Skip main navigation
Close Drawer MenuOpen Drawer Menu
×

Insulin Effect on Renal Sodium Reabsorption in Adolescent Offspring of Essential Hypertensive Parents

Originally published1 Dec 1995https://doi.org/10.1161/01.HYP.26.6.1089Hypertension. 1995;26:1089–1092

    Abstract

    Abstract We previously showed that children and adolescent offspring of patients with essential hypertension have an increased proximal renal sodium reabsorption as measured by lithium fractional excretion. Insulin has been shown to have antinatriuretic properties and to be increased (hyperinsulinemia) in essential hypertension. The aim of this study was to evaluate the role of insulin on the increased proximal renal sodium reabsorption previously reported. Lithium and sodium fractional excretions were measured 3 hours before and 3 hours after an intravenous glucose tolerance test in 20 normotensive adolescents with a family history of essential hypertension (F+, 14.8±0.5 years) and 10 normotensive control subjects without a family history of hypertension (F−, 15.2±0.9 years). Results are mean±SEM. Lithium fractional excretion before glucose loading was 16.1±1.8% in F+ versus 23.5±2.0% in F− (P<.02) and after glucose loading was 14.7±1.3% in F+ versus 20.9±1.7% in F− (P=NS). Lithium fractional excretion did not change after intravenous glucose loading in either group. The insulin area under the curve was 2815±499 in F+ versus 2290±418 μU/mL per hour in F− (P=NS). There was no correlation between lithium fractional excretion and insulin area under the curve. Fractional excretion of sodium before glucose loading was 0.99±0.1% in F+ versus 0.99±0.1% in F− (P=NS) and after glucose loading was 0.77±0.1 in F+ versus 0.85+0.1% in F− (P<.01 versus values before loading in both groups). In summary lithium fractional excretion did not change after the intravenous glucose loading, and no correlation was found with insulin levels. Thus, insulin does not appear to be involved in the decreased lithium fractional excretion in F+. However, sodium fractional excretion diminished significantly after the intravenous glucose loading. Therefore, our findings in physiological conditions in humans show that one possible role of insulin in the development of hypertension is through an antinatriuretic effect distal to the proximal tubule.

    Hyperinsulinemia and insulin resistance have been extensively reported in adults with hypertension, raising the hypothesis that insulin may be involved in the pathogenesis of essential hypertension.12 Such a hypothesis is strengthened by studies demonstrating that normotensive adolescents and men with a family history of hypertension are insulin resistant and tend to show higher fasting serum insulin levels.34

    It has been suggested that hyperinsulinemia could lead to hypertension by means of its known sodium-retaining effect, among other effects.56 In hypertensive patients adequate renal sodium excretion is achieved only at elevated blood pressures.7 This rightward shift of the pressure-natriuresis curve may be the consequence of alterations in renal hemodynamics, but it also could be due to abnormalities of renal tubule sodium reabsorption.8

    We and others previously reported an increased sodium reabsorption in the proximal tubule of normotensive offspring of parents with essential hypertension.910 Thus, the aim of the present study was to evaluate the role of the insulin response to an intravenous glucose load in the increased proximal renal sodium reabsorption found in offspring of hypertensive parents.

    Methods

    Twenty F+ (mean±SEM) (14.8+0.5 years) and 10 F− (15.2+0.9 years) matched for BMI and pubertal stage (Tanner stages III and IV) were included in the study. All subjects were studied at the Hypertension Clinic of our medical center, were healthy, and were taking no medication.

    Blood pressure of parents was assessed personally by one of the authors. Procedures were explained carefully to both parents and children, and informed consent was obtained from parents.

    All subjects came to the clinic after an overnight fast and after receiving 300 mg/m2 of lithium carbonate at 10 pm the night before. At 6 am subjects emptied their bladders completely, and urine was collected until 9 am for measurement of sodium, potassium, creatinine, and lithium. At 9 am a butterfly-like needle was placed in an antecubital vein and a blood specimen was obtained for measurement of glucose, insulin, lithium, creatinine, sodium, and potassium. An intravenous glucose load (0.25 g/kg, 25% solution) was then infused over ≈2 minutes in a contralateral vein. Blood samples were obtained at 1, 3, 5, and 7 minutes after glucose injection for measurement of insulin and at 10, 20, 30, 40, 50, and 60 minutes for insulin and glucose. A second urine collection was performed between 9 am and noon for sodium, potassium, creatinine, and lithium. Patients received an oral water load (20 mL/kg and diuresis) throughout the study. Sodium, potassium, and creatinine levels were measured by an automated method (Beckman Instruments). Lithium was measured by atomic absorption spectophotometry (Perkin Elmer), and insulin was measured by radioimmunoassay.

    For statistical analysis comparisons between and within groups were calculated by paired and unpaired t tests. Pearson correlation coefficients were used to assess relations between variables. A value of P<.05 was accepted as significant. Findings are expressed as mean±SEM.

    Results

    Table 1 shows clinical findings of subjects. There were no significant differences in BMI, creatinine clearance, or systolic and diastolic blood pressure between F+ and F−.

    Table 2 shows the calculated variables both before and after the IVGTT. FeLi was significantly lower in the F+ (16.1±1.8% in F+ versus 23.5±2.0% in F−; P<.02) and did not change after the intravenous glucose load in either group (14.7±1.3% in F+ versus 20.9±1.7% in F−, respectively; P=NS versus before IVGTT) (Fig 1). The IAUC was comparable in both groups (2815±499 μU/mL per hour in F+ versus 2290±418 μU/mL per hour in F−; P=NS). There was no correlation between FeLi and IAUC (Fig 2). FeNa was similar in both groups (0.99±0.1% F+ versus 0.99±0.1% in F−; P=NS) and decreased significantly after the intravenous glucose load to a comparable extent in both groups (0.77+0.13% in F+ versus 0.85±0.1% in F−; P<.01 versus before IVGTT) (Fig 3). No correlation was found between FeNa and IAUC. Fractional excretion of potassium was similar before and after intravenous glucose loading in both groups.

    When we segregated the F+ according to IAUC level (<2500 or >2500 U/mL per hour), on the basis of our previous findings in normotensive adolescents with normal BMI we could establish that FeNa decreased significantly in adolescents with the higher insulin levels (1.02±0.16 before IVGTT versus 0.67±0.19 after IVGTT; P<.005), whereas no change could be detected in adolescents with lower IAUC levels (0.95±0.14 before IVGTT and 0.88±0.17 after IVGTT; P=NS) (Fig 4).

    Discussion

    Our findings indicate that F+ have an increased renal proximal sodium reabsorption as measured by FeLi when compared with F− matched for BMI and pubertal stage. Insulin may not account for this finding, since no relation could be established between the FeLi and either basal insulin or the IAUC after an intravenous glucose challenge. Moreover, no significant change in the FeLi was observed in either group after hyperinsulinemia ensuing from the intravenous glucose load. In contrast, FeNa decreased significantly after glucose loading in both groups under study. To our knowledge this is the first study evaluating the in vivo effects of endogenous insulin on sodium reabsorption that suggests that the antinatriuretic effect may be distal to the proximal tubule.

    Although the sodium-retaining effects of insulin have been known for a long time11 the mechanisms involved and the site of insulin action both have been controversial matters.12 Several studies indicated that insulin may control sodium reabsorption along the whole nephron. The ability of insulin to increase sodium reabsorption in the proximal convoluted tubule has been established convincingly in in vitro studies.1314 In contrast, in vivo studies in animals failed to demonstrate increased proximal tubule sodium reabsorption during insulin antinatriuresis,1516 suggesting that the antinatriuretic effect of insulin is exerted predominantly in postproximal tubules.

    Feraille et al17 showed time and dose dependence of insulin action in rats on sodium reabsorption along the different nephron segments. Thus, although the collecting ducts were less sensitive, they displayed an earlier response to insulin than the proximal tubules. Furthermore, the threshold concentrations of insulin on sodium reabsorption were found to lie in the proximal tubule and thick ascending limb within the fasting range, whereas it was within the range of postprandial stimulated plasma insulin concentrations in the collecting tubules. The above could in part explain our findings of an antinatriuretic effect of insulin distal to the proximal tubules. Finally, previous studies conducted in humans indicated that exogenous insulin increases sodium reabsorption despite either no changes or a slight decrease in proximal sodium reabsorption, again supporting a postproximal tubule site for insulin action.561819

    Although specific insulin-binding sites were demonstrated along the entire nephron the number of insulin binding sites and affinity constants varied significantly among different nephron segments, with the greatest number of insulin binding sites of high affinity found in proximal and distal convoluted tubule segments.20 Our present and past findings3 further support previous contentions2122 that insulin resistance associated with essential hypertension is relatively selective for glucose metabolism in certain target tissues and that hyperinsulinemia may result in increased insulin effects in areas where insulin sensitivity is preserved such as the renal tubule.

    Mean insulin levels and mean IAUC after an intravenous glucose challenge in the F+ included in the present study were similar to those of the F− at variance with our previous findings.3 This is explained by the fact that obese children were included in both groups because we were presently interested only in the role of endogenous insulin on sodium handling.

    FeLi has been shown to accurately reflect proximal tubule sodium reabsorption in sodium-replete humans.23 The increased renal proximal sodium reabsorption found in offspring of hypertensive parents was related to the family history of hypertension and was independent of the BMI.

    Renal blood flow has been shown to be lower and filtration fraction and renal vascular resistance higher in children of hypertensive parents at such an early age as 11 years old compared with children of normotensive parents.24 A rise in filtration fraction increases peritubular capillary oncotic pressure because more ultrafiltrate is formed and plasma proteins become more concentrated, thus enhancing the uptake of sodium and water.25

    A diminished FeLi reflecting an increased renal proximal sodium reabsorption in these high-risk adolescents may indicate a physiological adaptive mechanism to the hemodynamic changes described in this population. An increased activity of the sympathetic nervous system26 and/or the renin-angiotensin system27 also could account for the increased proximal sodium reabsorption.

    In summary normotensive adolescent offspring of hypertensive parents have an increased renal proximal sodium reabsorption that is not related to endogenous insulin levels. However, FeNa diminished after the insulin response to the intravenous glucose load. Therefore, our findings under physiological conditions in humans show that one possible role of insulin in the development of hypertension may be exerted through an antinatriuretic effect distal to the proximal tubule.

    Selected Abbreviations and Acronyms

    BMI=body mass index
    F+=normotensive adolescents with a family history of essential hypertension
    F−=normotensive (control) adolescents without a family history of hypertension
    FeLi=fractional excretion of lithium
    FeNa=fractional excretion of sodium
    IAUC=insulin area under the curve
    IVGTT=intravenous glucose tolerance test

    Figure 1.

    Figure 1. FeLi (FELi) before and after IVGTT in F+ and F−. *P<.02 F+ vs F− before IVGTT.

    Figure 2.

    Figure 2. Relation between FeLi (FELi) and IAUC.

    Figure 3.

    Figure 3. FeNa before and after IVGTT in F+ and F−. *P<.01 vs before IVGTT.

    Figure 4.

    Figure 4. FeNa before and after IVGTT in F+ according to their IAUC. *P<.005.

    Table 1. Clinical Findings of Subjects Studied

    Age, yBMI, kg/m2Clcr, mL/minSBP, mm HgDBP, mm Hg
    F−15.2 ±0.927.1±1.8140±16122±5.076.4±2.4
    F+14.8±0.525.6±1.5123±7.5126±2.381.4 ±1.7

    Values are mean±SEM.

    Clcr indicates creatinine clearance; SBP, systolic blood pressure; and DBP, diastolic blood pressure.

    Table 2. Calculated Variables Both Before and After an IVGTT

    VariablesF−F+
    BeforeAfterBeforeAfter
    Urinary output, mL/min2.7±085.7±0.912.6 ±0.45.4±0.71
    Creatinine clearance, mL/min114 ±19124±10.6109.4±9.7108±8.6
    Sodium clearance, mL/min1.3±0.31.2±0.21±0.10.8±0.1
    FeNa, %0.99±0.10.85±0.110.99±0.10.77±0.11
    Lithium clearance, mL/min28.1±625.6±2.517.6 ±2.4216.1±2
    FeLi, %23.5±220.9±1.716.1 ±1.8214.7±1.3
    FeK, %10.7±1.510.7±1.511.2 ±1.512.6±2.1

    FeK indicates potassium fractional excretion. Values are mean±SEM.

    1P<.01 vs before IVGTT.

    2P<.02 vs F−.

    This work was supported by grant CONICET National Research Council for Science and Technology, Argentina PID 3340/92.

    Footnotes

    Correspondence to Beatriz Grunfeld, La Pampa 3635, Buenos Aires 1430, Argentina.

    References

    • 1 Ferrannini E, Buzzigoli R, Bonadona R, Giorico MA, Olegigini M, Graziadei L, Pedrinelli R, Brandi L, Bebvilaqua S. Insulin resistance in essential hypertension. N Engl J Med.1987; 317:350-357. CrossrefMedlineGoogle Scholar
    • 2 Shen D-C, Shei S-M, Fuh M-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. CrossrefMedlineGoogle Scholar
    • 3 Grunfeld B, Balzaretti M, Romo M, Gimenez M, Gutman R. Hyperinsulinemia in normotensive offspring of hypertensive parents. Hypertension. 1994;23(suppl I):I-12-I-15. Google Scholar
    • 4 Beatty OL, Harper R, Sheridan B, Atkinson AB, Bell PM. Insulin resistance in offspring of hypertensive parents. Br Med J.1993; 307:92-96. CrossrefMedlineGoogle Scholar
    • 5 DeFronzo RA, Cooke CR, Andres R, Falcone GR, Davis PJ. The effects of insulin on renal handling of sodium, potassium, calcium and phosphate in man. J Clin Invest.1975; 55:845-855. CrossrefMedlineGoogle Scholar
    • 6 Skott P, Hother-Nielsen O, Bruun EN, Giese J, Beck-Nielsen H, Parving HH. Effects of insulin on kidney function and sodium excretion in healthy subjects. Diabetologia.1989; 32:694-699. CrossrefMedlineGoogle Scholar
    • 7 Guyton AC, Langston JB, Navar G. Theory for renal autoregulation by feedback at the juxtaglomerular apparatus. Circ Res. 1964;14/15(suppl I):I-187-I-197. Google Scholar
    • 8 Luke RG. Essential hypertension: a renal disease? A review and update of the evidence. Hypertension.1993; 21:380-390. LinkGoogle Scholar
    • 9 Grunfeld B, Simsolo R, Romo M, Gimenez M. Na:Li countertransport in erythrocytes does not correlate with either increase renal proximal tubule reabsorption or decrease fractional uric acid excretion in normotensive children offspring of hypertensive parents. Am J Hypertens.1992; 5:67. Abstract. Google Scholar
    • 10 Burnier M, Biollaz J, Magnin JL, Bidlingmeyer M, Brunner HR. Renal sodium handling in patients with untreated hypertension and white coat hypertension. Hypertension.1993; 23:496-502. Google Scholar
    • 11 Miller JH, Bogdonoff MD. Antidiuresis associated with administration of insulin. J Appl Physiol.1953; 6:509-512. Google Scholar
    • 12 Gupta AK, Clark RV, Kirchner KA. Effects of insulin on renal sodium excretion. Hypertension. 1992;19(suppl I):I-78-I-82. Google Scholar
    • 13 Hammerman MR, Rogers S, Hansen VA, Gavin JR III. Insulin stimulates Pi transport in brush border vesicles from proximal tubular segments. Am J Physiol.1984; 247:E616-E624. MedlineGoogle Scholar
    • 14 Baum M. Insulin stimulates volume absorption in the rabbit proximal convoluted tubule. J Clin Invest.1987; 74:1104-1109. Google Scholar
    • 15 De Fronzo RA, Goldberg M, Agus ZS. The effects of glucose and insulin on renal electrolyte transport. J Clin Invest.1976; 58:83-90. CrossrefMedlineGoogle Scholar
    • 16 Kirchner KA. Insulin increases loop segment chloride reabsorption in the euglycemic rat. Am J Physiol.1988; 255:F1206-F1213. MedlineGoogle Scholar
    • 17 Feraille E, Marsy S, Cheval L, Barlet-Bac C, Khadouri C, Favre H, Doucet A. Sites of antinatriuretic action of insulin along rat nephron. Am J Physiol.1992; 263:F175-F179. MedlineGoogle Scholar
    • 18 Stevinkel P, Bolinder J, Alvestrand A. Effects of insulin on renal haemodynamics and the proximal and distal tubular sodium handling in healthy subjects. Diabetologia.1992; 35:1042-1048. CrossrefMedlineGoogle Scholar
    • 19 Abouchacra S, Baines AD, Zinman B, Skorecki KL, Logan AG. Insulin blunts the natriuretic action of atrial natriuretic peptide in hypertension. Hypertension. 1994;23(pt 2):1054-1058. Google Scholar
    • 20 Butlen D, Vadrot S, Roseau S, Morel F. Insulin receptors along the rat nephron: [125I] insulin binding in microdissected glomeruli and tubules. Pflugers Arch.1988; 412:604-612. CrossrefMedlineGoogle Scholar
    • 21 Rocchini AP, Katch V, Kveselis D, Moorehead C, Martin M, Lampman R, Gregory M. Insulin and renal sodium retention in obese adolescents. Hypertension.1989; 14:367-374. LinkGoogle Scholar
    • 22 Finch D, Davis G, Bower K, Kirchner K. Effect of insulin on renal sodium handling in hypertensive rats. Hypertension.1990; 15:514-519. LinkGoogle Scholar
    • 23 Koomans HA, Boer WH, Dorhont Mees EJ. Evaluation of lithium clearance as a marker of proximal tubule sodium handling. Kidney Int.1989; 36:2-12. CrossrefMedlineGoogle Scholar
    • 24 van Hooft IMS, Grobbee DE, Derkx FHM, De Leeuw PW, Schalekamp MADH, Hofman A. Renal hemodynamics and the renin-angiotensin-aldosterone system in normotensive subjects with hypertensive and normotensive parents. N Engl J Med.1991; 324:1305-1311. CrossrefMedlineGoogle Scholar
    • 25 Romero JC, Lahera V, Ruilope L. Role of nitric oxide on the intrarenal regulation of nephron function and its relevance to hypertension. In: Laragh JH, Brenner BM, eds. Hypertension: Pathophysiology, Diagnosis and Management. 2nd ed. New York, NY: Raven Press; 1995:1385-1404. Google Scholar
    • 26 Winternitz SR, Katholi RE, Oparil S. Role of the renal sympathetic nerves in the development and maintenance of hypertension in the spontaneously hypertensive rat. J Clin Invest.1980; 66:971-978. CrossrefMedlineGoogle Scholar
    • 27 Hall JE, Guyton AC, Smith MJ, Coleman TG. Blood pressure and renal function during chronic changes in sodium intake: role of angiotensin. Am J Physiol.1980; 239:F271-F280.MedlineGoogle Scholar
    Back to top