Hemodynamics and Vascular Regulation

Insulin Induces Renal Vasodilation, Increases Plasma Renin Activity, and Sensitizes the Renal Vasculature to Angiotensin Receptor Blockade in Healthy Subjects

Todd S. Perlstein, Marie Gerhard-Herman, Norman K. Hollenberg, Gordon H. Williams and Abraham Thomas
JASN March 2007, 18 (3) 944-951; DOI: https://doi.org/10.1681/ASN.2006091026

Abstract

Insulin stimulates the renin-angiotensin system and induces renal vasodilation. The relationship between these opposing influences of insulin on renal vascular tone has not been explored. A hyperinsulinemic euglycemic clamp and sham insulin clamp each of 270 min duration were performed in 15 healthy individuals during high sodium balance. An angiotensin receptor blocker was administered at time 180 min. Renal plasma flow and plasma renin activity were measured serially. The response to insulin or sham insulin infusion was defined as the change from time 0 to 180 min; the response to angiotensin receptor blockade (ARB) was defined as the change from time 180 to 270 min. Insulin infusion increased plasma renin activity (P < 0.01) and renal plasma flow (P < 0.01); the latter effect plateaued by time 150 min. ARB caused a greater vasodilator response during insulin infusion compared with during sham insulin infusion (P = 0.02). Increasing renin response to insulin predicted blunting of the renal vasodilator response to insulin infusion (R2 = 0.36, P = 0.02) and sensitizing of the renal vasodilator response to ARB during insulin infusion (R2 = 0.59, P < 0.01). Insulin-induced activation of the renin-angiotensin system modulates insulin-induced renal vasodilation in healthy individuals. Further studies are warranted to address this balance in states of insulin resistance and the possible implications for the association of insulin resistance with risk for chronic kidney disease.

The success of blockade of the renin-angiotensin system (RAS) in improving the natural history of diabetic nephropathy (1) suggests that hyperglycemia-mediated activation of the RAS has an important role in the pathogenesis of diabetic kidney disease. It is interesting that renal structural features that are characteristic of diabetic nephropathy precede the appearance of overt diabetes, indicating that renal injury begins in the prediabetic phase (2). A cardinal feature of the prediabetic phase is insulin resistance and consequent hyperinsulinemia (3), raising the possibility that hyperinsulinemia itself may activate mechanisms of renal injury.

A growing body of experimental evidence suggests that insulin activates the RAS (4–8). Acute hyperinsulinemia increases plasma renin activity and plasma level of the potent renal vasoconstrictor angiotensin II (9–11). In seeming contradiction, acute hyperinsulinemia also induces nitric oxide (NO)-dependent renal vasodilation (12). The effect of insulin to stimulate both the RAS and NO in the renal vasculature is of particular interest given the key role of RAS/NO balance in renal physiology and pathophysiology (13) and the accumulating evidence that insulin resistance and hyperinsulinemia are risk factors for chronic kidney disease (14–16).

We sought to examine the relationship between insulin-induced renal vasodilation and insulin-induced activation of the RAS. We performed the hyperinsulinemic euglycemic clamp technique in healthy volunteers and compared the renal vasodilator response to angiotensin receptor blockade (ARB) during hyperinsulinemia with the response on a control study day. Renal vascular responsiveness to interruption of the RAS is increased in states of activation of the RAS, such as low sodium compared with high sodium balance (17), and has been used to demonstrate hyperglycemia-induced activation of the RAS (18–20). We examined the relationships between insulin-induced renal vasodilation, insulin-induced renin secretion, and insulin-induced sensitization of the renal vasculature to ARB. Our findings suggest that insulin simultaneously stimulates vasoconstrictor and vasodilator mechanisms in the human kidney and that insulin-induced RAS activation modulates the renal vasodilator effect of insulin.

Materials and Methods

Participants

Fifteen healthy volunteers (nine men and six women) participated in this study. Exclusion criteria were the presence of any chronic medical or psychiatric disorder, smoking, heavy alcohol use, overweight (body mass index [BMI] ≥25 kg/m2), the use of any medications including oral contraceptives, and the presence of hypertension or diabetes in any first-degree relative before the age of 55 yr. The mean age of the participants was 26 ± 0.8 yr, and the mean BMI was 22 ± 0.7 kg/m2. Baseline characteristics on the two study days were similar (Table 1). In particular, 24-h urinary sodium excretion, plasma renin activity, and baseline renal plasma flow were not different on the two study days. Informed consent was obtained from all participants. The studies were in accordance with guidelines and regulations of the institutional review board of the Brigham and Women’s Hospital.

View this table:
Table 1.

Baseline characteristics of the 15 participantsa

Protocol

Participants underwent two study days, a hyperinsulinemic euglycemic clamp study day and a control study day, during which sham insulin (and no dextrose) was infused (Figure 1). On the basis of previous data that the renal vasodilator response to insulin infusion in insulin-sensitive individuals plateaus before time 180 min (21), the insulin clamp was performed for 180 min before ARB administration. We believed that demonstrating the plateau of the renal vasodilator response to insulin before time 180 min would allow us to conclude that subsequent vasodilation after ARB administration was attributable to the ARB and not to an ongoing insulin effect. Given these considerations, we did not perform an additional study day of insulin alone for 270 min without ARB administration. The two study days were separated by at least 4 d and occurred in random order. Participants were blinded to the study day order. Five days before each study day, participants supplemented their usual diet with 144 mmol/d sodium. For 3 d before each admission, participants were asked to consume 200 to 300 g/d carbohydrate. Participants were admitted overnight to the General Clinical Research Center before each study day. A 24-h urine collection was obtained at the time of admission; studies were not performed unless the urinary sodium excretion was ≥180 mmol/24 h. Participants remained fasting and supine beginning at 10 p.m. until the end of the study. Studies were performed during high-salt diet balance and in the supine position to suppress the RAS. It is easier to demonstrate activation of the RAS under conditions of high salt balance (22,23).

Figure 1.
Figure 1.

Fifteen participants underwent a 270-min hyperinsulinemic euglycemic clamp and a sham insulin clamp on separate days. Angiotensin receptor blockade (ARB) was administered at time 180 min. Responses to hyperinsulinemia were calculated as the value at time 0 min subtracted from the value at time 180 min. Responses to ARB were calculated as the value at time 180 min subtracted from the value at time 270 min.

A hand or wrist vein was cannulated in one arm for blood sample drawing; the hand of this arm was placed in a “hot box” (150°F) for arterialization of the blood samples. An antecubital vein was cannulated in the other arm for infusion. The total study time was 330 min (−60 to 270 min; Figure 1). Renal plasma flow (RPF) was calculated as para-aminohippuric acid (PAH) clearance using the constant infusion technique without urine collection (24,25). At approximately 8 a.m. (time −60 min), PAH was infused, with a loading dose (8 mg/kg) administered over 2 to 3 min, and followed by an infusion rate of 12 mg/min for the remainder of the study period. This infusion rate achieves plasma PAH concentrations in the middle of the range in which tubular secretion dominates excretion, and steady state is achieved by 45 min (26). At this plasma level of PAH, clearance is independent of plasma concentration and, when corrected for individual body surface area (BSA), represents approximately 90% of RPF. PAH clearance was calculated using the formula IR/P, where I is the concentration of PAH in the infusate (determined in each participant), R is the rate of delivery of the infusate, and P is the plasma concentration of PAH (24). RPF was normalized to a body surface area of 1.73 m2.

At time 0 min, either a 0.9% normal saline infusion (for the control study day) or an insulin infusion (80 mU/m2 per min BSA as a continuous infusion preceded by a loading dose of 800 mU m2 BSA given over 1 min) was started and continued until time 270 min. The plasma glucose was determined in duplicate at the bedside every 5 min beginning at −10 min. On the insulin clamp study day, a 20% dextrose infusion was begun at time 4 min at a rate of 4 mg/kg per min. The dextrose infusion rate was adjusted as necessary to maintain the plasma glucose at 90 mg/dl. During the control study day, no dextrose was administered. The mean plasma insulin level was significantly higher during the hyperinsulinemic clamp study day than the sham clamp study day (102 ± 2.1 versus 2.8 ± 0.4 μU/ml; P < 0.01). The mean plasma glucose during the two study days was not different (86.7 ± 1.7 versus 86.1 ± 1.5 mg/dl; P = 0.76). The mean M value (glucose clamp–derived index of insulin sensitivity) was 11.9 ± 0.3 mg/kg per min.

The ARB irbesartan was administered 150 mg orally at time 180 min on each study day. BP and heart rate were measured every 15 min beginning at time −60 min using an automated oscillometric device (Dinamap; Critikon, Norderstadt, Germany), then every 5 min beginning at time 180 min.

Laboratory Procedures

Plasma glucose concentration was determined in duplicate by the glucose oxidase method on a Beckman Glucose Analyzer II (Beckman Instruments, Fullerton, CA). Blood samples were collected on ice when appropriate and spun immediately, and the plasma was stored at −80°C until the time of assay. Urine sodium was measured by ion-selective electrodes using automatically diluted urine specimens (COBAS Integra 400; Roche Diagnostics Corp., Indianapolis, IN). Plasma renin activity (PRA) was determined by RIA (DiaSorin, Stillwater, MN). In the GammaCoat [125I] PRA RIA kit, the antibody is immobilized onto the lower inner wall of the Gamma Coat tube. The PRA determination involves an initial incubation of plasma to generate angiotensin I (AngI), followed by quantification of AngI by RIA. The generation of AngI in vitro depends on pH of the incubation, extent of plasma dilution, choice of enzyme inhibitors, length of incubation, and length of RIA incubation. Our method uses a 3-h RIA incubation and an 18-h incubation if values are low (<1 ng/ml per h). The sensitivity is 0.01 ng/ml per h, and the precision is <10%. Samples in which the PRA was below the lower detection limit of the assay were assigned a value of 0.01 ng/ml per h. The ultrasensitive insulin assay is a paramagnetic-particle, chemiluminescence immunoassay for the quantitative determination of insulin levels in human serum or plasma (EDTA), using the Access Immunoassay System (Beckman Coulter, Chaska, MN). The sensitivity is 0.03 IU/ml (0.21 pmol/L), and the precision is 3 to 5.6%. Other assays were as described previously (27).

Calculations

BMI was calculated as weight (in kilograms) divided by height (in square meters). BSA was calculated as BSA = square root {[body weight (kg) × height (cm)]/3600}. The M value was calculated for times 150 to 180 min (28). Responses to insulin infusion or to sham insulin infusion were calculated as the value at time 0 min subtracted from the value at time 180 min. Responses to ARB were calculated as the value at time 180 min subtracted from the value at time 270 min.

Statistical Analyses

The primary end point studied was the magnitude of change in RPF in response to irbesartan. Statistical differences in RPF responses on the two study days were assessed by the paired t test. Univariate linear regression tested the strength of association between continuous variables. All calculated P values are two tailed. The null hypothesis was rejected at P < 0.05. All data are expressed as means ± SE of measurement.

Results

RPF and PRA Responses to Insulin Infusion (Time 0 to 180 min)

Insulin induced a significant (P < 0.01) mean increase in RPF of 114 ± 15 ml/min per 1.73 m2, a mean increase of 15 ± 3% from baseline (Figure 2). During the insulin infusion, RPF at times 150 versus 180 min (P = 0.43) was not different. No change in RPF was attributable to the infusion of normal saline on the sham insulin clamp study day (P = 0.93). These data confirm that insulin is a renal vasodilator and that the effect plateaus at 150 min (21). PRA increased in response to insulin infusion (0.25 ± 0.05 versus 0.45 ± 0.08 ng/ml per h; P < 0.01) and tended to lessen during the sham insulin infusion (0.27 ± 0.07 versus 0.19 ± 0.05 ng/ml per h; P = 0.13).

Figure 2.
Figure 2.

Renal plasma flow (RPF) during the hyperinsulinemic clamp and sham clamp study days. Insulin increased RPF by 15 ± 3%. The vasodilator effect of insulin plateaued by 150 min. No change in RPF was attributable to the sham insulin infusion. ARB significantly increased RPF during hyperinsulinemia and on the control study day. The renal vasodilator response to ARB was significantly greater during hyperinsulinemia compared with the control study day.

RPF and PRA Responses to ARB (Time 180 to 270 min)

ARB induced a significant rise in RPF during both insulin infusion (738 ± 34 versus 852 ± 46 ml/min per 1.73 m2; P < 0.01) and sham insulin infusion (621 ± 34 versus 676 ± 42 ml/min per 1.73 m2; P < 0.01; Figure 2). The rise in RPF in response to ARB was greater during insulin infusion than during sham insulin infusion (115 ± 21 versus 55 ± 13 ml/min per 1.73 m2; P = 0.02). This is consistent with insulin’s increasing renal vascular AngII activity. PRA increased in response to ARB during insulin infusion (0.45 ± 0.08 versus 1.65 ± 0.64 ng/ml per h; P = 0.06) and during sham insulin infusion (0.19 ± 0.05 versus 0.31 ± 0.08 ng/ml per h; P < 0.01).

Relationships between Insulin-Induced Renin Secretion, Insulin-Induced Renal Vasodilation, and Insulin-Induced Sensitization of the Renal Vasculature to ARB

The rise in PRA in response to insulin infusion (time 0 to 180 min) was inversely related to the change in RPF in response to insulin infusion (time 0 to 180 min; R2 = 0.36, P = 0.02; Figure 3). This suggests that insulin-induced activation of the RAS modulates the renal vasodilator response to hyperinsulinemia. The change in PRA during insulin infusion (time 0 to 180 min) was positively associated with the subsequent change in RPF in response to ARB during insulin infusion (time 180 to 270 min; R2 = 0.59, P < 0.01; Figure 4). Increased systemic RAS activity therefore largely accounts for insulin-induced sensitization of the renal vasculature to ARB.

Figure 3.
Figure 3.

The greater the rise in plasma renin activity (PRA) during insulin infusion, the lesser the renal vasodilator response to insulin infusion.

Figure 4.
Figure 4.

The greater the rise in PRA in response to hyperinsulinemia, the greater the subsequent rise in RPF in response to ARB.

During the hyperinsulinemic clamp study day, the total renal vasodilator response to insulin and ARB was remarkably constant over 15 participants (36 ± 2%). Whereas the total vasodilator response was similar, the relative amounts by which insulin (time 0 to 180) or ARB (time 180 to 270) contributed to the total RPF response varied widely (Figure 5A). During the hyperinsulinemic clamp study day, a greater renin response to insulin (time 0 to 180) distinguished participants whose vasodilator response to ARB was greater than the vasodilator response to insulin (Figure 5B).

Figure 5.
Figure 5.

Relationships between the renal vasodilator response to insulin infusion, the renal vasodilator response to ARB during insulin infusion, and activation of the renin-angiotensin system (RAS) during insulin infusion. (A) Participants varied greatly in the relative vasodilator responses to ARB and hyperinsulinemia. The y axis is the change in RPF in response to ARB or hyperinsulinemia. On the x axis, participant responses are paired; participants are ordered by ARB response more than insulin response. Of the 15 participants, eight had an ARB response greater than the insulin response. (B) The PRA response to insulin was greater in participants whose vasodilator response to ARB was greater than the vasodilator response to insulin.

Systemic Hemodynamic and Serum Potassium Responses

The mean arterial pressure did not change during the course of the insulin infusion (Figure 6). The systolic BP increased in response to insulin infusion, whereas the diastolic BP decreased in response to ARB during insulin infusion (Figure 6). No arterial pressure parameter changed significantly during the sham insulin study day (data not shown). Insulin infusion induced a small but significant increase in heart rate (time 0 to 180 min; 60.0 ± 1.5 versus 62.5 ± 2.5 beats per minute; P = 0.04). No change in heart rate was attributable to sham insulin (time 0 to 180) or ARB (time 180 to 270). Serum potassium concentration decreased significantly in response to the insulin infusion (time 0 to 180 min; 3.74 ± 1.6 versus 3.55 ± 1.5 mEq/L; P = 0.01) and was not further changed by ARB (time 180 to 270 min). Serum potassium did not change during sham insulin infusion.

Figure 6.
Figure 6.

Arterial pressure and RPF during hyperinsulinemic clamp study day.

Discussion

We found that insulin simultaneously induces renal vasodilation and sensitizes the renal vasculature to ARB, the latter consistent with insulin-induced activation of the RAS. The net effect of insulin that we observed was vasodilation, indicating that in insulin-sensitive individuals, the vasodilator influence of insulin is greater than the vasoconstrictor influence of insulin on the renal vasculature. Because the renal vasodilator effect has been shown to be mediated by NO (12), these findings could be interpreted as indicating that on average, in insulin-sensitive individuals, the vasodilator effect of insulin-induced NO stimulation is greater than the vasoconstrictor effect of insulin-induced RAS activation on the renal vasculature.

The rise in renin in response to insulin infusion seems to predict the net effect of insulin on renal vascular tone: The greater the rise in PRA in response to insulin, the lesser the renal vasodilation in response to insulin; the greater the rise in PRA in response to insulin, the greater the insulin-induced response of the renal vasculature to ARB. The first of these findings suggests that insulin-mediated activation of the RAS counterbalances or modulates and is not in response to insulin-mediated renal vasodilation. The second of these findings suggests that insulin-induced activation of the systemic RAS results in increased renal vascular AngII activity.

PRA increased after administration of ARB during insulin infusion and during sham insulin infusion, consistent with interruption of “short feedback” by AngII (29). The rise in renin tended to be greater during insulin infusion, consistent with insulin-induced activation of the RAS. BP did not change significantly with ARB administration, suggesting that the rise in renin secretion was not in response to hemodynamic effects of ARB.

We found a net vasodilatory influence of insulin on the renal vasculature. This is in agreement with some (12,21,30) but not all (31,32) previous studies of the effect of insulin on renal vascular tone. The strict criteria by which we selected our participants were intended to maximize insulin sensitivity at baseline. Because the renal vasodilator effect of insulin is impaired in insulin resistance (21), less stringent participant selection criteria may have limited the ability of some studies to detect insulin-mediated renal vasodilation. Our data suggest that activation of the RAS counterbalances insulin-mediated renal vasodilation. To maximally suppress the RAS, we studied individuals who were on high sodium intake and remained supine beginning the night before the study until its completion. Studies that did not control for these elements may have allowed for greater RAS activation and therefore less observed insulin-mediated renal vasodilation. Despite stringent participant selection and control of sodium intake and posture, we found a widely variable renal vascular response to insulin, ranging from a 5 to 30% increase in RPF. This wide variability suggests that there are environmental or genetic determinants of the RPF response to hyperinsulinemia for which we are not able to account. This variability also suggests that previous studies of smaller sample size may have had limited ability to detect insulin-mediated vasodilation (31,32). We did not explore the mechanism of insulin-induced renal vasodilation; however, it has been established that it is largely dependent on NO (12). Accordingly, the magnitude of renal vasodilation that we observed is nearly identical to that observed when normotensive individuals received an infusion of the NO precursor l-arginine (33).

We did not include a third study day of insulin alone without ARB administration because we did not believe that it would change the outcome of the study. To ensure that an observed post-ARB vasodilation was not due to an ongoing insulin effect, we conducted the hyperinsulinemic clamp for 180 min before ARB administration, allowing us to confirm that the plateau of insulin-induced renal vasodilation is achieved before 180 min in insulin-sensitive individuals (21). The finding that the vasodilator response to ARB during insulin infusion was predicted by increased PRA makes an ongoing insulin effect even less likely, because PRA predicted blunting of the renal vasodilator response to insulin.

Additional limitations warrant consideration. Our study was of healthy white volunteers; care must be exercised in extending these results to other populations. Our study does not address the effect of chronic hyperinsulinemia or insulin resistance. The renal vasodilator response to ARB is only an indirect indication of renal vascular AngII activity; a direct assessment in healthy volunteers is not yet feasible.

There are several potential mechanisms by which hyperinsulinemia may have increased renin secretion. Hyperinsulinemia activates the sympathetic nervous system, and renal sympathetic nerve activity stimulates renin secretion (34,35). Insulin is a vasodilator; therefore, an insulin-mediated fall in renal perfusion pressure might decrease stretch of the afferent arteriole and stimulate renin secretion via a baroreceptor mechanism (36). However, because mean arterial pressure did not change during insulin infusion, the potential contribution of this mechanism seems to be small. Insulin stimulates proximal sodium resorption (37); therefore, decreased delivery of sodium chloride to the macula densa might stimulate renin secretion during insulin infusion (35).

The renal vasodilation and the sensitization to ARB during hyperinsulinemia that we observed may in part be due to the effects of glucose itself or glucose metabolism. Regarding the former, exposure to hyperglycemia alone is capable of stimulating the RAS (38), although the contribution of hyperglycemia per se is likely small given that euglycemia was carefully maintained throughout the study. Regarding the latter, there is physiologic coupling of changes in blood flow and changes in metabolism during insulin infusion (39). In addition, acute hyperglycemia activates the RAS in type 1 diabetes, a state in which compensatory hyperinsulinemia cannot occur (20). For these reasons, glucose itself or glucose metabolism may account in part for the observations that were made in this study.

Insulin-induced hypokalemia may also contribute to insulin-induced renin secretion (40), although the data supporting this are inconsistent. Trovati et al. (11) found that co-administration of potassium (despite which plasma potassium decreased 0.3 mEq/L) prevented the rise in renin in response to hyperinsulinemia. Skott et al. (37) observed a fall in plasma potassium with no change in PRA during hyperinsulinemic euglycemic clamp technique. Hyperglycemia (accompanied by reactive hyperinsulinemia) caused plasma potassium to decrease by 0.3 mEq/L without an increase in PRA (19), whereas in a study of oral glucose loading in healthy volunteers, a fall in plasma potassium of 0.3 mEq/L was accompanied by a doubling of PRA (40). The extent to which the drop in potassium of 0.2 mEq/L accounted for the rise in PRA in our study is therefore unclear. Similarly, data are conflicting as to whether acute hypokalemia is responsible for insulin-induced antinatriuresis (41,42).

Increasingly, evidence implicates insulin in activation of the RAS. Insulin induces upregulation of vascular AngII type 1 receptor gene expression in vascular smooth muscle cells (VSMC) by posttranscriptional mechanisms (5). Insulin stimulates VSMC angiotensinogen expression and production and stimulates AngII-dependent VSMC proliferation (43). Insulin-induced stimulation of VSMC AngII depends on mitogen-activated protein kinase signaling pathway (6), suggesting that this effect would be intact in states of insulin resistance (44). Insulin also increases angiotensinogen and AngII expression in human adipocytes (4). Angiotensin-converting enzyme inhibition or ARB can prevent and reverse insulin-induced hypertension in rats (8). As already described, acute hyperinsulinemia increases PRA and circulating AngII levels in healthy volunteers (9–11). We are not aware of previous human data addressing the effect of insulin-induced RAS activation on renal physiology.

It seems contradictory that insulin could induce renal vasodilation while increasing activity of the renal vasoconstrictor AngII. This was also observed in studies of acute hyperglycemia in healthy volunteers (19). It is interesting that in these studies of acute hyperglycemia, the level of hyperinsulinemia achieved in response to glucose infusion was similar to that achieved in our study, suggesting that the previously observed glucose-induced renal vasodilation or glucose-induced sensitization of the renal vasculature to ARB might have been due in part to reactive hyperinsulinemia. Also supporting the simultaneous presence of vasodilator and vasoconstrictor influences, patients with type 2 diabetes and the highest baseline RPF demonstrated the greatest renal vasodilator response to ARB (45). Collectively, these observations suggest that the forces that lead to renal vasodilation and renal vasoconstriction are linked (45). In this regard, our data are similar to the observations that insulin simultaneously stimulates insulin and endothelin in the human forearm (46) and that, in the presence of inhibitors of insulin-mediated vasodilation, insulin in fact stimulates vasoconstriction (47). The relative contributions of insulin in increasing NO and activating the RAS likely determine the net effect of insulin on renal physiology and pathophysiology (13).

This study was performed in insulin-sensitive individuals; therefore it does not provide direct insight into what the effects of acute hyperinsulinemia would be in individuals with insulin resistance. We speculate which of the observed effects might also be present in individuals with insulin resistance. With regard to insulin-induced vasodilation, ter Maaten et al. (21) showed that insulin-mediated renal vasodilation is impaired in insulin resistance. We are not aware that the renin-stimulating effect of insulin has been studied in insulin resistance. Ter Maaten et al. (48) also showed that insulin-stimulated renal sodium reabsorption is intact in insulin resistance; therefore, the macula densa mechanism of stimulating renin secretion might remain intact. Insulin-stimulated sympathetic nervous system activity is not impaired in insulin resistance per se (49); therefore, β1 adrenergic receptor stimulation might also be intact in insulin resistance. We postulate that if our experiment were repeated in individuals with insulin resistance, then insulin-mediated renal vasodilation would be impaired (21), whereas insulin-stimulated renin secretion would be relatively preserved. It follows that insulin-induced augmentation of the renal vasodilator response to ARB by insulin might also be preserved or even increased.

Conclusion

We found that acute hyperinsulinemia simultaneously causes renal vasodilation and activation of the RAS in healthy volunteers. The degree of RAS activation seems to modulate the renal vasodilator response to hyperinsulinemia and sensitize the renal vasculature to ARB. These data suggest that hyperinsulinemia-mediated activation of the RAS may contribute to the association of insulin resistance and hyperinsulinemia with risk for chronic kidney disease, and further studies to address this possibility are warranted.

Disclosures

None.

Acknowledgments

This research was supported by the following grants: National Institutes of Health (NIH) grants JL47651, JL59424, and DK63214; Specialized Center of Research in Hypertension from the National Heart, Lung, and Blood Institute (HL55000); and National Center for Research Resources (General Clinical Research Centers) in Boston (M01 RR 02635). T.S.P. was supported by NIH Training grant T32 HL007609 and NIH (National Heart, Lung, and Blood Institute) K30 grant HL04095. A.T. was supported by NIH grant K23 RR017394 from the National Center for Research Resources.

This work was presented as an abstract at the International Aldosterone Conference in Boston, MA; June 22 to 23, 2006.

We gratefully acknowledge the assistance of the dietary, nursing, administrative, and laboratory staff of the Brigham and Women's Hospital General Clinical Research Center.

Footnotes

  • Published online ahead of print. Publication date available at www.jasn.org.

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Insulin Induces Renal Vasodilation, Increases Plasma Renin Activity, and Sensitizes the Renal Vasculature to Angiotensin Receptor Blockade in Healthy Subjects
Todd S. Perlstein, Marie Gerhard-Herman, Norman K. Hollenberg, Gordon H. Williams, Abraham Thomas
JASN Mar 2007, 18 (3) 944-951; DOI: 10.1681/ASN.2006091026
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