Forearm norepinephrine spillover during standing,
hyperinsulinemia, and hypoglycemia
Deanna S.
Paramore,
Carmine G.
Fanelli,
Suresh D.
Shah, and
Philip
E.
Cryer
Division of Endocrinology, Diabetes, and Metabolism, General
Clinical Research Center and the Diabetes Research and Training
Center, Washington University School of Medicine, St. Louis,
Missouri 63110
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ABSTRACT |
Plasma norepinephrine (NE) concentrations are a
fallible index of sympathetic neural activity because circulating NE
can be derived from sympathetic nerves, the adrenal medullas, or both and because of regional differences in sympathetic neural activity. We
used isotope dilution measurements of systemic and forearm NE spillover
rates (SNESO and FNESO, respectively) to study the sympathochromaffin
system during prolonged standing, hyperinsulinemic euglycemia, and
hyperinsulinemic hypoglycemia in healthy humans. Prolonged standing led
to decrements in blood pressure without increments in heart rate, the
pattern of incipient vasodepressor syncope. FNESO was not increased
(0.58 ± 0.20 to 0.50 ± 0.21 pmol · min
1 · 100 ml tissue
1), suggesting
that the approximately twofold increments in plasma NE and SNESO were
derived from sympathetic nerves other than those in the forearm (with a
possible contribution from the adrenal medullas). Hyperinsulinemia per
se (euglycemia maintained) stimulated sympathetic neural activity, as
evidenced by increments in FNESO (0.57 ± 0.11 to 1.25 ± 0.25 pmol · min
1 · 100 ml tissue
1,
P < 0.05), but not adrenomedullary
activity. Hypoglycemia per se stimulated adrenomedullary activity
(plasma epinephrine from 190 ± 70 to 1720 ± 320, pmol/l,
P < 0.01). Although SNESO
(P < 0.05) and perhaps plasma NE
(P < 0.06) were raised to a greater extent during hyperinsulinemic hypoglycemia than during
hyperinsulinemic euglycemia, FNESO was not. Thus these data do not
provide direct support for the concept that hypoglycemia per se also
stimulates sympathetic neural activity.
sympathetic nervous system; adrenal medullas; epinephrine; hypoglycemia
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INTRODUCTION |
ALTHOUGH THE PLASMA norepinephrine (NE) concentration
is often viewed as an index of sympathetic neural activity, circulating NE can be derived from sympathetic postganglionic neurons, the adrenal
medullas, or both (45). Furthermore, the plasma NE concentration is the
result of the rate of NE appearance in plasma [conventionally referred to as the NE spillover rate (16) because the vast majority of
the NE released from axon terminals of sympathetic postganglionic neurons is dissipated locally by neuronal reuptake or metabolism and
does not enter the circulation (45)] and the rate of NE disappearance from plasma (often expressed as the plasma NE metabolic clearance rate). Thus measurements of NE kinetics are required to
document the extent to which an increment in the plasma NE concentration is the result of increased spillover (an index of release) or decreased clearance (16). Nonetheless, the systemic plasma
NE spillover rate, like the plasma NE concentration, is a marker of
sympathetic neural activity, adrenomedullary activity, or both.
Furthermore, regional variations in sympathetic neural activity can
complicate interpretation of the plasma NE concentration (16).
Approaches to quantitation of sympathetic neural activity per se
include 1) direct measurement with
microneurography (4, 46, 56), 2)
measurement of tissue NE concentrations with microdialysis (24, 31),
and 3) NE isotope dilution
measurements across a specific organ or tissue that does not include
the adrenal medullas (16). Although it is more sensitive than plasma NE
concentrations to changes in sympathetic neural activity (22),
microneurography is technically demanding, limited to measurement of
muscle and skin sympathetic neural activity, and, because it becomes
progressively more stressful over time, not optimal for prolonged or
repeated experiments. Tissue NE levels are difficult to quantitate with microdialysis (10, 24, 31); not only is a sensitive assay required, but
calibration is problematic. Based on these considerations, and given
our earlier experience with measurements of systemic NE kinetics (32),
we selected measurements of forearm NE kinetics (11, 29) to quantitate
sympathetic neural activity. This requires only the addition of deep
venous sampling and measurements of forearm blood flow (23) to the
basic method (32).
The forearm NE spillover technique also has limitations. First, it
provides only an index of sympathetic neural NE release because the
vast bulk of NE released is dissipated locally and does not enter the
circulation (45). Second, it reflects NE release in only one region and
therefore cannot assess regional differences in sympathetic neural
activity (34). Third, the tracer technique per se involves several
assumptions. For example, the fundamental assumption of the systemic NE
clearance method and thus the systemic NE spillover calculation that
the tracer mixes with a constant fraction of NE released at sympathetic
nerve terminals has been challenged (10, 14). Furthermore, although we
have found no differences between systemic NE kinetic data calculated
from arterial and arterialized venous sampling but substantially higher
values calculated from venous sampling (32), the optimal sampling site
has not been determined (40). Nonetheless, as an index of NE release
from sympathetic postganglionic neurons, and thus of sympathetic neural
activity, forearm NE spillover rates (FNESO) have been found to be
increased during lower body negative pressure (27, 29), during
euglycemic hyperinsulinemia (29), during angiotensin II infusion (11),
and after a meal (54). We used this technique to distinguish
sympathetic neural from adrenomedullary activation during prolonged
standing, hyperinsulinemic euglycemia, and hyperinsulinemic
hypoglycemia in healthy human subjects.
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METHODS |
Subjects. Five healthy subjects (3 women and 2 men) gave their written consent to participate in
study 1. Their mean ± SD age was
30 ± 5 yr (range 24-36 yr), and their mean body mass index (BMI) was 24.2 ± 7.6 kg/m2
(range 16.6-36.6 kg/m2).
Five healthy subjects (3 women and 2 men) gave their written consent to
participate in study 2. Their mean ± SD age was 35 ± 4 yr (range 28-40 yr), and their mean
BMI was 23.6 ± 1.5 kg/m2
(range 22.2-25.5 kg/m2).
Both studies were approved by the Washington University Radioactive Drug Research Committee and the Washington University Human Studies Committee and were performed in the outpatient facilities of the Washington University General Clinical Research Center (GCRC).
Protocols. Subjects presented to the
GCRC early in the morning after an overnight fast. A catheter was
inserted in a retrograde fashion in a deep antecubital vein in the
dominant arm; this was flushed frequently with saline. In the
contralateral arm, intravenous lines were inserted into a hand vein,
with that hand kept in an ~65°C box to provide arterialized
venous samples and in an antecubital vein for infusions
([3H]NE in both
studies and, in study 2, insulin and
glucose). Equipment for venous occlusion plethysmography (venous
occlusion cuff, mercury strain gauge, and wrist occlusion cuff) was
placed on the arm with the deep antecubital intravenous catheter.
In study 1, subjects were studied on
two occasions in random sequence, separated by at least 1 mo, one time
in the supine position throughout [supine in the first 30-min
time segment (T1) and supine in
the second 30-min time segment (T2)],
the supine to supine limb, and one time in the supine position in
T1 and after
30-60 min in the standing position in
T2 (60 min in the first two subjects, who found this difficult to complete, and 30 min in
the next three subjects), the supine to prolonged standing limb. In
study 2 subjects were studied, in the
supine position, on three occasions in random sequence each separated
by at least 1 mo, one time during saline infusion in
T1,
T2, and the third time segment
(T3), the
control limb, one time during saline infusion in
T1 and insulin
infusion with maintenance of euglycemia (see below) in
T2 and
T3, the
euglycemic limb, and one time during saline infusion in
T1, insulin
infusion with euglycemia in
T2, and insulin
infusion with hypoglycemia (see below) in
T3, the euglycemic to hypoglycemic limb. Arterialized venous and deep antecubital venous samples (obtained simultaneously) for NE mass and
radioactivity, forearm blood flow measurements, arterialized venous
samples for hormone and metabolic substrate/intermediate levels,
assessments of symptoms, and heart rate and blood pressure measurements
were obtained serially, and the electrocardiogram was monitored
throughout during hypoglycemia.
NE kinetics were calculated from arterialized venous samples obtained
20, 25, and 30 min into 30-min infusions of
[3H]NE
(levo-[ring-2,5,6-3H]NE,
40-60 Ci/mmol; New England Nuclear, Boston, MA; 10 nCi · kg
1 · min
1)
as described previously (32).
[3H]NE concentrations
and NE specific activities (NE SA) were determined after organic
extraction of NE from plasma (32). The systemic NE metabolic clearance
rate (SNEMCR) and spillover rate (SNESO) were calculated as
where
[3H]NE IR is the
[3H]NE infusion rate,
and
where
NE SA is the norepinephrine specific activity. The forearm NE metabolic
clearance rate (FNEMCR) and spillover rate (FNESO) (11, 29) were
calculated from forearm plasma flow [FPF = forearm blood flow(1
hematocrit) in
ml · min
1 · 100 ml tissue
1] and
forearm fractional extraction of NE
(Fex
[3H]NE)
where
the subscripts A and V indicate arterial and venous, respectively.
Hence
Forearm
blood flow was measured by venous occlusion plethysmography (Parks
Medical Electronics, Aloha, OR; see Ref. 21) at the 20-, 25-, and
30-min time points during each
[3H]NE infusion along
with measurements of NE mass and radioactivity at the same time points.
To exclude the hand from the measurement of blood flow, the wrist cuff
was inflated to ~230 mmHg for 2 min before recordings and was
maintained during the recordings. Each blood flow value was the mean of
five consecutive recordings.
In study 1, after instrumentation and
a 30-min rest period,
[3H]NE was infused for
30 min, there was a 30-min washout period, and
[3H]NE was again
infused for 30 min. Isotopic steady state is achieved after <20 min
(32). On one occasion the subject remained supine throughout; on the
other occasion the subject was supine during the first
[3H]NE infusion and
standing during the second infusion.
In study 2, again after
instrumentation and a 30-min rest period,
[3H]NE was infused
over 30 min three times with 30-min washout periods between infusions,
on three occasions in random sequence: one time with saline infusion
through all three segments
(T1,
T2, and
T3); one time
with saline infusion in
T1 and insulin
infusion (12.0 pmol · kg
1 · min
1) in
T2 and
T3 with
euglycemia (~4.6 mmol/l) maintained by variable 20% glucose infusion
through T2 and
T3 (43); and one
time with saline infusion in
T1, insulin
infusion in T2
and T3,
euglycemia (~4.6 mmol/l) in
T2, and
hypoglycemia (~2.8 mmol/l) in
T3 (43).
Analytical methods. Plasma glucose was
measured with a glucose oxidase method (Beckman Glucose Analyzer 2;
Beckman Instruments, Fullerton, CA). Plasma NE and epinephrine
concentrations were measured with a single isotope derivative
(radioenzymatic) method (44), and those of insulin (28), C-peptide
(28), glucagon (15), pancreatic polypeptide (20), cortisol (18), and
growth hormone (42) were measured with radioimmunoassays. Serum
nonesterified fatty acid levels were measured with an enzymatic
colorimetric method (26), and blood
-hydroxybutyrate (37), lactate
(30), and alanine (7) levels were measured with enzymatic techniques. Neurogenic (autonomic) and neuroglycopenic symptom scores were determined as described previously (43, 52).
Statistical methods. Contrasts over
time (T1 vs.
T2 in
study 1 and
T1 vs.
T2 and
T3 in
study 2) within each study limb
[i.e., each study day: the supine to supine day and the supine to
prolonged standing day in study 1 and
the saline infusion day (control limb), the saline then insulin and
glucose infusion day (euglycemic limb), and the saline then insulin
then hypoglycemia day (euglycemic to hypoglycemic limb) in
study 2] were analyzed by
t-test for paired data. Contrasts
between limbs were analyzed by general linear models procedure repeated
measures analysis of variance (ANOVA) for limb × time interactions.
In this report, P values for time contrasts are shown
without further notation, and those for limb × time interactions are
shown with the notation ANOVA. P
values <0.05 were considered to indicate statistically significant differences. Data are expressed as means ± SE except where the SD
is specified.
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RESULTS |
Study 1. Mean blood pressures, which
did not change over time in the
T1 and
T2 time segments
in the supine to supine limb, decreased from 93 ± 8 mmHg in
T1 to 69 ± 6 mmHg in
T2
(P < 0.02) in the supine to
prolonged standing limb (Fig. 1). There was
a significant limb × time interaction (ANOVA, P < 0.02).
There were no changes in heart rates (Fig. 1). Plasma pancreatic
polypeptide concentrations, which did not change over time in the
supine to supine limb, increased from 11 ± 2 to 42 ± 9 pmol/l
(P < 0.01) in the supine to
prolonged standing limb (Fig. 2). There was
a significant limb × time interaction (ANOVA, P < 0.01).
Forearm blood flows, which did not change over time in the supine to
supine limb, fell from 1.79 ± 0.29 to 0.72 ± 0.21 ml · min
1 · 100 ml tissue
1
(P < 0.05) in the supine to
prolonged standing limb (Fig. 2). There was a significant limb × time
interaction (ANOVA, P < 0.05). Plasma epinephrine
concentrations, which did not change over time in the supine to supine
limb, increased from 130 ± 30 to 630 ± 70 pmol/l
(P < 0.01) in the supine to
prolonged standing limb (Fig. 3). There was
a significant limb × time interaction (ANOVA, P < 0.01). Plasma NE concentrations,
which did not change in the supine to supine limb, increased from 0.72 ± 0.12 to 1.53 ± 0.26 nmol/l
(P < 0.01) in the prolonged standing
limb (Fig. 3). There was a significant limb × time interaction
(ANOVA, P < 0.01).

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Fig. 1.
Mean ± SE blood pressures (A)
and heart rates (B) in healthy
subjects with the subjects supine (Su, open bars) during two
consecutive periods separated by 30 min on one occasion and supine and
then standing (St, filled bars) for 30-60 min on another occasion
in study 1. * Significant
difference from the baseline value on the same occasion.
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Fig. 2.
Mean ± SE plasma pancreatic polypeptide concentrations
(A) and forearm blood flow rates
(B) in healthy subjects with the
subjects supine (open bars) during two consecutive periods separated by
30 min on one occasion and supine and then standing (filled bars) for
30-60 min on another occasion in study
1. * Significant differences from the baseline
values on the same occasion.
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Fig. 3.
Mean ± SE plasma epinephrine concentrations
(A) and plasma norepinephrine (NE)
concentrations (B) in healthy
subjects with the subjects supine (open bars) during two consecutive
periods separated by 30 min on one occasion and supine and then
standing (filled bars) for 30-60 min on another occasion in
study 1. * Significant
differences from the baseline values on the same occasion.
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NE SA were stable at the 20-, 25-, and 30-min sampling times with the
subjects in the supine and in the standing positions [data not
shown but as also documented previously (30)]. Thus mean data
from these three samples were used to calculate NE kinetic values
during the final 10 min of each 30-min
[3H]NE infusion.
Systemic NE spillover rates (SNESO), which did not change over time in
the supine to supine limb, increased from 2.16 ± 0.39 to 4.62 ± 1.29 nmol/min (P < 0.05)
in the supine to prolonged standing limb (Fig.
4). There was a significant limb × time
interaction (ANOVA, P < 0.05).
However, FNESO, which did not change over time in the supine to supine
limb, did not increase (0.58 ± 0.20 to 0.50 ± 0.21 pmol · min
1 · 100 ml tissue
1) in the
prolonged standing limb (Fig. 4). SNEMCR and FNEMCR (data not shown)
did not change significantly over time in either limb, and there was no
significant limb × time interaction.

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Fig. 4.
Mean ± SE systemic (A) and
forearm (B) NE spillover rates in
healthy subjects with the subjects supine (open bars) during two
consecutive periods separated by 30 min on one occasion and supine and
then standing (filled bars) for 30-60 min on another occasion in
study 1. * Significant
difference from the baseline value on the same occasion.
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Study 2. Plasma glucose concentrations
were stable through the
T1,
T2, and
T3 segments in
the control (saline infusion) limb, through the
T1 (saline) and
the T2 and
T3
(hyperinsulinemic euglycemia) time segments in the euglycemic limb, and
during the T1
(saline) and T2
(hyperinsulinemic euglycemia) time segments of the euglycemic to
hypoglycemic limb of the study (Fig. 5).
Plasma glucose levels were decreased from 4.7 ± 0.1 mmol/l during
the T2 time
segment to 2.9 ± 0.1 mmol/l in the
T3 time segment
of the latter limb of the study (Fig. 5). Plasma insulin
concentrations, which did not change over time in the control limb,
were raised comparably during the
T2 and
T3 time segments
in both the euglycemic and the euglycemic to hypoglycemic limbs (Table
1). There was not a significant limb × time interaction. Some of the insulin values were below the detection
limit of 24 pmol/l and were assigned that value for calculation of the
means. Plasma C-peptide concentrations, which did not change over time
in the control limb, decreased during the
T2
(P < 0.05) and
T3
(P < 0.001) time segments in the euglycemic limb and the
T2
(P < 0.05) time segment in the
euglycemic to hypoglycemic limb (Table 1). C-peptide levels decreased
further during hypoglycemia
(T3 time segment
in the euglycemic to hypoglycemic limb) compared with during euglycemic
hyperinsulinemia (ANOVA, P < 0.01).

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Fig. 5.
Mean ± SE plasma glucose concentrations at the end of the
T1,
T2, and
T3 time segments
in the control limb, the euglycemic (Eu) limb, and the euglycemic to
hypoglycemic (Eu Hypo) limb in healthy subjects during saline
infusions (open bars) and insulin infusions with euglycemia
(crosshatched bars) or hypoglycemia (filled bar) in
study 2.
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Table 1.
Plasma insulin, C-peptide, pancreatic polypeptide, glucagon, growth
hormone, and cortisol concentrations
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Mean blood pressures, which did not change in the control and
euglycemic limbs, decreased slightly in the euglycemic to hypoglycemic limb (P < 0.05; Table
2). There was a significant limb × time interaction (ANOVA, P < 0.05).
Systolic and diastolic blood pressure patterns were similar (Table 2),
again with significant limb × time interactions (both ANOVA,
P < 0.05). Heart rates did not change significantly in any
of the limbs (Table 2). Rates of forearm blood flow, which did not
change during the control and the euglycemic limbs, increased from 1.48 ± 0.31 to 2.52 ± 0.49 ml · min
1 · 100 ml tissue
1
(P < 0.05) in the
T3 time segment
in the euglycemic to hypoglycemic limb (Fig.
6). The increase in forearm blood flow was
greater in the euglycemic to hypoglycemic limb than in the euglycemic limb (ANOVA, P < 0.01) despite
comparable hyperinsulinemia (Table 1).

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Fig. 6.
Mean ± SE forearm blood flow in the final 10 min of the
T1,
T2, and
T3 segments in
the control limb, the euglycemic limb, and the euglycemic to
hypoglycemic limb in healthy subjects during saline infusions (open
bars) and insulin infusions with euglycemia (crosshatched bars) or
hypoglycemia (filled bar) in study 2.
* Significant difference from the baseline value on the same
occasion.
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Plasma epinephrine concentrations, which did not change in the control
and euglycemic limbs, increased from 190 ± 70 to 1,720 ± 320 pmol/l (P < 0.0001) in the
T3 time segment
in the euglycemic to hypoglycemic limb (Fig.
7). The increase in plasma epinephrine levels was greater in the euglycemic to hypoglycemic limb than in the
euglycemic limb (ANOVA, P < 0.01).
Plasma NE concentrations, which were unchanged in the control limb and
did not increase significantly in the euglycemic limb, increased from
1.04 ± 0.15 to 1.57 ± 0.18 nmol/l
(P < 0.05) in the
T3 time segment
in the euglycemic to hypoglycemic limb (Fig.
8). However, the
T1 to
T3 increase in
plasma NE levels in the euglycemic to hypoglycemic limb was not
significantly greater than the apparent increase in the euglycemic limb
(ANOVA, P = 0.11), nor was the T2 to
T3 increase (ANOVA,
P = 0.05).

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Fig. 7.
Mean ± SE plasma epinephrine concentrations at the end of the
T1,
T2, and
T3 segments in
the control limb, the euglycemic limb, and the euglycemic to
hypoglycemic limb in healthy subjects during saline infusions (open
bars) and insulin infusions with euglycemia (crosshatched bars) or
hypoglycemia (filled bar) in study 2.
* Significant difference from the baseline value on the same
occasion.
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Fig. 8.
Mean ± SE plasma NE concentrations at the end of the
T1,
T2, and
T3 segments in
the control limb, the euglycemic limb, and the euglycemic to
hypoglycemic limb in healthy subjects during saline infusions (open
bars) and insulin infusions with euglycemia (crosshatched bars) or
hypoglycemia (filled bar) in study 2.
* Significant difference from the baseline value on the same
occasion.
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In addition to decrements in endogenous insulin secretion, hypoglycemia
elicited increments in plasma pancreatic polypeptide, glucagon, growth
hormone, and cortisol concentrations (Table 1). Increments in each of
these were significantly greater in the euglycemic to hypoglycemic limb
than in the euglycemic limb (ANOVA, P < 0.01 for pancreatic polypeptide and glucagon and
P < 0.05 for growth
hormone and cortisol). Serum nonesterified fatty acid levels were
suppressed during hyperinsulinemia in both the euglycemic (P < 0.001) and the euglycemic to
hypoglycemic (P < 0.0001) limbs (Table 3). Blood
-hydroxybutyrate
patterns were similar (Table 3). Blood lactate concentrations, which
did not change in the control limb and appeared to increase in the
euglycemic limb, increased during the
T2 time segment
(P < 0.001) and the
T3 time segment
(P < 0.02) in the euglycemic to
hypoglycemic limb (Table 3). Blood alanine concentrations did not
change in any of the limbs (Table 3).
NE SA were stable at the 20-, 25-, and 30-min sampling times in all
three limbs (data not shown). Thus mean data from these three samples
were used to calculate NE kinetic values during the final 10 min of
each 30-min [3H]NE
infusion in each time segment of each limb. SNESO, which did not change
in the control limb and did not increase significantly in the
euglycemic limb, increased from 3.45 ± 0.69 to 5.59 ± 0.88 nmol/min (P < 0.05) in the
euglycemic to hypoglycemic limb (Fig. 9).
Although the T1
to T3 increase in
SNESO in the euglycemic to hypoglycemic limb was not significantly
grater than that in the euglycemic limb (ANOVA,
P = 0.14), the
T2 to
T3 increase was greater in the euglycemic to hypoglycemic limb (ANOVA,
P < 0.05). FNESO, which did not
change in the control limb, increased from 0.57 ± 0.11 to 1.25 ± 0.25 pmol · min
1 · 100 ml tissue
1
(P < 0.05) in the euglycemic limb
and from 0.36 ± 0.08 to 1.03 ± 0.37 pmol · min
1 · 100 ml tissue
1
(P < 0.05) in the euglycemic to
hypoglycemic limb (Fig. 10). The increase
in forearm NE spillover was not significantly greater in the euglycemic
to hypoglycemic limb than in the euglycemic limb. SNEMCR and FNEMCR did
not change over time in any of the three limbs (data not shown).
Neurogenic symptom scores, which did not change in the control and
euglycemic limbs, increased from 1.2 ± 0.4 to 4.0 ± 0.9 (P < 0.02) in the euglycemic to
hypoglycemic limb (other data not shown). Neuroglycopenic symptom
scores did not change significantly over time in any of the three limbs
(data not shown).

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Fig. 9.
Mean ± SE systemic NE spillover rates during the last 10 min of the
T1,
T2, and
T3 segments in
the control limb, the euglycemic limb, and the euglycemic to
hypoglycemic limb in healthy subjects during saline infusions (open
bars) and insulin infusions with euglycemia (crosshatched bars) or
hypoglycemia (filled bar) in study 2.
* Significant difference from the baseline value on the same
occasion.
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Fig. 10.
Mean ± SE forearm NE spillover rates during the last 10 min of the
T1,
T2, and
T3 segments in
the control limb, the euglycemic limb, and the euglycemic to
hypoglycemic limb in healthy subjects during saline infusions (open
bars) and insulin infusions with euglycemia (crosshatched bars) or
hypoglycemia (filled bar) in study 2.
* Significant difference from the baseline value on the same
occasion.
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Relative increments in FNESO were consistently greater than those in
SNESO under the various study conditions in study
2. During hyperinsulinemic euglycemia in the euglycemic
limb of the study the increases were 1.9- vs. 1.4-fold, respectively,
from the T1 to
the T2 segment
and 2.2- and 1.4-fold, respectively, from the
T1 to the
T3 segment; in
the euglycemic to hypoglycemic limb they were 2.0- vs. 1.3-fold,
respectively, from the
T1 to the
T2 segment.
During hyperinsulinemic hypoglycemia in the euglycemic to hypoglycemic
limb the increases were 2.8- vs. 1.6-fold, respectively, from the
T1 to the
T3 segment and
1.4- vs. 1.2-fold in the
T2 to the
T3 segment.
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DISCUSSION |
We used measurements of FNESO, coupled with those of SNESO and plasma
NE and epinephrine concentrations, to distinguish sympathetic neural
from adrenomedullary activation during prolonged standing, hyperinsulinemic euglycemia, and hyperinsulinemic hypoglycemia in
healthy human subjects. The data indicate that increments in plasma NE
concentrations (and SNESO) can be dissociated from sympathetic neural
activity in one region, the forearm, during prolonged standing, that
hyperinsulinemia per se stimulates the sympathetic neural but not the
adrenomedullary component of the sympathochromaffin system, and that
while hypoglycemia per se stimulates the adrenomedullary component it
may not stimulate the sympathetic neural component.
Prolonged (30-60 min) standing was associated with decrements in
systolic and diastolic (and therefore mean) blood pressures and forearm
blood flow without an increment in heart rate, a pattern suggesting
that sympathetic neural activity was no longer increased substantially,
and parasympathetic neural activity was increased, in healthy young
adults. This hemodynamic pattern is that of the vasodepressor
(vasovagal, neurocardiogenic) response that can lead to syncope (53).
There is considerable evidence, based on measurements of plasma NE
concentrations (21, 41, 48, 58), cardiac and renal NE spillover rates
(16), and microneurography (25, 35, 36, 57), that a decrease in
sympathetic neural activity is a key component of the vasodepressor
response. The present findings of increments in plasma NE
concentrations and SNESO, but not FNESO, are consistent with that
construct. Taken at face value the data suggest that the raised plasma
NE concentrations and SNESO were the result of increased NE release
from sympathetic nerves other than those in the forearm (16) (and to
some extent from the adrenal medullas given the observed 5-fold
increase in the plasma epinephrine concentration). In addition, the
finding of increased plasma pancreatic polypeptide levels, a putative marker of pancreatic parasympathetic outflow (41), could explain the
absence of an increase in heart rate if parasympathetic outflow to the
heart parallels that to the pancreas. However, at the time of incipient
vasodepressor syncope, when the subjects were studied, they still had
measurable, albeit reduced, blood pressures and had not lost
consciousness. Therefore, although likely less than shortly after
standing, (6, 45, 51), net sympathetic neural activity must have been
increased to some extent.
The assumption that infused labeled NE mixes with a constant fraction
of NE released at sympathetic nerve terminals, which is implicit in the
application of the clearance concept to the quantification of NE
kinetics, has been challenged by Christensen and Knudsen (10). If this
condition is not met when the capillary surface exchange area is
increased (14) or decreased, the plasma NE spillover rate would be
overestimated or underestimated, respectively. This might explain a
reported discrepancy between muscle sympathetic nerve activity measured
with microneurography and plasma NE concentrations (both increased) and
plasma NE spillover (unchanged) during lower body negative pressure, a
condition in which the capillary surface exchange area would be
expected to be decreased (10). The latter would also be expected during
prolonged standing in the present study; our methods did not include a
measure of capillary surface exchange area (14). Thus the FNESO could
have been underestimated. Finally, with respect to such technical
issues, the calculated forearm NE plasma appearance rate, which
includes an extraction term, has been reported to be influenced to a
lesser degree by local changes in NE clearance and blood flow (7) than
the spillover rate (8). However, the pattern of findings reported here
was the same when expressed as the appearance rate, albeit with larger variances, as it was when expressed as the spillover rate in both study 1 and study
2.
Compared with the plasma NE concentration and the SNESO, the FNESO was
more variable when measured three times with the subjects in the supine
position, perhaps because of variation in the measurement of forearm
blood flow.
To assess the extent to which increments in plasma NE concentrations
during hyperinsulinemia and hypoglycemia are the result of sympathetic
neural activation, adrenomedullary activation, or both, subjects were
studied (in the supine position) during saline infusion,
hyperinsulinemic euglycemia, and hyperinsulinemic hypoglycemia.
Euglycemic hyperinsulinemia caused increments in FNESO and apparent
increments in SNESO and plasma NE levels, with no change in plasma
epinephrine concentrations. Thus hyperinsulinemia per se stimulates the
sympathetic neural, but not the adrenomedullary, component of the
sympathochromaffin system. This pattern, a significant increment in
FNESO without significant increments in plasma NE or SNESO, suggests
that the forearm NE spillover measurement, like microneurography (22),
is a more sensitive measure of sympathetic neural activation than the
plasma NE concentration (or the SNESO) at least under this condition.
Our finding of unaltered plasma epinephrine concentrations during
hyperinsulinemic euglycemia is consistent with most, but not all,
previous studies. For example, Tack et al. (49) found 90 min of
hyperinsulinemic euglycemia to be associated with statistically significant increments in arterial plasma epinephrine concentrations. However, the increments were small (from 240 ± 40 to 340 ± 50 pmol/l); the stimulated levels were probably not high enough to exert
biological effects (12, 13).
Plasma epinephrine concentrations (and forearm blood flows) did not
change during hyperinsulinemic euglycemia but increased substantially
during hyperinsulinemic hypoglycemia. Clearly, hypoglycemia per se
stimulates adrenomedullary activity. Despite an apparent stepwise
increase from the
T1 (saline) to
the T2
(hyperinsulinemia euglycemia) to the
T3
(hyperinsulinemic hypoglycemia) time segments in the euglycemic to
hypoglycemic limb, increments in plasma NE concentrations from
T1 to
T3 (ANOVA,
P = 0.11) and from
T2 to T3 (ANOVA,
P = 0.05) were not significantly
greater than those in the euglycemic limb. Similarly, despite an
apparent stepwise increase from the
T1 to the
T2 to the
T3 time segments
in the euglycemic to hypoglycemic limb, increments in SNESO from
T1 to T3 were not
significantly greater than those in the euglycemic limb (ANOVA,
P = 0.14), although the increments from
T2 to
T3 were
significantly greater (ANOVA, P < 0.05). Although the latter finding suggests greater NE release during
hyperinsulinemic hypoglycemia than during comparably hyperinsulinemic
euglycemia, it does not identify the source. Given substantial
adrenomedullary stimulation, evidenced by a ninefold increase in plasma
epinephrine concentrations, it is conceivable that the additional NE
was derived from the adrenal medullas. The forearm NE spillover data
are consistent with that interpretation. Neither the absolute values
nor the increments in FNESO were greater in the euglycemic to
hypoglycemic limb than in the euglycemic limb. Thus the present data do
not provide direct support for the concept that hypoglycemia per se also stimulates the sympathetic neural component of the
sympathochromaffin system. As in study
1, there was considerable scatter in the forearm NE
spillover data in study 2. That, and
our small samples sizes, might have obscured differences between the
magnitude of the responses to hyperinsulinemic hypoglycemia and
euglycemia. Nonetheless, although the present data do not exclude the
possibility that hypoglycemia per se stimulates sympathetic neural
activity in sites other than the forearm, they are consistent with the
possibility that hypoglycemia per se stimulates the adrenal medullas
and not the sympathetic nervous system.
To our knowledge, all studies of sympathetic neural responses to
hypoglycemia have employed insulin-induced hypoglycemia and are,
therefore, potentially confounded by insulin-stimulated sympathetic neural activity. We are not aware of published studies, using microeurography, regional NE spillover, or microdialysis to measure sympathetic neural activity separately from adrenomedulary activity, that have contrasted sympathetic neural activity during
hyperinsulinemic euglycemia and hyperinsulinemic hypoglycemia over the
same time frame as was done in the present study. However, using
microneurography, Frandsen et al. (19) found increments in muscle
sympathetic nerve activity during hyperinsulinemic euglycemic clamps
and further increments during subsequent hypoglycemic clamps at the
same insulin infusion rate in healthy human subjects.
Hyperinsulinemia per se lowered plasma C-peptide and glucagon levels,
raised blood lactate levels, and suppressed nonesterified fatty acid
levels. Hyperinsulinemic hypoglycemia lowered plasma C-peptide levels
further and raised plasma glucagon, epinephrine, NE, pancreatic
polypeptide, growth hormone and cortisol levels, and SNESO and FNESO.
Despite adrenomedullary activation and increased growth hormone and
cortisol secretion, serum nonesterified fatty acid levels remained
suppressed, an effect attributable to the potent antilipolytic action
of ongoing hyperinsulinemia and the relatively short duration of
activation of these lipolytic factors.
Although it is a simple and often useful index, the plasma NE
concentration is a fallible index of sympathetic neural activity because circulating NE can be derived from sympathetic nerve terminals, the adrenal medullas, or both and because of regional differences in
sympathetic neural activity under various conditions. Albeit in the
uncommon circumstance of prolonged standing, the present data indicate
that increments in plasma NE concentrations (and SNESO) can be
dissociated from sympathetic neural activity in one region, the
forearm, as assessed by the FNESO. Furthermore, the present data
confirm that hyperinsulinemia per se stimulates sympathetic neural
activity (1, 2, 4, 5, 9, 29, 39, 47, 50, 55), here assessed with the
FNESO, without stimulating adrenomedullary activity, an issue that is
still debated (33). Finally, although they confirm that hypoglycemia
per se activates adrenomedullary activity (45), the present data do not
provide direct support for the concept that hypoglycemia per se
stimulates sympathetic neural activity (3, 4, 17, 31). Increments in
forearm NE spillover during hyperinsulinemic hypoglycemia were not
significantly greater than those during hyperinsulinemic euglycemia.
 |
ACKNOWLEDGEMENTS |
We acknowledge the technical assistance of Krishan Jethi, Mary
Hamilton, Joy Brothers, Carolyn Fritsche, and Zina Lubovich, the
assistance of the nursing staff of the Washington University General
Clinical Research Center, and the assistance of Kay Kerwin in the
preparation of this manuscript.
 |
FOOTNOTES |
This work was supported, in part, by National Institutes of Health
Grants R01 DK-27085, M01 RR-00036, P60 DK-20579, and T32 DK-07120 and
by a fellowship grant from the American Diabetes Association.
The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement"
in accordance with 18 U.S.C. §1734 solely to indicate this fact.
Address for reprint requests: P. E. Cryer, Campus Box 8127, Washington
Univ. School of Medicine, 660 South Euclid Ave., St. Louis, MO 63110.
Received 11 March 1998; accepted in final form 28 July 1998.
 |
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