Effect of Exogenous Insulin on Blood Pressure

Regulation in Healthy and Diabetic Subjects

HEINRICH VIERHAPPER

SUMMARY To define the role of insulin in blood pressure regulation, the hormone's action on renal
sodium handling, potassium balance, pressor reactivity, and the release of catecholamines and aldo-
sterone are summarized. Insulin-stimulated renal sodium reabsorption induces expansion of the
extracellular volume, increase in cardiac output, and ultimately, hypertension. On the other hand, the
insulin-induced shift of potassium into the cell interior is transient and appears to be of little conse-
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quence for long-term blood pressure control. Although the release of norepinephrine is stimulated by
insulin, a norepinephrine-mediated pressor effect is prevented in healthy men by a simultaneous
norepinephrine-antagonistic action of insulin. The latter causes the fall in blood pressure seen after
intravenous insulin in patients with autonomic dysfunction who lack the rise in norepinephrine
release. Both in healthy and in diabetic men, exogenous insulin does not modify the pressor effect of
angiotensin II, although it impairs the secretion of aldosterone during stimulation by supraphysiologi-
cal doses of angiotensin II. (Hypertension 7 [Suppl II]: II-49-H-53, 1985)

KEY WORDS • sodium • potassium • pressor reactivity • aldosterone

B LOOD pressure is controlled in humans by a

variety of hemodynamic, metabolic, and en-
docrine variables that are constantly reacting
to each other and with exogenous stimuli. Thus abnor-
mal behavior of one regulatory mechanism is bound to
these direct actions of insulin and defines their actual
importance for blood pressure regulation in healthy
men and in patients with diabetes mellitus.

Insulin and Sodium Metabolism

induce additional derangements of other mechanisms.
Consequently, where this cybernetic system is reset to
maintain blood pressure at an elevated level, hyperten-
sion has been defined as a "disease of regulation."1
With regard to the high prevalence of hypertension
among patients with diabetes mellitus,2 some attention
has been given to the possible role of insulin within the
complex interactions of blood pressure-regulating
mechanisms. Insulin-induced decrease in blood glu-
cose concentrations even in the physiological range
provokes a rise in plasma epinephrine and other insu-
lin-counteracting hormones, thus indirectly affecting
the cardiovascular system. In addition, insulin may
directly interfere with blood pressure control by its
influence on renal sodium handling, potassium bal-
ance, pressor reactivity, and the release and/or actions
of catecholamines, renin, and aldosterone. This re-
view summarizes the available evidence concerning
From the Division of Clinical Endocrinology and Diabetes Melli-
tul, Medizinischc Universitatsklinik, Vienna, Austria.
Address for reprints: Dr. Heinrich Vierhapper, Division of Clini-
cal Endocrinology and Diabetes Mellitus, I. Medizinische Univer-
sitatsklinik, Lazarettgasse 14, A-1090 Vienna, Austria.
11-49
Increases in plasma insulin concentrations in the
physiological range directly stimulate sodium reab-
sorption by the distal nephron.3 Thus a sodium-retain-
ing effect of acutely administered insulin is seen in
diabetics with previous poor metabolic control.4 In
patients with type II diabetes and/or obesity, insulin
resistance with respect to glucose metabolism induces
hyperinsulinemia. The last may in turn stimulate sodi-
um absorption by the kidney, ultimately leading to an
increase in exchangeable sodium and to expanded ex-
tracellular volume. Endogenous hyperinsulinemia in
insulin-resistant patients may explain why no differ-
ence has been observed in exchangeable sodium be-
tween insulin-treated and untreated diabetics, whereas
exchangeable sodium is increased by about 10% in
diabetic subjects as compared to healthy age- and
weight-matched controls. 3
Continued expansion of the extracellular volume by
sodium retention increases cardiac output, enhances
pressor responsiveness to angiotensin II6 and norepi-
nephrine,7 and eventually results in hypertension. The
antinatriuretic effect of insulin is finally overcome by a
rise in renal perfusion pressure, and a new equilibrium
 11-50 DIABETES AND HYPERTENSION
is established.3 If, on the other hand, obese subjects are
treated with a hypocaloric diet, plasma insulin falls and
the ensuing negative sodium balance lowers blood
pressure. These assumptions help to explain the effect
of weight reduction on blood pressure control in pa-
tients with obesity and type II diabetes.
Insulin and Potassium Metabolism
Insulin profoundly influences the distribution of po-
tassium between extracellular and intracellular fluid
compartments.8 On the other hand, experimental evi-
dence indicates that the secretion of insulin is altered
by changes in the concentrations of potassium, 9 ' l0
although there is little evidence that changes in
plasma potassium concentrations in the physiological
range indeed influence peripheral insulin levels in
humans." 112
The reactivity of vascular smooth muscle depends
on extracellular potassium concentrations during brief
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periods of exposure and during steady-state condi-
tions. 1314 Both long-term depletion and supplemen-
tation of potassium decrease vascular pressor re-
sponsiveness to angiotensin II in the rat, 1516 and a
potassium-enriched diet exerts a hypotensive effect in
humans. 17 ' 18 For these reasons, the effect of insulin on
potassium balance might be considered as yet another
potential point of action on blood pressure regulation
in humans.
The decrease of serum potassium concentrations in-
duced by insulin does not affect total body potassium
content, however, since it depends exclusively on ex-
trarenal mechanisms, 19 that is, on an influx of potas-
sium into the cell interior of both splanchnic and pe-
ripheral tissues. It is of interest in this context that
patients with type II diabetes exhibit relative end-organ
resistance to insulin-stimulated potassium transport.20
Furthermore, during experiments using the euglyce-
mic-clamp technique, an effective counterregulatory
mechanism to prevent hypokalemia in fact resulted in a
rise in serum potassium concentrations during pro-
longed infusions of insulin.21 Thus the insulin-induced
shift of potassium into the cell interior appears to be
transient. For these reasons, insulin is not likely to
influence blood pressure regulation in humans by
changes in potassium homeostasis.
Insulin and Catecholamine Release
In subjects with an intact autonomic nervous sys-
tem, intravenous insulin induces a rise in plasma nor-
epinephrine even when blood glucose concentrations
are kept constant. Concentrations of epinephrine re-
main unchanged. 22 - a It has been argued that an acute
insulin-induced decrease in plasma volume is counter-
balanced by a rise in sympathetic nervous system ac-
tivity in order to maintain blood pressure at normal
levels at the expense of an increase in heart rate.24-23
This acute fall in plasma volume after administration
of insulin seems to be catecholamine mediated, how-
ever, since it is not seen in sympathectomized individ-
uals. 2627 Therefore it is assumed at present that in
healthy subjects, an initial insulin-induced rise in plas-
ma norepinephrine results in venous constriction, a
SUPPL II HYPERTENSION, VOL. 7, No 6, NOV-DEC 1985
rise in capillary pressure, and thus in a reduction of
plasma volume.28
Since the plasma clearance of norepinephrine does
not change after intravenous insulin22'M and since the
rise in norepinephrine after intravenous insulin appar-
ently reflects an increase in sympathetic nervous activ-
ity, the administration of insulin should induce a rise in
blood pressure. This has indeed been shown in the
dog,29 where the rise in blood pressure during a eugly-
cemic-clamp study depended on alpha-adrenergically
mediated vasoconstriction. Simultaneously, however,
insulin exerts a vasodilator effect in the skeletal muscle
that appears to be independent of the sympathetic ner-
vous system.29 This vasodilator activity of insulin,
which has yet to be confirmed in humans28 might help
to resolve the hitherto puzzling question of how insulin
increases the release and at the same time antagonizes
the actions of norepinephrine. It then would be under-
standable why only a small rise in blood pressure re-
sults from the opposing actions of insulin after its acute
administration in healthy humans. 30
In sympathectomized individuals, insulin failed to
induce a rise in norepinephrine and these patients con-
sequently demonstrated an attenuated vasoconstrictor
activity and a fall in blood pressure after insulin admin-
istration.31 Similar observations were reported in dia-
betics with autonomous dysfunction.32'33 The behavior
of pulse rate with intravenous insulin was quite vari-
able in this group of patients, but blood pressure de-
creased even in those in whom tachycardia was seen,
suggesting that the apparent lack of vasoconstriction
was the decisive factor for the inability of these pa-
tients to maintain blood pressure.33
Unfortunately, blood glucose concentrations were
not kept constant during these early human experi-
ments, thus leaving unsolved the question of whether
the observed changes in blood pressure had been due to
insulin per se or due to the metabolic effects of insulin-
induced hypoglycemia, that is, due to epinephrine-
induced vasodilatation.29
Insulin and Pressor Reactivity
In the isolated perfused tails of male rats (a model
without interference of changing blood glucose con-
centrations) an attenuated pressor responsiveness to
norepinephrine was induced by supraphysiological
doses of insulin.34 Although some effect of insulin was
seen at a concentration of 150 /xU/ml, it was clearly
more marked at a concentration of 120 mU/ml, a dose
far beyond physiological levels. For unexplained rea-
sons, the effect was absent in female animals.
A reduction in the response to vasoconstrictor stim-
uli in the nondiabetic rat was also seen after long-term
insulin therapy.35 In comparison to healthy animals,
however, alloxan-diabetic insulin-deficient rats exhib-
it reduced responses to several vasoconstrictor stimuli.
Insulin replacement abolishes this abnormality and re-
stores pressor responsiveness. To resolve this apparent
discrepancy, it was suggested that hyperglycemia and/
or hyperglucagonemia may be largely responsible for
the impaired pressor responsiveness in this animal
model. Normalization of these metabolic derange-
 INSULIN AND BLOOD PRESSURE REGULATION/Wer/iapper
ments by insulin replacement in turn caused a normal-
ization of vascular function.36 Thus insulin exerts a
dual effect in the alloxan-diabetic rat: While directly
inhibiting vascular reactivity it simultaneously im-
proves pressor responsiveness indirectly by correcting
metabolic derangements.
In humans, the available evidence of the role of
insulin on vasoreactivity is based on observations
made when plasma insulin concentrations are acutely
raised into the pharmacological range. In insulin-
dependent diabetics who are regularly confronted with
this situation, this approach at least bears resemblance
to their clinical situation, although the acute effects of
insulin may well be altered by long-term insulin ther-
apy, endogenous hyperinsulinemia, or the metabolic
abnormalities that are by definition present in these
patients. Concerning healthy humans, the possible im-
pact of changes in plasma insulin within the physio-
logical range on vascular reactivity can hardly be in-
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ferred by extrapolation of results obtained during the
acute administration of large doses of insulin.
Bearing these limitations in mind, we studied the
effect of a pharmacological dose of insulin on pres-
sor reactivity to angiotensin II in healthy men37 and
in patients with insulin-dependent diabetes. Eugly-
cemia was maintained by adequate administration of
dextrose.
To induce a comparable state of insulinemia in the
diabetic group, each patient was given his last dose of
intermediate-acting insulin 24 hours prior to the test,
followed by a constant infusion of 0.75 U of rapidly
acting insulin/m2 body surface/hr for 12 hours prior to
the experiment. Two consecutive angiotensin II-infu-
sion tests were performed with an equilibration period
of 120 minutes between them. Sixty minutes before the
beginning of the second angiotensin II infusion, a con-
tinuous infusion of regular insulin was begun in
healthy individuals (2.5 U/m2/hr). In diabetics the dose
of intravenous insulin was increased to 7.5 U/m2/hr.
Plasma concentrations of potassium (diabetics: 4.1 ±
130 HEALTHY MEN
120
110-
100-
I 90
af
80
0J
-15
MINUTES
5 I 0 S
ANOCTENSN I ( nfl Kg ' min"' )
FIGURE 1. Effect of induced hyperinsulinemia (•
ng-kg'1 •min~l) in healthy men and in insulin-dependent diabetic men as compared with a control experiment
without hyperinsulinemia (o o^ (BPm = mean blood pressure).
11-51
0.4 mmol/L; healthy individuals: 4.2 ± 0.2 mmol/L)
were found to be unchanged after the first infusion of
angiotensin II (diabetics: 3.9 ± 0.3 mmol/L; healthy
men: 4.3 ± 0.2 mmol/L). Sixty minutes after the onset
of induced hyperinsulinemia, however, plasma potas-
sium fell to 3.5 ± 0.3 mmol/L (p < 0.05) in diabetics
and to 3.6 ± 0.2 mmol/L (p < 0.005) in healthy
individuals and remained at this level until the end of
the second infusion (diabetics: 3.3 ± 0.3 mmol/L;
healthy men: 3.6 ± 0.2 mmol/L). In both groups,
basal blood pressure was similar at the beginning of
either infusion of angiotensin II (Table 1) and the pres-
sor response to angiotensin II was unchanged by hy-
perinsulinemia (Figure 1). These results did not sup-
port the notion that an altered vascular reactivity to
angiotensin II contributes to the hemodynamic effect
of insulin in healthy and in diabetic men. It remains to
be determined whether insulin affects the response to
other pressor agents in a different way and whether
chronic effects of insulin therapy (notably sodium
retention) contribute to the increased pressor respon-
siveness seen in diabetic patients compared to healthy
controls.38-39
TABLE 1. Effect of Hyperinsulinemia on Serum Concentrations
of Potassium and Sodium and on Basal Mean Blood Pressure in Six
Healthy Men and in Six Insulin-Dependent Diabetic Patients (mean
± SD)
Healthy men IDD patients
Hyperin- Hyperin-
Control sulinemia Control sulinemia
K+ (mmol/L) 4.2±0.2 3.6±0.2* 4.1 ±0.4 3.5±0.3*
Na+ (mmol/L) 142 ±2 140±4 142 ±1 144±2
mBP (mm Hg) 94±11 95 ±12 87±7 84±6
BG (mmol/L) 4.3±0.4 5.4±1.2* 4.5±0.9 4.9±0.9
Concentrations of blood glucose (BG) were maintained at eugly-
cemic levels by intravenous dextrose.
*p < 0.05, compared with control group by Student's two-tailed
t test for matched pairs.
INSULIN- DCPENDENT DIABETICS
30 *5
MINUTES
5 O 20
ANGKJTENSIN I I ng Kg"' min"1)
• ) on the pressor action of angiotensin II (5, 10, and 20
 11-52 DIABETES AND HYPERTENSION SUPPL II HYPERTENSION, VOL 7, No 6, NOV-DEC 1985

Insulin and the Secretion of Renin diabetics without hyporeninemic hypoaldosteronism

Insulin-induced hypoglycemia stimulated renin se-
cretion in intact animals40 and in humans.41 This in-
crease in renin secretion may represent a response to
the counterregulatory rise in catecholamines42 and not
to insulin itself. In the isolated, perfused rat kidney,
insulin exerted a dose-dependent, calcium-mediated
suppression of renin release. 43 The significance of this
finding for the regulation of blood pressure in humans
has yet to be determined.
(i.e., with a normal concentration of renin), the in-
crease of 18-hydroxycorticosterone and of aldosterone
in response to sodium depletion, upright posture, and
angiotensin II was similar to that seen in healthy con-
trols.48 49 Excessive production of aldosterone is obvi-
ously not the cause of diabetes-associated hyperten-
sion.48 On the basis of the data available at present,
insulin apparently does not exert its effect on blood
pressure by an action on aldosterone secretion.

Insulin and the Secretion of Aldosterone Conclusions

Changes in extracellular and/or intracellular44 con-
centrations of potassium profoundly influence the reg-
ulation of aldosterone biosynthesis and serve to ex-
plain the acute effects of insulin on aldosterone
secretion in humans. Both in healthy men 4546 and in
anephric patients,44 basal plasma aldosterone concen-
trations decreased during hyperinsulinemia. This led
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Exogenous insulin influences blood pressure regula-
tion in humans both indirectly by its effect on carbo-
hydrate metabolism and by several direct actions that
are of either immediate or long-term importance for
specific blood pressure-regulating mechanisms. Since
these direct actions were studied under experimental
conditions where other variables were kept constant, it
is difficult to evaluate their actual importance in vivo,

to the assumption that either the glomerulosa cells may

not share the influx of potassium during hyperinsuline-
mia47 and/or that extracellular rather than intracellular
concentrations of potassium regulate human aldoste-
rone secretion. After a slight decrease in basal plasma
aldosterone, however, we observed increased angio-
tensin H-induced aldosterone secretion during eugly-
cemic hyperinsulinemia in healthy men (Table 2). 37
This could indicate that intracellular potassium content
of glomerulosa cells was augmented to an extent to
interfere with dynamic changes in aldosterone secre-
tion induced by supraphysiological doses of angioten-
sin II. The above-mentioned end-organ resistance
against insulin-mediated potassium transport20 could
explain why this effect was not seen in diabetic pa-
tients (Table 2).
As pointed out previously, insulin does not influ-
ence external potassium balance and its impact on in-
ternal potassium balance is transient. Furthermore, in
where blood pressure is determined by mutual interac-
tions between a large number of agonistic and antago-
nistic mechanisms.
At present, it appears that insulin influences blood
pressure regulation in humans primarily by its antina-
triuretic action, which contributes to hypertension by
an increase in extracellular volume. The insulin-
induced decrease in vasoreactivity is of practical
importance in patients with autonomic dysfunction,
in whom intravenous insulin induces orthostatic
hypotension.
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TABLE 2. Effect ofHyperinsulinemia on Basal and Angiotensin Il-Stimulated Plasma Concentrations ofAldosterone in
Six Healthy Men and Six Insulin-Dependent Diabetic Patients (mean ± SD)
Plasma aldosterone (ng/dl) Rise above basal concentrations
Hyperin- Hyperin-
Control sulinemia Control sulinemia
Healthy men
Basal 6.3±2.2 5.0±1.2 — —
Angiotensin II
5 ng-kg" 1 -min" 1 8.0±1.3 7.0 + 2.2 1.7±2.0 1.9±1.6
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Insulin-dependent diabetic men
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 INSULIN AND BLOOD PRESSURE REGULATION/Vierhapper
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 Effect of exogenous insulin on blood pressure regulation in healthy and diabetic subjects.
H Vierhapper

Hypertension. 1985;7:II49
doi: 10.1161/01.HYP.7.6_Pt_2.II49
Hypertension is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231
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