) and subjects with BMI >25 kg · m^-2 (-0.2±0.2 µmol · min^-1 · kg^-1, n=34, P=.14). Consequently, endogenous glucose output was assumed to be nil in all studies.

Normality of distributions was tested with the use of the Shapiro-Wilk W test. Only fasting plasma insulin values had a right-skewed distribution and were therefore transformed into their natural logarithm before use in statistical calculations. Data are given as mean±SD. A dummy variable was introduced to account for between-center differences and was included in all regression models. Simple and multiple regression analyses were carried out by standard techniques. Confidence intervals (95%) were calculated for regression coefficients.

	Results

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The characteristics of the study group (Table 1) show wide ranges of age, BMI, fasting plasma insulin concentrations, and degree of insulin sensitivity. Insulin sensitivity (as the M value) was inversely related to both systolic and diastolic blood pressure, whereas fasting plasma insulin was correlated with diastolic blood pressure only (Fig 1). The relationship between insulin sensitivity and blood pressure was essentially similar in men and women. By defining obesity as a BMI >27 kg · m^-2, 74 subjects (or 22%) were obese. In the lean subgroup, the correlation coefficient for the relationship between diastolic blood pressure and insulin sensitivity was .31 (P<.0001), whereas it was .19 (P=.10) among the obese. The corresponding coefficients for systolic blood pressure values were .21 (P<.001) in the lean and .07 (P=NS) in the obese.

View this table: [in this window] [in a new window]   Table 1. Population Characteristics

View larger version (43K): [in this window] [in a new window]   Figure 1. Relationship between systolic (upper panels) and diastolic (lower panels) blood pressure values and fasting plasma insulin concentration (log transformed) or insulin sensitivity (M value) in 333 normotensive, nondiabetic Europeans. The dotted lines represent 95% confidence bands for the true mean of the dependent variable.

In univariate analysis, blood pressure, fasting insulin level, M value, age, and BMI were mutually interrelated (Table 2). Therefore, the statistical dependence of systolic and diastolic blood pressures on the other variables was further analyzed with multiple linear regression. Sex, age, and insulin sensitivity were independently associated with systolic blood pressure, together explaining 9% of its variability (r=.31, P<.0001), whereas diastolic blood pressure values were simultaneously related to age, insulin sensitivity, and fasting insulin levels; together, these variables explained 18% of the variability of diastolic blood pressure (r=.43, P<.0001). When comparing simple with partial coefficients (Fig 2), BMI was not independently associated with diastolic blood pressure when accounting for the other variables.

View this table: [in this window] [in a new window]   Table 2. Correlation Matrix

View larger version (41K): [in this window] [in a new window]   Figure 2. Simple (dotted histograms) versus partial (full histograms) correlation coefficients for systolic and diastolic blood pressures. The two dotted lines represent the limits of statistical significance (at P<.05) for the regression coefficients. BMI indicates body mass index; M, M value; and FPI, fasting plasma insulin concentration.

To quantify the impact of each covariate (sex, age, BMI, and fasting plasma insulin) on the relationship between insulin sensitivity and blood pressure, we calculated the predicted increments in systolic and diastolic blood pressure for a 30% increase in insulin resistance (relative to the population mean) when sequentially adjusting for covariates. As depicted in Fig 3, an increase in insulin resistance of 10 µmol · min^-1 · kg^-1 was associated with 2 mm Hg increments in both systolic and diastolic blood pressure levels regardless of adjustment for covariates. Moreover, when all of the covariates were included in the model, the influence of insulin sensitivity on blood pressure was similar for systolic (1.4±0.6 mm Hg, P<.01) and diastolic (1.4±0.4 mm Hg, P<.001) blood pressure, although the 95% confidence limits indicated a stronger association with the latter than the former. For comparison purposes, we calculated in a similar manner the impact on systolic and diastolic blood pressures of a 10-year increase in age or an increase in BMI of 3 kg · m^-2 (Fig 3). Although the effect of this age difference was significant for both blood pressure values (and was similar to that observed for a 30% increase in insulin resistance), the effect of BMI was no longer significant when the relationship was adjusted for insulin sensitivity or fasting insulin concentration.

View larger version (33K): [in this window] [in a new window]   Figure 3. Predicted blood pressure increments associated with given changes in insulin sensitivity (left), age (middle), or body mass index (BMI) (right) after adjustment for each single covariate and all together (indicated on the abscissae). Boxes indicate the 95% confidence limits of the predictions.

Because insulin sensitivity and fasting plasma insulin levels were strongly related to one another (Table 2), it was somewhat unexpected to find that both made an independent contribution to blood pressure variability in multivariate analysis. We therefore tested whether insulin levels and sensitivity showed a significant interaction in predicting blood pressure. After adjusting for age, sex, and BMI in a multiple regression model, insulin sensitivity and fasting plasma insulin showed a significant (P<.03) negative interaction on diastolic (but not systolic) blood pressure such that (1) small changes in fasting insulin within the lower half of its concentration range were associated with large changes in diastolic blood pressure and (2) this effect was attenuated by the presence of progressive insulin resistance up to insulin levels of 250 pmol/L, after which the effect was actually reversed. Thus, it can be calculated that a decrease in insulin sensitivity from 40 to 20 µmol · min^-1 · kg^-1 would be associated with an increase in diastolic blood pressure of 4 mm Hg in a subject with normal fasting insulin (50 pmol/L), an increase of only 1 mm Hg if the subject is mildly hyperinsulinemic (150 pmol/L), and a decrease of 1 mm Hg if the subject is very hyperinsulinemic (350 pmol/L).

In the data subset in which WHR measurements were available, there was no independent association of WHR with either measure of blood pressure when simultaneously accounting for BMI. The same was true when using waist circumference as an index of body fat distribution.

When all the above analyses were repeated on the full data set (508 cases), the results were qualitatively the same, although the regression coefficients were slightly different. Also, the pattern of associations was not substantially different when using different indices of insulin sensitivity (the M value normalized by lean body mass or the M/I ratio, ie, the ratio of M to steady-state plasma insulin levels).

	Discussion

Top Abstract Introduction Methods Results Discussion Appendix 1 References

 
The present study demonstrates that in normotensive, nondiabetic white Europeans, arterial blood pressure is inversely related to insulin sensitivity and directly related to fasting plasma insulin concentration in either sex, at any age and regardless of body size. Insulin sensitivity, as measured in euglycemic clamp studies performed at physiological insulin concentrations, showed similar associations with systolic and diastolic blood pressures, whereas fasting insulinemia was only related to diastolic blood pressure. The association between insulin sensitivity and blood pressure was stronger in nonobese than in obese subjects, in accordance with previous findings.^{9 17} In the largest published series using the clamp technique, Saad et al²⁶ also found a significant negative association between the M value and mean blood pressure in 53 nondiabetic white subjects but not in comparable groups of Pima Indians or blacks living in the southwestern United States. Of note is that in the study by Saad et al,²⁶ subjects were all young (30±7 [SD] years) and obese (BMI=32.9±9.3 kg · m^-2), so the association between insulin sensitivity and blood pressure could not be verified across a wide range of age and body mass.

In our cohort, the relationship was such that systolic blood pressure was 1.7 mm Hg, and diastolic blood pressure was 2.3 mm Hg, higher for each 10-unit increase in insulin resistance (ie, a 10 µmol · min^-1 · kg^-1 decrement in the M value). Although small in absolute terms, a difference in blood pressure of 2 mm Hg is relevant at the population level. In fact, as the cutoff points for the diagnosis of hypertension (140/90 mm Hg) are close to the modes of the respective frequency distribution functions, a small shift in the distribution translates into a large increase in the prevalence of hypertension (a shift to the right of 2 mm Hg moves 6% of the population into the hypertensive range²⁷ ; for an age-adjusted prevalence of hypertension of 20%, this is a 30% increase). Moreover, on the basis of available prospective studies, it is possible to predict that the a 2-mm Hg increment in arterial blood pressure will produce an increase in incidence of 17% for cerebrovascular disease and 10% for ischemic heart disease.²⁸

Because blood pressure, age, body mass, fasting insulin, and insulin sensitivity were highly interrelated variables in this as in other published series,²⁹ the true dependence of systolic or diastolic blood pressure on the other variables had to be extracted by multivariate analysis. Using this approach, insulin sensitivity remained a significant negative correlate of both measures of blood pressure. In contrast, multiple adjustment completely neutralized the statistical effect of BMI on diastolic blood pressure levels (Fig 2). Thus, the predicted effect on diastolic blood pressure of a 3-unit increase in BMI (9 kg) resisted adjustment for age but lost significance when controlling for either fasting insulin or the M value (or both) (Fig 3). Therefore, whereas age raises blood pressure through mechanisms unrelated to insulin action or concentrations, the effect of obesity on blood pressure control appears to be mediated by insulin resistance. A corollary of these results is that although body mass has typically been viewed as a major confounder in the relationship between insulin and blood pressure,³⁰ the reverse interference, of insulin sensitivity in the relationship between body weight and blood pressure, has been ignored, possibly leading to an overestimation of the role of obesity in blood pressure homeostasis. For example, in our data the sex-adjusted prediction for an increase in body size of 9 kg was an increment in diastolic blood pressure of 1.4 mm Hg (Fig 3) or 0.15 mm Hg per kg of weight increase. This figure is very similar to that calculated in the San Antonio Heart Study,³⁰ a population-based survey, as well as in several previous series.^{31 32} Yet, on adjustment of this prediction by the other covariates in our database, the effect of weight change was canceled. Clearly, the conclusion—that insulin action is the mechanism transducing the effect of body size on blood pressure—is limited by the cross-sectional nature of the present data and is confined to the normotensive, nondiabetic segment of an ethnically homogeneous population.

Of some interest is the independent contribution to blood pressure of fasting plasma insulin concentrations and insulin sensitivity. Although closely related to one another, hyperinsulinemia and insulin resistance are connected in a complex physiological subsystem in which the kinetics of insulin metabolism, ß-cell sensitivity to glucose, and chronic effects of raised glucose and insulin concentrations all play a role. The "effect" on blood pressure of these two variables was nonlinear because of the presence of a significant interaction. Thus, increases in plasma insulin concentration in the low-normal range were associated with relatively large blood pressure increments in subjects with normal-high insulin sensitivity but not in insulin-resistant subjects. This result is compatible with the notion that insulin may interfere in blood pressure control through distinct mechanisms that are differentially affected by insulin resistance. In particular, of those insulin effects that can raise blood pressure, ie, antinatriuresis and sympathetic nervous system activation,^{18 19} the former has been shown to be normally sensitive in metabolically insulin-resistant individuals (obese³³ and hypertensive³⁴ subjects), whereas the latter has been found to be attenuated in the presence of obesity.³⁵ On the other hand, the ability of acute hyperinsulinemia to induce vasodilatation via release of endothelial nitric oxide³⁶ has been reported to be impaired in obese³⁷ or hypertensive individuals,³⁸ ie, in insulin-resistant states. Clearly, the observed statistical interaction between insulin levels and sensitivity is only a distant reflection of multiple physiological interactions. Furthermore, saturation of any one mechanism may prevent the full deployment of others. The strength, time scale, and circumstances of the opposing pressor and depressor effects of insulin must be fully characterized by clinical investigation.

	Acknowledgments

 
On behalf of EGIR, we wish to thank Groupe Lipha in the person of Dr Christophe Pasik for generous support of the activities of the group.

	Appendix 1

Top Abstract Introduction Methods Results Discussion Appendix 1 References

 
European Group for the Study of Insulin Resistance
H. Beck-Nielsen (University of Odense, Denmark), P. Bell (University of Belfast, UK), E. Bonora (University of Verona, Italy), B. Capaldo (Federico II University, Naples, Italy), P. Cavallo-Perin (University of Turin, Italy), S. Del Prato (University of Padova, Italy), E. Ferrannini (University of Pisa, Italy), D. Fliser (University of Heidelberg, Germany), A. Golay (University of Geneva, Switzerland), L.C. Groop and Mikko Lehtovirta, (Lund University, Sweden), S. Jacob (Stadtklinik, Baden-Baden, Germany), M. Laakso (University of Kuopio, Finland), N. Lalic (University of Belgrade, Serbia), G. Mingrone (Catholic University, Rome, Italy), A. Mitrakou (University of Athens, Greece), G. Paolisso (University of Naples II, Napoli, Italy), K. Rett (University of München, Germany), U. Smith (University of Göteborg, Sweden), M. Weck (Kreischa, Germany), H. Yki-Järvinen (University of Helsinki, Finland).

Received May 7, 1997; first decision May 28, 1997; accepted May 28, 1997.

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