(Hypertension. 1998;31:104.)
© 1998 American Heart Association, Inc.
Scientific Contributions |
Acute Effects of Blood Pressure Elevation on Insulin Clearance in Normotensive Healthy Subjects
From the Clinical Pharmacology and Therapeutics Unit, University of Melbourne, Department of Medicine, Austin and Repatriation Medical Centre, Heidelberg, Australia.
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Abstract |
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Abstract—Reduced clearance of insulin from plasma contributes to the hyperinsulinemia associated with essential hypertension (EH); however, the association between impaired insulin clearance and EH remains unexplained. Whether elevated blood pressure (BP) affects insulin clearance is unknown; therefore, we used the hyperinsulinemic euglycemic clamp to determine the effects of BP elevation on insulin clearance and sensitivity in eight healthy volunteers. Placebo infusion increased mean BP by 2.6±1.6 mm Hg, which was significantly less than rises produced by phenylephrine, an
1-adrenoceptor agonist (+11±1.8 mm Hg,
P<.05), or by angiotensin II (+13±1.3
mm Hg, P<.01). Although ß-adrenoceptor stimulation
with isoproterenol did not change mean BP (+3.6 mm Hg,
P=NS), it significantly increased systolic
pressure (+23±2.8 mm Hg versus +2.3±4.6 mm Hg with
placebo P<.01). Insulin secretion (ie, C-peptide
concentrations) was not affected by any of the treatments; however,
phenylephrine significantly reduced the
metabolic clearance rate of insulin
(MCRinsulin) (16.6±1.0 mL/kg per minute with placebo
versus 13.6±0.7 mL/kg per minute with phenylephrine,
P<.01) and thereby increased plasma insulin
concentrations (66±5.1 µU/mL with placebo versus 79±4.1 µU/mL
with phenylephrine, P<.05).
Phenylephrine also increased glucose utilization
(42±5.8 µmol/kg per minute during placebo versus 58±4.8
µmol/kg per minute during phenylephrine,
P<.05); however, this was proportional to the increased
insulin concentrations; therefore, insulin sensitivity was unchanged.
MCRinsulin and plasma insulin concentrations were not
affected by angiotensin II; however, glucose utilization
increased to 51±2.7 µmol/kg per minute (P<.01
versus placebo), indicating insulin sensitivity was increased.
MCRinsulin was unaffected by isoproterenol. Thus,
-adrenergic stimulation but not increased BP per se is a potent
regulator of insulin clearance and plasma insulin concentrations.
Key Words: insulin • hypertension, essential • sympathetic nervous system • renin-angiotensin system • metabolism
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Introduction |
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Although EH is associated with impaired insulin-mediated glucose uptake (ie, insulin resistance), glucose homeostasis is maintained by elevation of plasma insulin concentrations.1 2 However, this shift in steady state is not without cost. In addition to its effects on glucose metabolism, insulin can also modify plasma lipid concentrations,3 renal electrolyte handling,4 sympathetic nervous system activity,5 and vascular smooth muscle cell growth.6 Given these actions, it is hardly surprising that hyperinsulinemia is an independent risk factor for the development of coronary and carotid atherosclerotic disease.7 8 Hence, in insulin-resistant states, euglycemia appears to be maintained at the expense of increased risk of cardiovascular disease.9
The plasma insulin concentration is ultimately determined by a balance between the rate of pancreatic beta cell secretion of insulin and the rate of insulin removal from plasma. Whether insulin secretion is increased in EH remains unclear; however, several studies have found that patients with EH have impaired ability to clear insulin from plasma.10 11 12 13 14 Insulin is predominantly cleared by metabolic degradation via a receptor-mediated process,15 16 and until lately it was thought that the defect in insulin clearance in EH may have been another manifestation of the primary defect responsible for impaired insulin-mediated glucose uptake. However, Lender et al14 have recently reported that the association between impaired insulin clearance and EH is independent of the effect of insulin on glucose metabolism.
Mechanisms of blood pressure regulation that have been linked to the
pathogenesis of EH include activation of the sympathetic nervous
system17 and/or the renin-angiotensin
system.18 In addition to modulating blood
pressure, both the sympathetic nervous system and the
renin-angiotensin system have metabolic actions
including effects on insulin sensitivity.19 20 21 22 23
Moreover, elevation of blood pressure with either
-adrenoceptor24 or angiotensin
receptor stimulation22 has increased insulin
concentrations during euglycemic
hyperinsulinemia. Thus, an alternative hypothesis
to explain the association between impaired insulin clearance and EH
could be that clearance of insulin is directly reduced by elevated
blood pressure or by mechanisms that increase blood pressure. In the
present study, we have measured the acute effects of -adrenergic
stimulation (with phenylephrine), ß-adrenergic
stimulation (with isoproterenol), and angiotensin receptor
stimulation (with Ang II) on insulin clearance in normotensive
nondiabetic subjects. In these experiments, drug doses were titrated
against changes in blood pressure and/or heart rate.
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Methods |
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Eight healthy male subjects (aged 23±0.8 years, BMI of 22.9±0.9 kg/m2 and resting blood pressure of 125±4.4/68±3.0 mm Hg) participated in this double-blind, placebo-controlled, random-order study. Each individual was studied on four separate days at 1- or 2-week intervals. All studies were preceded by a 12-hour fast and by abstinence from coffee, tea, and alcohol for 24 hours. Between the study days, the subjects maintained their usual daily routine and diets. The study protocol was approved by the Austin Hospital Ethics and Research Committee, and informed written consent was obtained from each patient.
The hyperinsulinemic euglycemic clamp was used to measure acute changes in MCR of insulin (MCRinsulin)22 25 and insulin sensitivity. On the patient’s arrival at the clinic, cannulas were inserted into veins in the cubital fossa of the right arm (and used for all infusions) and retrogradely into a left wrist vein (which was placed in a water bath heated to 42°C for sampling of arterialized blood). During the euglycemic clamp, blood pressure was continuously measured from the middle finger of the right hand using the Finapres device (Ohmeda) and each 10 minutes from the left arm (Dinamap, Critikon).
After measurement of baseline blood glucose concentrations (Reflolux S, Boehringer Mannheim BmbH), a primed constant infusion of insulin was given at 40 mU/m2 per minute (Actrapid, Novo Nordisk Pharmaceutical). While insulin was infused, blood glucose concentrations were measured each 5 minutes, and 20% glucose was infused to maintain euglycemia. The MCRinsulin and insulin sensitivity were measured for the first time in the period between 60 and 90 minutes after the insulin infusion was begun, and this period was defined as "pretreatment." Infusions of placebo (ie, saline), phenylephrine (160 ng · kg-1 · min-1), isoproterenol (1.25 ng · kg-1 · min-1) or Ang II (0.25 ng · kg-1 · min-1) commenced 90 minutes after the insulin infusion was begun. The infusion rates of the pressor agents were adjusted each 5 minutes until finger diastolic blood pressure had increased by 10 mm Hg, pulse rate had increased by 10 beats per minute, and/or 30 minutes had elapsed. Because phenylephrine caused pulse rate to fall in some subjects, the rate of phenylephrine infusion was decreased to the previous level if the pulse rate fell below 40 beats per minute. The next period, beginning 120 minutes after commencement of hyperinsulinemia and continuing until the end of the experiment, was defined as the "treatment" period and was 30 minutes in duration. In this period the infusion rates of the pressor agents were kept constant, and a second measurement of MCRinsulin and insulin sensitivity was made. Because it is recognized that steady state is never satisfactorily achieved using this experimental technique,26 the treatment period was extended for a further 30 minutes in a subgroup of subjects (n=5) to establish that changes in MCRinsulin and insulin sensitivity produced by the pressor agents were maintained.
Blood samples were taken each 5 minutes immediately before hyperinsulinemia was begun (n=3) and each 10 minutes from the 60th minute of hyperinsulinemia until completion of the experiment. The blood was kept on ice until the plasma was separated by centrifugation. The plasma was stored at -20°C until insulin and C-peptide concentrations were measured by radioimmunoassay (Phadeseph, Kabi Pharmacia, and Byk-Sangtec Diagnostica, respectively).
Calculations
C-peptide is cosecreted in equimolar concentrations with
insulin; therefore, plasma concentration of C-peptide was used as an
index of insulin secretion (IS).27 When insulin
secretion is suppressed, the MCRinsulin is equal
to the steady state plasma insulin concentration divided by the insulin
infusion rate.27 28 The IS index was calculated
by dividing the glucose infusion rate by the plasma insulin
concentration. All values obtained during the "baseline" period
(the 15 minutes preceding hyperinsulinemia), the
pretreatment period, and the first 30 minutes of the treatment period
were averaged for each subject. Values recorded during the second
30 minutes of the treatment period were also averaged, and these values
were compared with the first 30 minutes of the treatment period using
the paired t test (Table 1).
Since no significant differences were detected between the first and
second halves of the treatment period, all values recorded during
this time were averaged so as to obtain a single treatment value for
all subjects.
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Statistics
All data are presented as mean±SEM. The difference
between pretreatment and treatment values was taken as a measure of the
effects of treatment, and the paired sample t test (using
the Bonferroni correction) was used to make between-day comparisons of
placebo with phenylephrine, isoproterenol, and Ang II;
within-day comparisons were also made between pretreatment and
treatment values.
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Results |
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Blood Pressure and Pulse Rate
As expected, Finapres and Dinamap measurements of mean and diastolic blood pressures were similar. However, the finger systolic blood pressure includes a component of the reflected pulse wave29 ; therefore, Finapres systolic blood pressure tended to be higher than the Dinamap measurement. Despite these differences, the pattern of change in finger blood pressure during the treatments was similar to the concurrently recorded arm blood pressure pattern.
Blood pressure and pulse rate in the pretreatment period did not differ between the study days (Table 2). The infusions of the active agents rapidly increased blood pressure: within 15 minutes of commencement, the infusion rates were within ±1-dose increments of the final infusion rate in all subjects. The average infusion rates of phenylephrine, isoproterenol, and Ang II during the treatment period were 800±160, 11.9±1.8, and 5.6±1.1 ng · kg-1 · min-1, respectively. Mean and diastolic blood pressures were significantly increased by the phenylephrine and Ang II infusions (Table 1), and systolic blood pressure was increased by all treatments. Isoproterenol also increased the pulse rate, whereas phenylephrine infusion caused the pulse rate to fall. The target pulse rate or diastolic blood pressure was always reached during the isoproterenol and Ang II infusions; however, phenylephrine caused bradycardia in three subjects, which prevented further dose increments.
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Euglycemic Clamp Data
On the placebo day, the baseline blood glucose and plasma insulin
concentrations were 4.7±0.2 mmol/L and 7.4±0.7 µU/mL,
respectively, and these values did not differ from corresponding
baseline values recorded on the other days (ie, 4.5±0.1
mmol/L and 7.1±0.7 µU/mL with phenylephrine,
4.6±0.1 mmol/L and 6.8±0.7 µU/mL with isoproterenol, and
4.7±0.1 mmol/L and 8.3±1.7 µU/mL with Ang II). As expected,
infusion of insulin increased the pretreatment insulin concentrations
(to 66±5.2 µU/mL on the placebo day, 64±4.5 µU/mL prior to
phenylephrine, 64±4.1 µU/mL prior to isoproterenol, and
63±5.3 µU/mL prior to Ang II); however, blood glucose concentrations
remained similar to the baseline concentrations (ie, 4.8±0.2
mmol/L with placebo, 4.6±0.2 mmol/L with phenylephrine,
4.5±0.1 mmol/L with isoproterenol, and 4.6±0.1 mmol/L with Ang II).
In comparison to fasting concentrations of C-peptide (ie, 435±138
pmol/L), pretreatment–C-peptide values were low, consistent
with suppressed insulin secretion,30 and did not
differ between the study days (Fig 1).
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P<.05 compared with pretreatment.Administration of placebo during the treatment period did not affect glucose, insulin, or C-peptide concentrations (Fig 1). In contrast, phenylephrine infusion increased plasma insulin concentrations (by 24%, P<.01 compared with placebo); however, this was not explained by increased secretion of insulin because there was no change in plasma C-peptide (Fig 1). Thus, compared with placebo, phenylephrine infusion significantly reduced the MCRinsulin (Table 3). Consistent with the rise in plasma insulin concentrations, phenylephrine infusion also increased the rate of glucose utilization (by 30%, P<.05 compared with placebo; Fig 1); however, the increase in glucose utilization was approximately proportional to the increase in the plasma insulin concentration, thus the insulin sensitivity index was unchanged (Fig 1).
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Infusion of Ang II did not significantly affect plasma insulin or C-peptide concentrations; hence the MCRinsulin was unchanged (Table 3). Although plasma insulin concentrations remained stable, the rate of glucose utilization increased by 37% (P<.01 compared with placebo). Therefore, Ang II infusion apparently increased insulin sensitivity (Fig 1).
Despite having significant effects on blood pressure and pulse rate, isoproterenol infusion did not affect any of the euglycemic clamp variables (Fig 1). Although C-peptide concentrations appeared to increase, this rise was not statistically significant (P=.34) and was only from 66±13 pmol/L to 95±24 pmol/L, which is very small in absolute terms, ie, fasting C-peptide concentrations in our subjects were 435±138 pmol/L, and C-peptide concentration may increase to over 2500 pmol/L following oral glucose ingestion.27 Therefore, these data indicate that ß-adrenergic stimulation did not change insulin secretion or the MCRinsulin.
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Discussion |
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Insulin Clearance
To investigate the association between EH and abnormalities in insulin and glucose metabolism, we used the hyperinsulinemic euglycemic clamp to measure the acute effects of
-adrenoceptor, ß-adrenoceptor, and
angiotensin receptor stimulation on insulin clearance. In
this technique, steady state hyperinsulinemia is
achieved by infusing insulin at a constant rate, and hypoglycemia is
prevented by infusing glucose. This method does not allow the precise
quantification of endogenous secretion of insulin unless an
exorbitant period is allowed for plasma C-peptide concentrations to
reach steady state (ie, the plasma half-life of C-peptide is 40
minutes).28 30 However, C-peptide concentrations
observed in the present study did confirm that
endogenous insulin secretion was practically negligible
during the pretreatment period30 and was not
increased by any of the treatments that we used. Therefore, under these
conditions the MCRinsulin was equal to the steady
state plasma insulin concentration divided by the insulin infusion
rate.27 28
The particularly novel finding of this study was that
phenylephrine, a selective
1-adrenoceptor agonist, increased plasma
insulin concentrations by 24%. However, since
phenylephrine did not affect insulin secretion, the rise in
plasma insulin concentrations must have been caused by reduced
clearance of insulin from plasma. This observation is corroborated by
and apparently explains the finding of Lager et
al,24 who observed a 25% increase in plasma
insulin concentrations when propranolol was used to unmask
the -adrenoceptor stimulating properties of epinephrine
during euglycemic hyperinsulinemia. In
the present study, the decrease in the
MCRinsulin during phenylephrine
infusion was substantial (ie, -20%) and was produced by a dose that
increased mean blood pressure by only 9.4 mm Hg more than
placebo. Thus, it appears that the MCRinsulin
(and consequently plasma insulin concentrations) is very sensitive to
acute changes in -adrenergic activity.
In previous studies, ß-adrenergic stimulation has not modified
insulin concentrations during euglycemic
hyperinsulinemia.19 24
Outwardly, this implies that insulin clearance has not changed;
however, under some conditions, ß-adrenergic stimulation increases
endogenous insulin secretion.31
Therefore, accurate measurement of the MCRinsulin
during ß-adrenergic stimulation required the simultaneous
measurement of insulin secretion. In the present study, we
found that infusion of isoproterenol, a nonspecific ß-agonist, did
not modify either insulin secretion or the
MCRinsulin. Since infusion of epinephrine
(a ß-adrenergic stimulant with weaker -adrenoceptor stimulating
properties) also does not modify insulin
clearance,19 24 our data suggest that the
metabolic effects of epinephrine are
consistent with the reported predominance of ß-adrenoceptor
stimulation at the doses used in those
studies.24
Insulin clearance was also unaffected by Ang II at a dose that increased diastolic blood pressure to 89 mm Hg. In contrast, Buchanan et al22 reported that higher doses of Ang II (ie, 20 ng · kg-1 · min-1 compared with the 5.6 ng · kg-1 · min-1 used in the present study) substantially increased plasma insulin concentrations during hyperinsulinemia. C-peptide concentrations were not measured in the Buchanan study; therefore, it remains unclear whether the effects of high-dose Ang II on insulin concentrations are due to reduced insulin clearance or increased insulin secretion. Regardless of how those very high doses modified insulin concentrations, it appears that this effect of Ang II is not produced by the more moderate doses that were used in the present study.
Mechanism of the Effect of Phenylephrine
These studies were not designed to test how insulin clearance was
altered; therefore, we can only speculate on the mechanism of these
changes. Because infused insulin is efficiently extracted from plasma
by the liver (
50%) and the kidneys
(30%),32 insulin clearance is probably
regulated by organ blood flow.33 -Adrenergic
stimulation has decreased hepatic blood flow in animal
models,34 suggesting a
hemodynamic explanation for the reduction in
MCRinsulin produced by phenylephrine.
Ang II, a potent inhibitor of renal blood
flow,22 did not affect the
MCRinsulin, thus suggesting that
phenylephrine-mediated changes in insulin clearance were
more likely to have been caused by a decrease in hepatic rather than
renal blood flow.
Another possible explanation for the effects of
phenylephrine on the MCRinsulin is
that hepatic and/or renal insulin receptor binding affinity was
altered. Insulin is removed from hepatic or portal blood after binding
to hepatocyte receptors, which are subsequently
internalized and degraded.15 16 Although
traditionally it has been thought that ß- but not -adrenoceptor
stimulation reduces insulin receptor affinity,35
Desoye et al36 recently demonstrated decreased
insulin receptor binding of rodent adipocytes after
1-adrenergic stimulation. Similar effects are
yet to be demonstrated in human tissue; however,
1-adrenoceptors are present on both
hepatocytes and renal cells37 and are
known to influence intracellular glucose metabolism of
hepatocytes.38
Implications of the Present Study
It would appear that the association between reduced insulin
clearance and EH does not relate to increasing blood pressure per se.
Although blood pressure was significantly elevated by each of the
infusions that we used, only -adrenergic stimulation affected the
MCRinsulin. Thus, it appears that
phenylephrine’s effect on insulin clearance was a specific
effect of -adrenergic stimulation. The magnitude of this effect was
sufficient to suggest that the level of sympathetic nervous system
activity could be an important determinant of in vivo plasma insulin
concentrations. However, since ß-adrenergic stimulation had no effect
on insulin metabolism, the effect of sympathetic nervous
system activation on insulin clearance may be dependent on the receptor
subtype that is stimulated. Morover,
2-adrenoceptor stimulation inhibits pancreatic
secretion of insulin39 40 ; therefore, the net
effect of sympathetic nervous system activity on plasma insulin
concentrations may ultimately depend on the balance between changes in
insulin secretion and clearance.
These findings might explain an unexpected metabolic effect
produced by treating EH with 1-adrenoceptor
blockers. Pollare et al20 reported that although
prazosin substantially increased insulin sensitivity, the initial rise
in plasma insulin concentrations produced by intravenous
glucose administration was reduced. In contrast, other pharmacological
measures that improve insulin sensitivity (eg,
angiotensin-converting enzyme
inhibition,23 oral hypoglycemic
treatment41 ) usually augment first-phase insulin
release. Pollare et al23 explained their findings
by suggesting that prazosin may have decreased insulin secretion by
allowing unopposed 2-adrenoceptor stimulation.
However, the results of the present study predict that
1-adrenergic blockade would augment insulin
clearance and therefore could provide an alternative explanation for
the reduction in plasma insulin concentrations.
These data also provide a potential mechanism by which EH could be
linked with reduced insulin clearance. However, it is important to
stress that there are problems in extrapolating from short-term
physiological actions in healthy subjects to the
longer term clinical situation. For example, it is unknown whether the
acute reduction of insulin clearance produced by
phenylephrine infusion would be sustained during prolonged
periods of -adrenergic stimulation or whether -adrenergic
activity is persistently elevated in hypertensive patients. Therefore,
we would suggest that further studies are required before our
observations can be invoked to explain the association of EH with
impaired insulin clearance.
Insulin Sensitivity
One factor that appears to regulate the effect of insulin on
glucose metabolism is the rate of delivery of insulin to
skeletal muscle-the major site of insulin-mediated glucose uptake.
Consequently, it has been hypothesized that insulin resistance is
associated with EH because of reduced blood flow to skeletal
muscle.5 42 Based on this hypothesis, it might be
predicted that elevating blood pressure with vasoconstricting agents
would simultaneously impair insulin sensitivity because of
an associated fall in skeletal muscle blood flow. However, in the
present study, both Ang II and phenylephrine increased
glucose utilization during euglycemic
hyperinsulinemia, and at least in the case of Ang
II, this rise in glucose utilization was mediated by an increase in
insulin sensitivity. Other investigators have recently reported similar
effects of Ang II infusion, and this action apparently reflects
diversion of blood flow from insulin resistant tissues, such as
the splanchnic circulation, to skeletal
muscle.22
Thus, at least in the short-term, it appears that systemic
vasoconstriction does not necessarily impair insulin sensitivity.
Moreover, if the acute action of Ang II on insulin sensitivity was
sustained over the longer term, the increase in insulin sensitivity
produced by long-term angiotensin-converting enzyme
inhibition23 would be not be due to reduced
production of Ang II but could be due to some other mechanism,
such as an increase in bradykinin concentrations. Similarly, these data
suggest that the increase in insulin sensitivity produced by
-adrenergic blocker treatment of EH may not be due to increased
skeletal muscle blood flow as has been speculated by some
investigators.5 42
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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This study was supported by a grant from the Austin Hospital Medical Research Foundation. Dr O’Callaghan is supported by a National Heart Foundation of Australia Overseas Fellowship. We gratefully acknowledge the nursing assistance given by Margaret Bretherton and Jean Chare.
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Footnotes |
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Reprint requests to Dr C. J. O’Callaghan, Department of Vascular Medicine, Level 2, Clinical Sciences Bldg, University of Leicester, Leicester, LE2 OQJ, UK.
Received June 3, 1997; first decision June 24, 1997; accepted August 18, 1997.
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