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Insulin Resistance and Hyperinsulinemia Are Related to Plasma Aldosterone Levels in Hypertensive Patients

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Insulin Resistance and Hyperinsulinemia Are Related to Plasma Aldosterone Levels in Hypertensive Patients Cardiovascular and Metabolic Risk ORIGINAL ARTICLE Insulin Resistance and Hyperinsulinemia Are Related to Plasma Aldosterone Levels in Hypertensive Patients GIANLUCA COLUSSI, MD ELISA NADALINI, MD and maintenance of high blood pressure CRISTIANA CATENA, MD, PHD ALESSANDRA CHIUCH, MD in different ethnic groups (5), with a rela- ROBERTA LAPENNA, MD LEONARDO A. SECHI, MD tionship that is stronger in blacks (5) and in obese subjects (6). In the Framingham Offspring Study, normotensive subjects OBJECTIVE — An association between aldosterone and insulin resistance has been demon- with elevated plasma aldosterone levels, strated in obesity and primary aldosteronism and in blacks with the metabolic syndrome. The albeit within the normal range, were at aim of this study was to evaluate the relationship of plasma aldosterone with insulin sensitivity high risk of blood pressure elevation and in white subjects. subsequent development of hypertension (7). Moreover, recent evidence indicates RESEARCH DESIGN AND METHODS — In 356 patients with essential hypertension that chronic exposure to elevated aldoste- and 102 normotensive control subjects of comparable age and BMI, we measured, after discon- tinuation of treatment, plasma active renin, aldosterone, cortisol, glucose, insulin, and C-peptide rone levels might result in substantial levels and calculated markers of insulin sensitivity. Direct assessment of insulin sensitivity was damage of the heart and blood vessels. obtained in a subset of 64 hypertensive patients by a hyperinsulinemic clamp. This damage appears to be independent of the blood pressure level and might con- RESULTS — Hypertensive patients had significantly greater fasting plasma insulin and C- tribute to an increased risk of cardiovas- peptide concentrations and homeostasis model assessment (HOMA) indexes than normotensive cular events (8). control subjects. A positive association with increasing plasma aldosterone concentrations was A relationship between aldosterone demonstrated for plasma glucose, insulin, C-peptides, and HOMA. Assessment of insulin sen- and insulin resistance has been consis- sitivity by clamp showed a significant decrease of the metabolic clearance rate of glucose with tently demonstrated in obesity (9) and increasing aldosterone levels. Significant correlations were found between plasma aldosterone, primary aldosteronism (10). Two recent plasma insulin, and C-peptide levels, HOMA, and glucose metabolic clearance rate. Blood pressure and plasma potassium, plasma cortisol, and renin levels, but not BMI, were also directly studies that have been conducted in fam- correlated with plasma aldosterone. Multiple regression analysis showed that HOMA, together ilies of African descent in the Seychelles with plasma potassium, cortisol, and renin levels, was independently correlated with plasma (11) and in African Americans (12) have aldosterone. demonstrated that plasma aldosterone, but not plasma renin, is associated with CONCLUSIONS — This study demonstrates a direct relationship between aldosterone, in- the metabolic syndrome and with mark- sulin resistance, and hyperinsulinemia in white subjects. In patients with hypertension, this ers of insulin resistance. The present relationship might contribute to maintenance of high blood pressure and increased cardiovas- study has evaluated the relationship of cular risk. plasma aldosterone with glucose metabo- lism and insulin sensitivity in white pa- Diabetes Care 30:2349–2354, 2007 tients, the majority of whom had essential hypertension. eminal studies that were published in blacks (3). Population-based studies Ͼ20 years ago demonstrated an as- have subsequently suggested that insulin RESEARCH DESIGN AND sociation between hyperinsulin- resistance and hyperinsulinemia might S METHODS — A total of 356 patients emia, insulin resistance, and arterial contribute to progression of cardiovascu- with mild to moderate essential hyperten- hypertension (1,2). This association was lar disease (4). sion who were referred to the hyperten- confirmed even after adjustment for body Elevated plasma aldosterone levels sion clinic of our department were weight and was present in whites but not have been implicated in the development included in a cross-sectional study. High ●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●● blood pressure (systolic blood pressure From the Hypertension and Diabetes Unit, Division of Internal Medicine, Department of Experimental and Ն140 mmHg and/or diastolic blood pres- Clinical Pathology and Medicine, University of Udine, Udine, Italy. sure Ն90 mmHg) was measured at least Address correspondence and reprint requests to Leonardo A. Sechi, MD, Clinica Medica, University of Udine, Department of Experimental and Clinical Pathology and Medicine, Piazzale S. Maria della Misericor- twice on two different occasions and sub- dia, 1 Udine 33100, Italy. E-mail: [email protected]. sequently confirmed on at least two more Received for publication 16 March 2007 and accepted in revised form 8 June 2007. visits during the next 4 weeks. Blood Published ahead of print at http://care.diabetesjournals.org on 15 June 2007. DOI: 10.2337/dc07-0525. pressure was measured by a mercury Additional information for this article can be found in an online appendix at http://dx.doi.org/10.2337/ dc07-0525. sphygmomanometer after each subject Abbreviations: HOMA, homeostasis model assessment; QUICKI, quantitative insulin sensitivity check had been supine for 15 min. The average index. of three readings obtained in 5 min was A table elsewhere in this issue shows conventional and Syste`me International (SI) units and conversion recorded. The study patients seen at our factors for many substances. clinic are white, include individuals with © 2007 by the American Diabetes Association. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby all grades of hypertension living in north- marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. east Italy, and are representative of hyper- DIABETES CARE, VOLUME 30, NUMBER 9, SEPTEMBER 2007 2349 Aldosterone and insulin resistance tensive patients in this geographic area. Table 1—Clinical characteristics, laboratory variables, and glucose metabolism parameters Patients with secondary hypertension, se- of the study subjects vere hypertension (as defined by diastolic blood pressure Ն120 mmHg), renal fail- Ͻ Normotensive Hypertensive ure with creatinine clearance 30 ml/min group group P per 1.73 m2 of body surface area, urinary protein excretion Ն1.0 g/day, pregnancy, Clinical characteristics chronic debilitating illness, and recent n 102 356 — (within 6 months) myocardial infarction, Age (years) 51 Ϯ 14 49 Ϯ 12 0.154 unstable angina, or stroke were excluded. Sex (male) 71 (70) 195 (55) 0.028 Secondary causes of hypertension were SBP (mmHg) 129 Ϯ 11 160 Ϯ 19 Ͻ0.001 identified on the basis of extensive labo- DBP (mmHg) 79 Ϯ 7 100 Ϯ 11 Ͻ0.001 ratory testing (13). Primary aldosteron- BMI (kg/m2) 28.3 Ϯ 3.6 27.9 Ϯ 4.8 0.435 ism was screened by the demonstration of Laboratory variables an increased plasma aldosterone–to– Plasma sodium (mmol/l) 141 Ϯ 2 141 Ϯ 3 1.000 renin ratio in the presence of a plasma Plasma potassium (mmol/l) 4.3 Ϯ 0.3 4.0 Ϯ 0.4 Ͻ0.001 aldosterone concentration Ͼ150 pg/ml Plasma creatinine (␮mol/l) 84 Ϯ 25 88 Ϯ 17 0.062 and confirmed by the lack of aldosterone Urinary sodium (mmol/24 h) 120 Ϯ 52 132 Ϯ 67 0.098 suppression following an intravenous sa- Urinary potassium (mmol/24 h) 46 Ϯ 23 56 Ϯ 23 Ͻ0.001 line load (10,14). All measurements were Plasma active renin (pg/ml) 9.2 Ϯ 10.7 10.8 Ϯ 17.0 0.575 performed under a normal sodium diet, Plasma aldosterone (pg/ml) 131 Ϯ 77 167 Ϯ 123 0.005 and 24-h urinary sodium excretion was Plasma cortisol (nmol/l) 429 Ϯ 107 420 Ϯ 236 0.709 assessed in all patients. Patients treated with Triglycerides (mmol/l) 1.25 Ϯ 0.56 1.40 Ϯ 0.92 0.118 antihypertensive drugs were withdrawn Total cholesterol (mmol/l) 5.30 Ϯ 1.04 5.58 Ϯ 1.13 0.025 from treatment a minimum of 2 weeks be- HDL cholesterol (mmol/l) 1.43 Ϯ 0.41 1.42 Ϯ 0.42 0.831 fore diagnostic assessment. No patient was LDL cholesterol (mmol/l) 3.31 Ϯ 0.98 3.55 Ϯ 1.05 0.039 taking aldosterone antagonists. Glucose metabolism parameters Patients with essential hypertension Plasma glucose (mmol/l) 4.8 Ϯ 0.9 5.1 Ϯ 1.2 0.020 were compared with 102 normotensive Plasma insulin (pmol/l) 55.9 Ϯ 21.7 70.0 Ϯ 35.1 Ͻ0.001 subjects who were selected from the gen- Plasma C-peptide (nmol/l) 0.53 Ϯ 0.20 0.69 Ϯ 0.30 Ͻ0.001 eral population of the same geographic HOMA index 1.65 Ϯ 0.64 2.29 Ϯ 1.55 Ͻ0.001 area as the hypertensive patients after QUICKI 0.354 Ϯ 0.013 0.348 Ϯ 0.030 0.050 specification of inclusion criteria to avoid Data are means Ϯ SD or n (%) unless otherwise indicated. Comparisons were done by Student’s t test for age and BMI as potential confounding unpaired data. DBP, diastolic blood pressure; SBP, systolic blood pressure. variables. Normotensive control subjects were not taking any regular medications and did not have any concomitant dis- (microunits per millimeter) using the fol- pressed as the glucose metabolic clear- ease. Informed consent was obtained lowing formula: [(glucose ϫ insulin)/ ance rate (milliliters per kg body weight from the study participants, and the study 22.5]. Logarithmic values of fasting per minute) during 60 min of the clamp. protocol received approval by the local plasma glucose (milligrams/deciliter) and Sodium, potassium, and creatinine review committee. insulin (microunits per millimeter) con- were measured in plasma obtained after centrations were obtained to calculate the fasting for 12–14 h by automated analyz- Glucose metabolism evaluation and QUICKI using the following formula: ers. Plasma glucose was assayed using the laboratory measurements [1/(log glucose ϩ log insulin)].
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