Increased insulin resistance in salt sensitive essential ... - Nature

Journal of Human Hypertension (2001) 15, 481–485  2001 Nature Publishing Group All rights reserved 0950-9240/01 $15.00 www.nature.com/jhh

ORIGINAL ARTICLE

Increased insulin resistance in salt sensitive essential hypertension V Giner, A Coca and A de la Sierra Hypertension Unit, Department of Internal Medicine, IDIBAPS (Institut d’Investigacions Biome`diques August Pi i Sunyer), Hospital Clińic, University of Barcelona, Spain

Objective: To determine the possible relationship between insulin resistance and salt sensitivity in essential hypertension. Design and methods: We studied 17 non-obese, essential hypertensive patients (24-h blood pressure: 149 ⴞ 15/94 ⴞ 5 mm Hg) with normal glucose tolerance. Salt sensitivity was diagnosed in the presence of a significant increase (P ⬍ 0.05, more than 4 mm Hg) in 24-h mean blood pressure (MBP) when patients switched from a low-salt intake (50 mmol/day of Naⴙ) to a highsalt intake (240 mmol/day of Naⴙ), each period lasting 7 days. The insulin sensitivity index was determined by the euglycaemic hyperinsulinaemic clamp. Results: Six patients were classified as salt sensitive (24-h MBP increase: 6.2 ⴞ 1.1 mm Hg), and 11 as salt resistant (24-h MBP increase: ⴚ1.2 ⴞ 3.8 mm Hg). No significant differences were observed between salt sensitive and salt resistant patients regarding baseline

characteristics, fasting serum insulin, fasting serum glucose, glycosilated haemoglobin, total cholesterol, HDL-cholesterol, LDL-cholesterol, triglycerides, uric acid and microalbuminuria. Salt sensitive patients exhibited a reduced insulin sensitivity index compared with salt resistant patients (1.7 ⴞ 1.1 vs 3.5 ⴞ 1.2 mg/kg/min; P ⴝ 0.009). An inverse relationship (r ⴚ0.57; P ⴝ 0.016) between the insulin sensitivity index and 24-h MBP increase with high salt intake was found. Conclusion: Salt sensitive essential hypertensive patients are more insulin resistant than salt resistant patients when both salt sensitivity and insulin resistance are accurately measured. Indirect measures of both insulin and salt sensitivity and/or the presence of modifying factors, such as obesity or glucose intolerance, may account for differences in previous studies. Journal of Human Hypertension (2001) 15, 481–485

Keywords: insulin resistance; salt sensitivity; essential hypertension; dietary sodium

Introduction Hypertension in both obese and diabetic subjects has been reported to be sensitive to the pressor effect of salt intake. Such individuals are sensitive to insulin action on sodium metabolism but resistant to its effects on glucose disposal.1,2 The consequence of this partial insulin resistance is hyperinsulism and blood pressure elevation due to increased renal Na⫹ reabsorption and vasoconstriction.3,4 Bigazzi et al5 demonstrated higher levels of insulin, total cholesterol, low-density lipoprotein (LDL)cholesterol and urinary albumin excretion in salt sensitive hypertensives compared with salt resistant patients, suggesting that insulin resistance could be responsible for this atherogenic cluster. Studies of the association between salt sensitivity and insulin resistance have yielded contradictory results, in both normotensive6–8 and in hypertensive subCorrespondence: Dr V Giner Galvan˜, Hypertension Unit. Department of Internal Medicine, Hospital Clińico de Valencia, University of Valencia, Vicente Blasco Ibań˜ez 10, 04610, Valencia, Spain E-mail: ginerFvicgal얀gva.es Received 8 November 2000; revised and accepted 10 March 2001

jects.5,9–15 Some authors have found higher degrees of insulin resistance in salt sensitive hypertensive patients,9,10 whereas others have found no relationship in hypertensives,11 obese12 or normotensives.13 Finally, two reports in hypertensive patients have found an increase in insulin sensitivity in salt sensitive hypertensive subjects.14,15 The main reason explaining these contradictory results is the use of different methodologies to measure both salt sensitivity and insulin resistance. Although only one author9 used the less time-consuming intravenous method to determine blood pressure sensitivity to salt intake, diagnostic criteria were completely different among all studies that used oral salt load. There is also a high heterogeneity in the methodology applied to measure insulin sensitivity, and only three studies used the euglycaemic hyperinsulinaemic clamp technique,8,9,13 considered the gold standard method.16 Another limitation is the inclusion of some effect modifiers in the studied groups. Both salt sensitivity17 and insulin resistance18 increase with age, and some studies included only young1,6,7 or old people.14,15 On the other hand, obesity and glucose tolerance impairment were exclusion criteria in only two studies.9,10

Insulin resistance and salt sensitivity V Giner et al

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Given the existence of the commented heterogeneity in previous studies, we have used accurate methodologies to analyse the potential relationship between insulin resistance and sensitivity to the pressor effect of salt intake in a group of non-obese essential hypertensives without glucose intolerance.

Patients and methods Patient selection Seventeen outpatients with mild-to-moderate essential hypertension were recruited from the Hypertension Unit of the Hospital Clińic, Barcelona (Spain). Patients were 20–70 years old. None of the patients included had renal impairment, papilloedema, cardiac, coronary or cerebrovascular diseases, diabetes or pregnancy. All the patients had at least three office blood pressure measurements above 140/90 mm Hg after 4 weeks of an unrestricted salt diet without antihypertensive medication. Moreover, all patients had a 24-h diastolic blood pressure higher than 85 mm Hg, measured by ambulatory blood pressure measurement (ABPM), prior to their inclusion in the study. Essential hypertensive subjects with a body mass index (BMI) ⬎30 kg/m2 or an impaired 70 g glucose tolerance test according to 1997 ADA criteria19 were excluded. The protocol was approved by the Ethics Committee of the University Hospital and written informed consent was obtained from all participants. Measurement of salt sensitivity20 A low-salt diet containing less than 50 mmol sodium daily was administered for 14 days. The diet was designed by the hospital dietary department and contained 62 g of protein, 234 g of carbohydrate, 108 g of fat, 60 mmol of potassium and 20 mmol of calcium per day. The amount of calories remained constant for the whole study period. Patients daily drink was about 2 litres of water. This baseline diet was supplemented in a single-blind fashion by placebo tablets during the first 7 days (low-salt period) and by 12 tablets containing 17.8 mmol of sodium each for the second 7 days (high-salt period) in order to achieve a total NaCl intake of 260 mmol daily. Compliance with diet was assessed measuring 24-h urinary Na⫹ excretion daily. On the last day of each period a 24-h ABPM was carried out using an automated, non-invasive oscillometric device (Spacelabs 90207, Space Labs, Redmond, WA, USA). Blood pressure was registered automatically at 15-min intervals. Edited records obtained from ABPM during both salt-intake periods were individually analysed by means of SPSS Software. Salt-sensitivity was diagnosed when the increase in 24-h mean blood pressure (24-h MBP) from the low-salt period to the high-salt period was statistically significant (P ⬍ 0.05). Journal of Human Hypertension

Measurement of insulin sensitivity Prior to dietary sodium manipulation all patients underwent an euglycaemic hyperinsulinaemic clamp test as previously described by de Fronzo et al.21 The measurement was made after overnight fasting with the subject lying supine in a quiet room with a constant temperature of 21°C. Polyethylene cannulas were inserted into an antecubital vein for infusion of glucose and insulin and retrogradely into a contralateral wrist vein surrounded by a heated (60°C) box for blood sampling.22 A constant infusion of regular insulin (Lilly S.A., Madrid, Spain) was administered for 120 min at a rate of 40 mU per square meter of body-surface area per minute to achieve a plasmatic insulin level about 100 ␮U/mL (700 pmol/L). Plasma C peptide was determined to ensure that there was no endogenous insulin production during the test. Serum glucose concentration was held constant at baseline by variable-rate infusion of exogenous glucose adjusted on the basis of frequent blood glucose measurements. The quantity of glucose infused during the final 60 min corrected for the body surface area, provided an index of the insulin sensitivity (M) of the whole body expressed in terms of milligrams of glucose infused per kilogram of body weight per minute. Blood samples were obtained during the baseline period and then every 10 min until the end of the study. Plasma glucose was assayed by the glucose oxidase method (Beckman Glucose analyzer, Beckman Instruments). Serum insulin and C peptide were determined by radioimmunoassay. Statistical analysis The unpaired Student’s t-test and the non-parameter Mann–Whitney test were used when appropriate, to compare means between salt sensitive and salt resistant groups. The relationship between the insulin sensitivity index (M) and the 24-h MBP response to salt intake was analysed by means of the Pearson’s correlation coefficient. Values are expressed as mean ⫾ s.d. or median (range) for not normally distributed variables. A P value ⬍0.05 was considered statistically significant. Statistical analysis was performed with the aid of the SPSS Software.

Results From the initial 28 essential hypertensive patients screened, 11 had an impaired oral glucose tolerance test and were excluded. Thus, 17 essential hypertensive patients underwent both salt sensitivity and insulin sensitivity tests. The 24-h MBP change in the whole group followed a Gaussian distribution, ranging from a decrease of 9 mm Hg to an increase of 8 mm Hg without a clear cutoff. Six patients were diagnosed


Table 1 Baseline characteristics of essential hypertensive patients classified on the basis of their salt sensitivity status Salt sensitive (n = 6)

Salt resistant (n = 11)

P

49.6 ± 8.4 3/3 25.9 ± 2.2 139.7 ± 6.5 94.0 ± 4.5 109.5 ± 4.1 73.0 ± 7.4 7.2 ± 2.8 3.7 ± 2.0 6.2 ± 1.1 1.3 ± 3.5 35 ± 16 256 ± 78 68.4 ± 7.6 102.5 ± 37.2 4 [1.8–30]

52.7 ± 10.2 5/6 25.4 ± 2.1 153.5 ± 15.6 94.6 ± 5.9 115.6 ± 9.6 67.9 ± 9.3 −0.9 ± 6.8 −2.2 ± 3.9 −1.2 ± 3.8 2.3 ± 2.7 47 ± 32 230 ± 35 68.4 ± 7.6 96.4 ± 32.3 13 [2– 42]

0.542 0.868 0.684 0.058 0.838 0.270 0.163 0.015 0.004 ⬍0.0001 0.519 0.402 0.353 0.553 0.735 0.302

Age (years) Sex (M/F) BMI (kg/m2) Systolic BP (mm Hg) Diastolic BP (mm Hg) Mean BP (mm Hg) Heart Rate (bpm) Systolic BP increase (mm Hg) Diastolic BP increase (mm Hg) Mean BP increase (mm Hg) Heart rate increase (bpm) Low salt urinary Na+ (mmol/24 h) High salt urinary Na+ (mmol/24 h) Creatinine (␮mol/L) Creatinine clearance (ml/min) Microalbuminuria (␮g/min)

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BMI, body mass index; BP, blood pressure. BP increase means modification induced by high salt intake.

Table 2 Baseline metabolic parameters in essential hypertensive patients classified on the basis of their salt sensitivity status Salt sensitive (n = 6) Insulin (mU/L) Glucose (mmol/L) GHb (%) M (mg/kg/min) Total cholesterol (mmol/L) HDL cholesterol (mmol/L) LDL cholesterol (mmol/L) Triglycerides (mmol/L) Uric acid (␮mol/L)

Salt resistant (n = 11)

13.9 ± 9.5 8.3 ± 2.7 5.0 ± 0.3 4.9 ± 0.3 4.9 ± 0.3 4.4 ± 0.6 1.7 ± 1.1 3.5 ± 1.2 5.9 ± 0.7 5.5 ± 1.0 1.4 ± 0.2 1.5 ± 0.4 3.8 ± 0.7 3.5 ± 0.8 1.5 ± 0.5 1.3 ± 0.6 291 ± 121 309 ± 109

P

0.084 0.493 0.144 0.009 0.420 0.498 0.466 0.523 0.747

GHb: glycosilated haemoglobin. M: insulin sensitivity index.

as salt sensitive and the remaining 11 as salt resistant. All subjects classified as salt sensitive presented an increase of at least 4 mm Hg in 24-h MBP. As shown in Table 1, there were no differences in age, sex distribution, baseline 24-h blood pressure, BMI, or renal function between these two groups. Changes in 24-h blood pressure induced by high salt intake were: 7.2 ⫾ 2.8 mm Hg, 3.7 ⫾ 2.0 mm Hg and 6.2 ⫾ 1.1 mm Hg for systolic and diastolic blood pressure and MBP in the salt sensitive group, and ⫺0.9 ⫾ 6.8 mm Hg, ⫺2.2 ⫾ 3.9 mm Hg and ⫺1.2 ⫾ 3.8 mm Hg respectively in the salt resistant group. As shown in Table 2, no significant differences were detected between salt sensitive and salt resistant patients in baseline fasting serum insulin (13.9 ⫾ 9.5 vs 8.3 ⫾ 2.7 mU/L), fasting serum glucose (5.0 ⫾ 0.3 vs 4.9 ⫾ 0.3 mmol/L) and glycosilated haemoglobin (4.9 ⫾ 0.3 vs 4.4 ⫾ 0.6%). Likewise, total cholesterol, high-density lipoprotein (HDL)- cholesterol, LDL-cholesterol, triglycerides, uric acid and microalbuminuria did not differ between both groups.

Figure 1 Correlation between the insulin sensitivity index and the 24-h MBP response to salt intake in the whole group of essential hypertensive patients studied.

Salt sensitive essential hypertensive patients showed a significantly lower insulin sensitivity index (M) compared with salt resistant subjects (1.7 ⫾ 1.1 vs 3.5 ⫾ 1.2 mg/kg/min; P ⫽ 0.009) (Table 2). Furthermore, as shown in Figure 1, a significant inverse correlation was found between the insulin sensitivity index and 24-h MBP increase after high salt intake (r ⫺0.573; P ⫽ 0.016).

Discussion The present study shows that essential hypertensive patients with a higher blood pressure response to salt intake are relatively more resistant to insulin action. The absence of relationship between salt sensitivity and the other components of the insulin resistance syndrome, especially fasting serum insulin concentration, is of note. Several studies5–15 have addressed the issue of the possible relationship between salt sensitivity and Journal of Human Hypertension


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both insulin resistance and other glucose metabolic parameters, with some controversial results. In normotensive subjects, Sharma et al6,7 found a direct relationship between salt sensitivity and insulin response to an oral glucose tolerance test,6 a finding confirmed 2 years after measuring insulin sensitivity by the insulin suppression test.7 These results have recently been confirmed by another group in 47 normotensive subjects with a normal oral glucose tolerance test, who underwent the euglycaemic hyperinsulinaemic clamp.8 On the contrary, in 18 normotensive obese subjects, Egan et al12 did not find significant differences between salt sensitive and salt resistant subjects in the area under the curve of insulin after an oral glucose tolerance test. Moreover, on studying 28 normotensive subjects with a positive family history of hypertension, Mellander et al13 did not find any relationship between the blood pressure response to high salt intake and insulin sensitivity, measured by the euglycaemic clamp technique. These contradictory results obtained in normotensive subjects equally apply to the studies performed in essential hypertensive patients. Bigazzi et al5 studied 52 essential hypertensives classified on the basis of salt sensitivity and measured glucose and insulin response after an oral glucose tolerance test. They found that the area under the curve of the insulin response was higher in salt sensitive, compared to salt resistant patients. Galletti et al9 found a decreased insulin sensitivity in salt sensitive hypertensives after studying 99 patients with both a normal BMI and oral glucose tolerance test. Insulin sensitivity was measured by the euglycaemic hyperinsulinaemic clamp in only 18 patients, whereas salt sensitivity was determined by means of an acute intravenous saline load. Fuenmayor et al10 found the same results in a little group of nonobese essential hypertensive patients who underwent an insulin suppression test. In contrast with these results, Iwaoka et al11 studied 31 essential hypertensive patients after two periods of low and high salt intakes. The area under the curve of the insulin response after an oral glucose tolerance test did not differ between salt sensitive and salt resistant patients. Finally, Lind et al14 and Dengel et al15 found a higher insulin resistance in salt resistant, compared with salt sensitive hypertensive patients. Our results confirm those obtained by Galletti et al9 and Fuenmayor et al.10 Salt sensitive essential hypertensive patients exhibit a higher degree of insulin resistance, compared to salt resistant ones. Although the number of patients included in the present study is relatively low, it has the advantage that salt sensitivity was measured by the blood pressure response to low and high salt intake, whereas in Galletti’s study9 salt sensitivity was measured after an acute intravenous saline load. In this sense, a low correlation (R less than 0.7) was

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reported between acute saline load and the more physiological oral salt load method.23–25 We have not found differences between salt sensitive and salt resistant patients in baseline plasma glucose or insulin concentrations. The main reason could be due to the low number of patients analysed. The possible pathogenetic mechanisms of the relationship between salt sensitivity and insulin resistance are poorly known. Some evidence support the idea that they are both genetically determined.26,27 It has been proposed that insulin resistance and hyperinsulinism may predispose the development of salt sensitive hypertension through an increase in renal sodium reabsorption.3,28 Moreover, in response to high salt intake, salt sensitive hypertensives present alterations in both the sympathetic nervous and the renin-angiotensin systems29 which may promote vasoconstriction and decreased muscle blood flow leading to insulin resistance. In this sense, Baron et al30 demonstrated that insulin sensitivity is related to muscular blood flow increase induced by insulin itself. In summary, in a relatively small group of selected patients, we have found that salt sensitive essential hypertensives are relatively more resistant to insulin action than salt resistant patients. The presence of modifying factors, such as obesity or glucose intolerance, or the use of non-standard methodologies for the measurement of both salt sensitivity and insulin resistance may explain some of the contradictory results previously found in the literature.

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