Insulin Effect on Renal Sodium Reabsorption in Adolescent Offspring of Essential Hypertensive Parents
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.1 2 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.3 4
It has been suggested that hyperinsulinemia could lead to hypertension by means of its known sodium-retaining effect, among other effects.5 6 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.9 10 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.
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.
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⇓).
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.13 14 In contrast, in vivo studies in animals failed to demonstrate increased proximal tubule sodium reabsorption during insulin antinatriuresis,15 16 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.5 6 18 19
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 contentions21 22 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|
This work was supported by grant CONICET National Research Council for Science and Technology, Argentina PID 3340/92.
- Received June 19, 1995.
- Revision received August 1, 1995.
- Accepted October 6, 1995.
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