Clinical and Investigative Medicine

 

Effects of insulin on renal function, sympathetic nervous activity and forearm blood flow in normal human subjects

Florence Wong, MD
Laurence Blendis, MD
Alexander Logan, MD

Clin Invest Med 1997;20(5):344-353

[résumé]

Drs. Wong and Blendis are with the Department of Medicine, The Toronto Hospital, and Dr. Logan is with the Samuel Lunenfeld Research Institute of Mount Sinai Hospital; all of the authors are with University of Toronto, Toronto, Ont.

(Original manuscript submitted May 17, 1996; received in revised form July 10, 1997; accepted July 16, 1997)

Reprint requests to: Dr. Florence Wong, 9EN/220, The Toronto Hospital, 200 Elizabeth St., Toronto ON M5G 2C4; fax 416 340-5019; florence.wong@utoronto.ca

Contents

Abstract

 Objective: To assess fully the vasodilatory and sodium-retaining effects of insulin.

Design: Prospective physiologic study using a dose­
response protocol.

Setting: Clinical investigation unit of a tertiary referral hospital.

Participants: Six normal, healthy men.

Interventions: Subjects were given increasing doses of insulin intravenously from 10 to 1200 mU/m2 per minute, using the euglycemic "clamp" technique.

Outcome measures: Urinary sodium excretion, systemic and renal hemodynamics, plasma norepinephrine levels and forearm blood flow after each dose.

Results: Low doses of insulin (up to 20 mU/m2 per minute) produced a significant antinatriuresis (0.18 [SEM 0.05] v. 0.37 mmol per minute at baseline, p < 0.01) and antidiuresis (2.53 [SEM 0.67] v. 6.21 [SEM 1.66] mL per minute, p < 0.01) with no associated changes in renal hemodynamics or sympathetic nervous activity. Subsequent higher doses of insulin improved urinary volume and sodium excretion to above baseline levels associated with renal and forearm vasodilatation, although mean arterial pressure remained unaltered.

Conclusions: Hyperinsulinemia initially causes an antinatriuresis and antidiuresis through a direct action on the renal tubule. The subsequent phenomenon of escape from renal sodium retention may serve as a regulatory mechanism on sodium homeostasis in conditions associated with hyperinsulinemia and sodium retention.

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Résumé

Objectif : Évaluer à fond les effets de l'insuline sur la vasodilatation et la rétention sodique.

Conception : Étude physiologique prospective fondée sur un protocole dose­réaction.

Contexte : Service d'études cliniques d'un hôpital tertiaire.

Participants : Six hommes normaux en bonne santé.

Interventions : On a administré aux sujets, par voie intraveineuse, des doses croissantes d'insuline qui sont passées de 10 à 1200 mU/m2 par minute. On a utilisé la technique du clamp hyperinsulinique euglycémique.

Mesures des résultas : Natriurèse, hémodynamique systémique et rénale, taux plasmatiques de norépinéphrine et débit sanguin dans l'avant bras après chaque dose.

Résultats : Des doses faibles d'insuline (jusqu'à 20 mU/m2 par minute) ont produit une antinatriurèse importante (0,18 [ETM 0,05] c. 0,37 mmol par minute à la ligne de base, p < 0,01) et une antidiurèse (2,53 [ETM 0,67] c. 6,21 [ETM 1,66] mL par minute, p < 0,01) sans changements connexes de l'hémodynamique rénale ou de l'activité du système nerveux sympathique. Des doses plus élevées d'insuline administrées par la suite ont amélioré le volume urinaire et l'excrétion de sodium pour les porter au-dessus des taux de base associés à la vasodilatation dans les reins et l'avant-bras, même si la tension artérielle moyenne n'a pas changé.

Conclusions : L'hyperinsulinémie provoque au début une antinatriurèse et une antidiurèse par une action directe sur le tubule rénal. Le phénomène subséquent que constitue la disparition de la rétention du sodium dans les reins peut servir de méthode de régulation de l'hémostase du sodium dans des conditions associées à l'hyperinsulinémie et à la rétention sodique.

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Introduction

 Hyperinsulinemia and insulin resistance have been observed in many conditions, including obesity,1 diabetes,2 essential hypertension3 and cirrhosis.4 Recent attention has focused on the physiologic and pharmacologic effects of insulin as researchers attempt to explain the possible link between insulin and the pathophysiologic characteristics observed in these conditions. Apart from its hypoglycemic and metabolic effects, insulin has many other physiologic actions. Although insulin has long been recognized to be antinatriuretic,5­8 the mechanisms responsible are still unclear. Its antinatriuretic effect may be due to a direct effect of insulin on stimulating renal tubular sodium reabsorption,5,8 or the result of sympathetic activation, leading to increased renal sodium reabsorption.9 The effects of insulin on sympathetic nervous activity (SNA) are still controversial. Increased SNA, independent of hypoglycemia, has been reported to be associated with hyperinsulinemia.10,11 However, there is also evidence against the hypothesis that hyperinsulinemia increases SNA in humans.6,12,13 The increased sodium retention associated with hyperinsulinemia has been implicated in the pathogenesis of essential hypertension14,15 and the volume expansion observed in diabetes.16 Insulin has also been shown to have a vasodilatory effect on the skeletal circulation, leading to an increase in skeletal blood flow17­19 without affecting the systemic circulation.20 Its effects on the renal circulation are less well documented, although recent literature suggests that insulin also increases renal plasma flow.8,21 Whether insulin induces a vasodilatory response in the renal circulation to the same extent as in the skeletal circulation is also unknown. Renal vasodilatation could influence the altered renal sodium-handling effect of insulin; however, this has not been formally studied.

The aim of this study was to clarify the mechanisms responsible for the antinatriuretic effects of insulin in normal subjects using the euglycemic technique. In particular, we examined the relative contributions of renal hemodynamic changes and sympathetic activation. The extent of the renal vasodilatation relative to the skeletal vasodilatation was also assessed. Most studies assessing the effects of insulin in health and in disease states have examined doses in the physiologic and low pharmacologic range with various administration times. Full dose­response studies on the effects of insulin are lacking. Therefore, we designed a dose­response study to assess fully the effects of insulin on sodium homeostasis.

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Methods

Subjects

Study subjects were 6 healthy, normal male volunteers between the ages of 39 to 52 years (mean 45 [SEM 2] years). None had a history of hypertension, cardiovascular or renal disease. Subjects were excluded if their body mass was more than 20% above the middle range for medium-frame individuals (1979 Build Study, Society of Actuaries and Association of Life Insurance Medical Directors of America, 1980). None had received any medications within 2 weeks of the study. All subjects were screened by a pre-entry blood pressure measurement after a 10-minute rest and by a urinalysis. Each subject was maintained on a diet including 150 mmol sodium per day for 7 days before the study. Compliance with this diet was ascertained by measurement of the 24-hour urinary sodium excretion on the 7th day. All subjects refrained from ingesting caffeine or alcohol and from smoking for 48 hours before the study. Approval for the study was granted by the Human Experimentation Committee of the University of Toronto. All patients gave written informed consent.

Study protocol

All subjects were admitted into the Clinical Investigation Unit of the Toronto Hospital on the morning of the study, which was performed while the subjects were in the postabsorptive state after an overnight fast. The study was performed without sedation with subjects resting in the supine position, except when they were required to void. Increasing doses of insulin were given using the euglycemic clamp technique. Their effects on systemic hemodynamics, glomerular filtration rate (GFR) and effective renal plasma flow (RPF) -- as measured by inulin and para-amino-hippurate (PAH) clearances, respectively -- urinary sodium excretion, plasma norepinephrine (PNE) levels and forearm blood flow (FBF) were assessed.

An intravenous catheter was introduced in the left antecubital vein for infusions of inulin and PAH. A second (21-gauge butterfly) catheter was placed in a retrograde fashion in the superficial vein of the same hand for sampling of arterialized blood. A slow infusion of normal saline solution was continued throughout the study to maintain the retrograde catheter. The left hand was kept in a warming blanket with the temperature kept at a constant level of 69°C to ensure arterialization of the venous blood.11,22 A third catheter was introduced in an antecubital vein of the right arm and advanced to the thorax for infusions of insulin, glucose and po-
tassium. This method was used to avoid painful phlebitis, which the large doses of potassium and 20% glucose solution may produce. The periodic occlusion of the right forearm should not have interfered with the infusions, since they were delivered by an infusion pump.

At the beginning of the study, urine and blood samples were collected as blanks for inulin and PAH clearance measurements. A priming infusion containing 25% inulin (60 mg/kg) and 20% PAH (8 mg/kg) was administered as a bolus. Thereafter, inulin and PAH were infused continuously at a rate calculated to maintain their respective plasma concentrations at 20 and 1.5 mg/dL. After a 60-minute equilibration period, baseline measurements, including FBF (see below), blood samples for levels of PNE, insulin, electrolytes, glucose and hematocrit were obtained. Inulin and PAH clearance studies then began. Accurately timed urine collections were obtained by spontaneous voiding for measurements of inulin, PAH and sodium. Blood was sampled at the end of each clearance period for levels of inulin, PAH, PNE, insulin, electrolytes and hematocrit. The first collection was a 30-minute period for baseline measurements of inulin and PAH clearances before the administration of insulin. Thereafter, the duration of the collection periods was determined by the dose of insulin administered. Forearm blood flow was measured at the end of each period before the administration of the next insulin dose. Blood pressure and pulse were monitored automatically (Dinamap, model 845XT; Critikon, Tampa, Fla.) at half-hourly intervals throughout the study.

Euglycemic clamp technique

Intravenous insulin was given with the serum glucose clamped at the level of euglycemia, determined on the basis of plasma from the arterialized sample.23 A bolus of insulin (Humulin R, 100 U/mL, Eli Lilly Pharmaceutical, Toronto) at 840 mU/m2 was given for the first 10 minutes followed by a continuous infusion of insulin. Insulin was initially infused at a rate of 10 mU/m2 per minute, and this rate was maintained for at least 180 minutes to fully express insulin's action.24 Thereafter, the insulin infusion rate was increased sequentially to 20, 40, 100, 300, 600 and 1200 mU/m2 per minute. The rate was maintained for at least 120 minutes (rates of 20 and 40 mU/m2 per minute), at least 90 minutes (rates of 100 and 300 mU/m2 per minute) and at least 40 minutes (rates of 600 and 1200 mU/m2 per minute). The insulin infusion rate was maintained long enough to establish steady state conditions before measurements were made. Since it takes longer to establish steady state conditions at the lower insulin infusion rates,24 these were maintained for longer periods than the higher infusion rates. A fall in the plasma glucose level was prevented by infusing 20% glucose solution at variable rates adjusted to arterialized venous plasma glucose measurements made at 5-minute intervals. Throughout the study, potassium phosphate was infused to prevent hypokalemia and hypophosphatemia.25

Forearm blood flow

FBF was measured by venous occlusion strain gauge plethysmography (D.E. Hokanson, Issaquah, Wash.), devised by Whitney26 and discussed by Greenfield and associates.27 Whitney strain gauges were applied approximately 5 cm distal to the antecubital crease. The right arm was elevated and supported so that the proximal part of the forearm was approximately 10 cm above the anterior chest wall. Circulation to the hand was interrupted by inflating a cuff wrapped around the wrist to 180 mm Hg. A second cuff was wrapped around the arm above the antecubital crease and intermittently inflated to 40 mm Hg. The sequential inflation and deflation of this cuff was timed to give 5 measurements of FBF each minute, and the average was used for statistical calculations. FBF is expressed as mL/100 mL of tissue per minute. Forearm volume was assessed by water displacement.

Calculations

Renal vascular resistance (RVR) for each clearance period was calculated according to the following equation.
RVR = [MAP × 80] ÷ renal blood flow, and renal blood flow = renal plasma flow ÷ (1 - hematocrit)
where MAP is mean arterial pressure.
Forearm vascular resistance (FVR) was calculated according to the following equation.
FVR = (MAP × 80) ÷ FBF
FVR is expressed as mm Hg/mL/100 mL of tissue per minute. In calculating resistances, a conversion factor of 80 was used to convert into SI units of dyne·sec·cm-5.

Laboratory analysis

Serum and urinary electrolyte concentrations were determined by standard techniques. Plasma glucose levels were measured by the glucose oxidase method (Beckman Glucose Analyzer II, Beckman Instruments, Fullerton, Calif.). Blood samples for insulin and PNE determinations were collected in ice. All samples were centrifuged with minimal delay at 4°C and the supernatant frozen at -70°C until assay. Immunoreactive insulin was determined using the method of Livesey and associates.28 Plasma NE concentrations were determined using high performance liquid chromatography as described by Eriksson and Persson29 and by Weicker and colleagues with modifications as previously described.30 Plasma and urinary inulin and PAH were estimated by chemical analyses using the modifications of Wasler and associates31 (for inulin) and of Brun32 (for PAH). All samples belonging to the same subject for each parameter were batched and always assayed in the same run.

Statistical analysis

Differences over time for each parameter were assessed by repeated-measures analysis of variance (ANOVA). Dunnett's test was used to determine the statistical significance of differences between the control value and the repeated measurements. A p value of less than 0.05 was considered statistically significant.

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Results

All study subjects complied with the required dietary sodium intake. The mean 24-hour urinary sodium excretion (UNaV) on the day before the study was 148 (SEM 12) mmol.

Glucose use and insulin sensitivity

The baseline and steady state insulin concentrations for each insulin infusion are given in Table 1. The serum glucose level was clamped at 5.3 (SEM 0.2) mmol/L and the serum potassium level kept above 3.5 mmol/L throughout the study. Insulin sensitivity, expressed as M values, and glucose use, expressed in grams, are given in Table 2. The total amount of glucose infused during the study was mean 1103 (SEM 46) g.

Systemic and forearm vascular effects

Increasing doses of insulin had no significant effect on either MAP or heart rate (Table 1). The decrease in hematocrit was also not significant (0.40 [SEM 0.20] at baseline to 0.37 [SEM 0.20] at an insulin infusion rate of 1200 mU/m2 per minute, p > 0.05). Baseline FBF was 2.43 (SEM 0.37) mL per minute per 100 mL of tissue and baseline FVR was 43.44 (SEM 8.33) mm Hg/mL per minute per 100 mL of tissue. FBF increased and FVR decreased with insulin administration, and these changes were statistically significant with infusions of insulin at a rate greater than 100 mU/m2 per minute (3.95 [SEM 0.48] mL per minute per 100 mL of tissue for FBF, p < 0.01, and 25.08 [SEM 3.25] mm Hg/mL per minute per 100 mL of tissue for FVR, p < 0.05) (Fig. 1). Once a significant difference was reached, further increases in the insulin infusion rate did not result in further changes in FBF or FVR (Fig. 1).

Renal hemodynamics and sodium handling

Insulin produced a significant antinatriuresis and antidiuresis, which was most obvious at infusion rates of 10 and 20 mU/m2 per minute (Fig. 2). Urinary volume fell from a baseline of 6.21 mL per minute to 2.53 mL per minute at the insulin dose of 20 mU/m2 per minute (p < 0.01). Likewise, UNaV fell from a baseline of 0.37 (SEM 0.11) mmol per minute to 0.18 (SEM 0.05) mmol per minute at the insulin dose of 20 mU/m2 per minute (p < 0.01). However, at insulin doses of 40 mU/m2 per minute or greater, the natriuresis and antidiuresis were abolished, with UNaV and urinary volume returning to baseline levels (Fig. 2). Renal hemodynamics remained unchanged at doses that produced sodium and water retention. However, at doses of 40 mU/m2 per minute or greater there was a definite and significant decrease in RVR, from a baseline value of 10 558 (SEM 1175) dyne·sec·cm-5 to 6993 (SEM 722) dyne·sec·cm-5 (p < 0.05). Higher doses of insulin yielded further sequential decreases in RVR, reaching 4641 (SEM 554) dyne·sec·cm-5 at the highest dose of insulin given (p < 0.01). Similarly, there was a significant increase in RPF from the same dose. GFR, however, fluctuated with increasing insulin infusion rates, with an overall trend toward an increase in GFR at increasing doses of insulin; however, this trend did not reach significant levels (Fig. 3).

Individual dose­response curves for RBF and RVR were analysed and median effective doses (ED50s) determined. These were compared to ED50s for FBF and FVR (Fig. 4).

Effects on the sympathetic nervous system

Insulin produced no significant effects on the sympathetic nervous system as measured by PNE levels (Table 1).

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Discussion

This study confirms that, at physiologic doses, insulin is antinatriuretic and antidiuretic in normal, healthy subjects. However, the sodium- and water-retaining effects are abolished at pharmacologic doses of insulin, a result that has not previously been reported. Insulin exerts a vasodilatation effect on both the renal and skeletal circulations, but at doses much higher than those that produce antinatriuresis and antidiuresis.

The antinatriuretic effect of insulin is well documented6,22,33 and is thought to be due to increased tubular reabsorption of sodium rather than altered renal hemodynamics.8,33 Indeed, sodium retention associated with hyperinsulinemia has been reported in the presence of unaltered GFR, and our results agree with previous observations in this regard.8,33 Sodium retention occurred in our study subjects at doses of insulin that did not produce any changes in renal hemodynamics. The exact mechanism by which insulin stimulates increased tubular sodium reabsorption is less well defined. Both the proximal34 and distal renal tubules5,8,35 have been reported to be involved. However, insulin may exert its antinatriuretic effects via some other sodium-regulating systems such as the renin-angiotensin system, since plasma renin activity has been reported to show a dose-dependent increase with hyperinsulinemia.6 However, the co-administration of captopril did not abolish the sodium retention induced by insulin in a rat model of hyperinsulinemia.7 Insulin has also been reported to increase sympathetic nervous activity independent of hypoglycemia by its direct action on the central nervous system,36 measured either by PNE levels11 or by skeletal muscle microneurography.17 The increased sympathetic nervous activity then exerts a sodium-
retaining effect on the proximal renal tubule. We did not detect any appreciable increase in plasma NE levels or change in heart rate in our subjects, suggesting that the sodium retention was not mediated by an increase in sympathetic nervous activity. Indeed, failure of the PNE levels to increase with hyperinsulinemia has been previously reported.6,12,13,18 PNE levels represent only the total SNA, and a normal PNE level does not rule out selective increase in renal SNA as a cause of insulin-induced sodium retention. However, a recent study in normotensive and spontaneously hypertensive rats demonstrated no increase in renal SNA with hyperinsulinemia,37 suggesting that the antinatriuresis associated with hyperinsulinemia is due to factors other than an increase in renal SNA. Furthermore, a recent report documented an increase in PNE levels in subjects given infusions with either insulin and glucose or normal saline solution, which suggests that, in the studies reporting increased SNA with hyperinsulinemia, aspects of the procedure itself (such as discomfort from intravenous cannulas and from the use of a heating pad) could have caused the increased PNE levels.38 However, the normal PNE levels in our study, which used similar techniques, do not support this contention. Sympathetic nervous activation associated with hyperinsulinemia is therefore still controversial.

The sodium retention associated with hyperinsulinemia was abolished at pharmacologic doses of insulin; this effect may be due to down-regulation of insulin receptors. However, usually only about 5% of insulin receptors are occupied.39 Therefore, a reduced number of receptors should not result in a complete reversal of effects, but only a shift of the insulin dose response curve to the right. Furthermore, chronic and moderate elevations in insulin levels in conditions such as hypertension cannot lead to a habitual state of sodium retention and extracellular volume expansion; otherwise, these patients would become waterlogged. Therefore, some built-in counter-regulatory mechanism must reset the natriuretic threshold and eventually return the patient to sodium balance. Previous studies that confirmed the antinatriuretic effects of insulin used physiologic doses.5­8 This is the first study that has demonstrated the normalization of sodium retention at higher doses of insulin. We postulate that this is an indirect effect via an increase in RPF associated with higher doses of insulin, counteracting the direct sodium-retaining effect. Increased RPF, independent of changes in GFR, perturbs the balance of hydrostatic and oncotic pressures in the peritubular capillary network, leading to changes in interstitial pressure, thus favouring a fall in proximal tubular reabsorption of sodium.40,41

The divergent effects of different doses of insulin on the renal tubules and the renal vasculature suggest differential sensitivity of these structures to the sodium-retaining effects and vasodilatory effects of insulin. Alternatively, differences in tissue kinetics may explain why sodium retention occurred at physiologic doses while renal vasodilatation occurred at pharmacologic doses of insulin.

The ability of the kidneys to escape from the sodium-retaining effects may have physiologic significance. Many disease states, such as obesity, hypertension, diabetes and cirrhosis, are associated with hyperinsulinemia and insulin resistance. These conditions are also associated with sodium retention and overall volume expansion. The phenomenon of escape from the continuing sodium-retaining effects of increasing hyperinsulinemia may serve as a counter-regulatory mechanism to prevent excessive volume expansion, together with its many complications, as the disease progresses.

The increase in RPF was most likely due to a direct vasodilatory effect of insulin on the renal circulation. Such an effect has been reported in humans8 and animals.42 Furthermore, insulin has been demonstrated to attenuate the vasoconstrictive effects of angiotensin II in the isolated rat kidney, further confirming its vasodilatory action.43 Stenvinkel, Bolinder and Alvestrand8 observed a significant renal vasodilatation at an insulin dose of 40 mU/m2 per minute. We have now demonstrated that there is a dose-dependent renal vasodilatation associated with insulin. Indeed, RVR began to fall significantly at an insulin dose of 40 mU/m2 per minute and a serum insulin level of 451 (SEM 25) pmol/L. This significant decrease in RVR continued at higher doses of insulin, so much so that the RVR at an insulin dose of 1200 mU/m2 per minute was less than half of that
at baseline. Renal plasma flow, likewise, increased significantly and, at the highest dose given, reached almost twice the baseline value. The renal vasodilatation was unlikely to be due to a compensatory response to the volume of glucose infused to maintain euglycemia, since the hematocrit did not change significantly throughout the study.

The insulin-induced vasodilatation was not confined to the renal circulation. The forearm circulation also demonstrated significant vasodilatation at pharmacologic doses of insulin. Although the final extent of vasodilatation was similar in both vascular beds, the ED50 for the renal circulation was significantly less than that for the forearm circulation, once again suggesting either differential sensitivities of different tissues to insulin or differences in kinetics of insulin distribution in the 2 tissues. Differential response between the 2 vascular beds to the same stimulus has been reported in control subjects and in patients with cirrhosis, who also retain sodium.44 These differential responses may be necessary to fulfil physiologic requirements. We propose that, in this study, renal vasodilatation sufficient to produce antinatriuresis was physiologically more important than forearm vasodilatation to achieve increased glucose delivery in the resting state. The mean arterial blood pressure, however, did not change throughout the study. This absence of effects of insulin on the systemic vascular resistance is well documented,8,12,20 and, indeed, the sodium retention in the absence of significant reduction in systemic vascular resistance associated with hyperinsulinemia has been postulated as a pathogenic process leading to systemic hypertension.45

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Conclusion

In normal human subjects, insulin in normal physiologic doses is antinatriuretic and antidiuretic, most likely due to a direct effect of insulin on the renal tubule rather than to changes in renal hemodynamics or activation of the sympathetic nervous system. However, these effects are abolished at higher doses of insulin, mainly due to the vasodilatory effects of insulin on the renal vasculature, suggesting that there is an in-built physiologic regulatory mechanism on sodium homeostasis, which may be useful in conditions associated with hyperinsulinemia.

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Acknowledgements

 We wish to thank Ms. Julie Dionne for her expert technical assistance and Mrs. Nancy Law, nurse manager, and the dietetic staff of the Clinical Investigation Unit at The Toronto Hospital for their generous support.

This study was supported by grant-in-aid to Dr. Logan from the Heart and Stroke Foundation of Ontario (T1999) and a research grant from the Clinical Investigation Unit of The Toronto Hospital.

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| CIM: October 1997 / MCE : octobre 1997 |
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