Clinical Science (2000) 98, 627–632 (Printed in Great Britain)
The increase in sympathetic nerve activity after
glucose ingestion is reduced in type I diabetes
Jan FAGIUS* and Christian BERNE†
*Departments of Neurology and Clinical Neurophysiology, University Hospital, S-751 85 Uppsala, Sweden, and
†Department of Internal Medicine, University Hospital, S-751 85 Uppsala, Sweden
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Food intake is followed by an increase in baroreflex-governed sympathetic outflow to muscle
vessels. It is established that insulin contributes to this stimulation ; however, the increase occurs
(to a lesser degree) even in the absence of enhanced insulin secretion. To further elucidate
the role of insulin, muscle nerve sympathetic activity was recorded by microneurography,
and the increase after an oral 100-g glucose load in eight C-peptide-negative patients with type
I diabetes without any signs of neuropathy was compared with that in 16 healthy control
subjects. The level of sympathetic activity at rest was similar in the two groups (type I diabetes
patients, 19.5p2.4 bursts/min ; controls, 20.4p4.8 bursts/min ; meanspS.D.). Following glucose
intake there was a significant increase in activity in both groups, with maximum values at 30 min
of 24.3p3.7 bursts/min for type I diabetes patients and 34.4p9.1 bursts/min for controls. The
summarized response (during 90 min) of the diabetic patients was less than half that of the
control subjects (P l 0.0003). It is concluded that the response of muscle nerve sympathetic
activity to glucose ingestion is reduced to about half of its normal strength in the absence of
insulin, and that there is no difference in sympathetic outflow at rest between healthy subjects
and diabetic patients without polyneuropathy.
INTRODUCTION
Nutrient intake is followed by activation of the sympathetic nervous system in healthy humans [1–5]. In type
I diabetes the cardiovascular and noradrenaline response
to glucose intake is reduced, but is normalized by insulin
infusion [6]. In 1981 insulin was shown to exert a direct
effect, unrelated to hypoglycaemia, on human plasma
noradrenaline levels, indicating sympathetic nervous
system activation [7]. In view of the finding that high
blood pressure is associated with insulin resistance [8–10],
increasing attention has been paid to the influence of
insulin on sympathetic nerve activity and on blood
pressure regulation [11].
Using microneurography, it has been shown that the
blood pressure regulating and baroreflex-governed
muscle nerve sympathetic activity (MSA) [12] markedly
increases after food ingestion [3–5], and also increases
significantly during hyperinsulinaemic euglycaemic
clamps in both healthy and diabetic subjects [13–20].
Intake of nutrients (fat, protein) or xylose, which elicits
marginal or no insulin secretion, is followed by increased
MSA [3,4], indicating that insulin only accounts for a part
of the MSA response to a meal.
Key words : baroreflex, blood pressure regulation, eating, glucose ingestion, insulin, microneurography, sympathetic nervous
system, type I diabetes.
Abbreviation : MSA, muscle nerve sympathetic activity.
Correspondence : Dr Jan Fagius, Department of Neurology, University Hospital, S-751 85 Uppsala, Sweden (e-mail
jan.fagius!neurologi.uu.se).
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J. Fagius and C. Berne
In order to discriminate further between the role of
insulin and the effects of ingestion of glucose, we
investigated the response of MSA to an oral glucose
load in young, C-peptide-negative patients with type I
diabetes without signs of polyneuropathy, and compared
it with that in young, healthy subjects.
MATERIALS AND METHODS
the Declaration of Helsinki, and the study protocol was
approved by the Ethics Committee at the Medical Faculty
of Uppsala University.
Glucose intake
Anhydrous D-glucose (100 g) was dissolved in 300 ml of
water [energy content 1750 kJ (420 kcal)] and ingested in
the lying position through a straw once the MSA
recording position was attained (see below).
Subjects
Eight C-peptide-negative subjects (three men and five
women) with type I diabetes participated in the study.
Their age was 27.8p6.0 years (meanpS.D.), and the time
since onset of diabetes was 9.9p6.4 years. Haemoglobin
A1c was 7.3p1.1 % (range 5.7–8.8 %) and body mass
index was 23.3p2.1 kg\m#. All patients were treated
with three or four doses of soluble insulin before meals,
and with protamine or lente insulin at bedtime. Their
mean daily insulin dose was 56.3p14.3 units. No patient
had microalbuminuria on repeated tests, and four had
mild background retinopathy, as assessed by fundus
photography.
No patient had any symptoms of polyneuropathy.
Achilles tendon reflexes and vibration sense in the
toes were normal. The extensor digitorum brevis muscles
were intact. Motor nerve conduction velocity of the right
peroneal nerve, measured by standard techniques, was
normal (46.0p3.6 m\s ; k1.0p0.6 S.D. from the age and
body height weighted normal value). The sural sensory
nerve conduction velocity was 47.5p6.0 m\s (k0.7p0.5
S.D. from the normal value). All individual neurophysiological parameters were within normal limits.
Autonomic nerve function was assessed in three ways :
R-R interval variation during deep breathing at 0.1 Hz
(expressed as the ratio between the longest and the
shortest R-R interval), the Valsalva ratio (longest R-R
interval after a 15-s Valsalva manoeuvre divided by
shortest R-R interval during the strain), and R-R interval
variation with active movement from lying to standing
(the ‘ 30\15-ratio ’). The first of these tests evaluates vagal
heart rate regulation, whereas the other two are considered to include both vagal and sympathetic influence
on the heart [21]. The resulting ratios were 1.44p0.1,
1.79p0.4 and 1.64p0.3 respectively, i.e. normal values
for all participating patients [22,23].
The control group comprised 16 young, lean, healthy,
non-smoking volunteers (10 men and six women). Their
age was 25.9p2.4 years and their body mass index was
21.5p2.3 kg\m# (not significantly different from the
diabetic subjects). The sex ratio was not exactly the same
in the patient and control groups, but levels of MSA are
similar in male and female subjects [24].
All subjects participated after providing informed
consent. The study was carried out in accordance with
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Recordings
Subjects lay supine and comfortably in a quiet room with
an ambient temperature of approx. 23 mC. For MSA
recording, a tungsten microelectrode was inserted manually into the peroneal nerve at the right fibular head, as
described in detail previously [3,4,12,14]. Blood pressure
was measured continuously by a photoplethysmographic
finger cuff method, with the cuff applied to the right
middle finger (Finapres2 ; Ohmeda, Englewood, CO,
U.S.A.) [4]. ECG was recorded by chest surface electrodes.
All recorded signals were printed out on-line on paper,
and in addition were stored on tape for subsequent
analysis (FM tape recorder ; Sangamo Weston-Schlumberger, Sarasota, FL, U.S.A.).
General procedure
The subject arrived at the laboratory at 08.00 hours after
an overnight fast. No insulin was taken on the morning of the study. An indwelling Teflon catheter was
inserted into the left brachial vein. The procedure was
continued only if plasma glucose in the diabetic patients
was 3.5 mmol\l, since hypoglycaemia acts as a potent
activator of MSA [25,26].
When an electrode site yielding MSA with an acceptable signal-to-noise ratio was found, the activity was
monitored at rest for 20 min, whereupon the glucose
solution was given over 1–4 min.
In 13 healthy subjects and six diabetic subjects the
recording was stable throughout the experimental procedure. Therefore assessment of both burst frequency
and amplitude (see below) could be made. In three
healthy and two diabetic subjects, leg movements
changed the MSA recording position, and hence only
burst frequency was assessed.
Blood samples for determination of glucose were taken
15 min before, immediately before, and at 15, 30, 45, 60,
75 and 90 min after glucose ingestion.
In two of the diabetic patients the procedure was
repeated with insulin infusion at a rate corresponding
to the physiological secretion of insulin in healthy
subjects (algorithm according to Hegedu$ s et al. [6]).
Otherwise the procedure was identical. This procedure
Sympathetic response to glucose in type I diabetes
was intended to be performed in all diabetic subjects, but
after failure to find an acceptable recording position on
the second occasion in three consecutive patients this
intention was abandoned, in order to avoid repeated
exploration of the diabetic patients’ nerves.
Analysis procedure
Bursts of MSA were counted in 6-min periods
corresponding to the blood sampling occasions, and the
outflow was expressed as bursts\min (burst frequency).
Heart rate was recorded simultaneously.
The strength of an individual burst is reflected by the
burst amplitude in the mean voltage neurogram, and is
critically dependent on the intraneural electrode position.
Thus it cannot be compared between recordings, but
within a given recording assessment of burst amplitude
can be made, provided that the electrode position is
unchanged [3,25]. The recording remained stable in 13
healthy and six diabetic subjects, thus allowing measurement of burst amplitude at baseline and at the time of
maximal outflow of MSA. Thereby the amplitude of 50
consecutive bursts constituted the mean amplitude for
the period of analysis ; the measurement was made, in
arbitrary units, on a digitizing board (Hipad ; Houston
Instruments, Austin, TX, U.S.A.) connected to a computer.
The course of blood pressure was obtained from the
Finapres2 device, which delivers a continuous pressure
signal and numerical values for systolic and diastolic
pressure ; these are the averages of measurements every
2 s. From ten consecutive values noted every 1–2 min
throughout the experiment, a mean value for those
periods was obtained. The average of three or four such
mean values constituted the individual blood pressure
levels for each analysis period. Mean blood pressure was
calculated as diastolic pressurej1\3ipulse pressure.
Plasma glucose was analysed using a glucose oxidase
technique (Beckman model 2 ; Beckman Instruments,
Palo Alto, CA, U.S.A.). Fasting C-peptide was measured
by radioimmunoassay (RIA-gnost C-peptide ; Svenska
Hoechst, Stockholm, Sweden), with a lower detection
limit of
0.05 nmol\l. Haemoglobin A1c (reference
range 3.8–5.2 %) was measured by FPLC. Microalbuminuria was assessed by immunoturbidimetry. The
analyses were carried out in the routine service of the
Department of Clinical Chemistry, University Hospital,
Uppsala.
Statistical methods
Results are expressed as meanspS.D. The courses of
MSA, blood pressure, heart rate and plasma glucose for
each group of subjects were analysed by analysis of
variance (ANOVA, repeated measures) with Dunnett’s
t-test for multiple comparisons. Student’s t-test for
unpaired observations was applied when appropriate. A
P value 0.05 was considered statistically significant.
Figure 1
Plasma glucose levels following glucose ingestion
Glucose (100 g in 300 ml of water) was ingested at time 0 by patients with
type I diabetes (upper curve) and by control subjects.
Figure 2 Representative examples of MSA at rest and 30 min
after glucose ingestion in a healthy subject (A) and in a
patient with type I diabetes (B)
Mean voltage neurograms are shown, with the same time-scale in all panels.
Subjects ingested 100 g of glucose in 300 ml of water.
RESULTS
Plasma glucose
The course of plasma glucose for the two groups is
displayed in Figure 1. In the diabetic subjects the fasting
plasma glucose was relatively high (9.7p6.3 mmol\l),
since morning insulin was omitted. Their plasma glucose
reached 19.5p5.7 mmol\l at 90 min.
Sympathetic nerve activity
MSA at rest was similar in the control and diabetic
subjects, with values of 20.4p4.8 and 19.5p2.4 bursts\
min respectively at time 0 (P l 0.6).
In both groups of subjects, glucose ingestion was
followed by an increase in MSA, as exemplified in Figure
2 and summarized in Figures 3 and 4. For control subjects
the increase was highly significant (P 0.001) between
15 and 90 min after glucose intake, whereas the diabetic
subjects displayed a more moderate, albeit significant,
increase between 15 and 75 min (Figure 3). MSA peaked
at 30 min, reaching 24.3p3.7 bursts\min for the diabetic
patients and 34.4p9.1 bursts\min for the controls. For
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J. Fagius and C. Berne
correlate the bedtime insulin dose and the MSA response
to glucose, but no such correlation was found.
In the two diabetic patients given an insulin infusion,
the increase in MSA burst frequency was twice that
obtained in the absence of insulin (mean 50.8 compared
with 24.5 arbitrary units). As shown in Figure 4, the mean
response to glucose ingestion in these two subjects was
similar to that of all diabetic subjects, whereas the increase
in MSA on insulin infusion reflected that of the controls.
Blood pressure and heart rate
Figure 3 Time course of MSA (burst frequency) after glucose
intake in 16 healthy subjects ($) and eight patients with
type I diabetes (>)
Upper and lower asterisks indicate the level of significance compared with the
value at time 0 for the healthy and diabetic subjects respectively : *P 0.05,
**P 0.01, ***P 0.001.
Mean blood pressure remained stable in the diabetic
patients, whereas the control subjects displayed a minor
but significant increase towards the end of the experiment
(from 91p7 mmHg at time 0 to 95p7 mmHg at 90 min ;
P 0.01).
Mean heart rate was 62 beats\min at time 0 and 68
beats\min at 30 min in the control subjects (P 0.001) ;
the corresponding values for the diabetic subjects were 61
and 64 beats\min respectively (P 0.05).
DISCUSSION
Figure 4
Response of MSA to glucose ingestion
Values represent areas under the curves in Figure 3 for 16 healthy subjects (A) and
eight patients with type I diabetes (B) (***P 0.001). Bar C represents results
from two of the diabetic subjects, redisplayed separately, for comparison with
results after a second procedure (D), whereby insulin was added at a physiological
post-prandial level (see the text). No statistics apply to bars C and D, since
n l 2.
comparison of the total response of the two groups of
subjects, the areas under the curves of Figure 3 were
calculated, from baseline to a vertical line drawn at time
90 min. This area was significantly greater for the controls
than for the diabetic subjects (61.5p26.5 and 18.8p14.0
arbitrary units respectively ; P l 0.0003 ; Figure 4, bars A
and B).
Both groups also displayed an increase in burst
amplitude, with a mean increase of 20p9 % in the
diabetic patients (n l 6 ; see the Materials and methods
section) and 38p25 % in the control subjects (n l 13).
The range for the increase in amplitude was wide, and the
difference did not reach statistical significance (P l 0.10).
Since the possibility cannot be ruled out that some
long-acting insulin was still present in some diabetic
patients from the pre-study day, attempts were made to
# 2000 The Biochemical Society and the Medical Research Society
The main results of the present study were that patients
with type I diabetes without polyneuropathy displayed
an MSA response to glucose ingestion that was less than
half that of a group of healthy controls, and that the level
of MSA at rest was similar in the two groups.
Food intake is followed by a marked and sustained
increase in MSA. This response is greatest following
ingestion of glucose, whereas the response to other
nutrients is weaker [4]. Euglycaemic hyperinsulinaemia
is also accompanied by enhanced MSA [13–20],
suggesting that insulin secretion contributes to the
increase in MSA after food intake. The magnitude of
the response after insulin is, however, weaker than that
after glucose intake [14]. Moreover, ingestion of protein
and fat meals [4] or intake of the metabolically inert
hexose xylose [3], which are followed by a minor or no
insulin response, also causes a significant and sustained
increase in MSA, which is also weaker than that after
glucose intake. Vehicle (water) ingestion causes no change
in MSA [3,4].
Thus MSA seems to be dually stimulated after food
ingestion, directly from the gastrointestinal tract and by
secreted insulin. This assumption is corroborated by the
present observations in C-peptide-negative diabetic
patients, showing an increase in MSA after glucose intake
in the absence of endogenous insulin. Secondly, the
importance of insulin for the normal MSA response is
reflected by the diminished increase in MSA in diabetic
patients compared with control subjects. The difference
between MSA responses in control and diabetic subjects
is similar to that in healthy subjects following glucose
Sympathetic response to glucose in type I diabetes
compared with protein or fat ingestion [4], the latter
eliciting negligible insulin secretion.
In the two patients in whom we could successfully
carry out a second investigation with insulin infused at a
level corresponding to normal post-prandial physiological secretion, the responses in the absence and
presence of insulin corresponded well with the mean
responses of the diabetic and control subjects respectively
(see Figure 4). This observation is in agreement with that
of Hegedu$ s et al. [6], who reported a low noradrenaline
response to oral glucose in patients with type I diabetes
and a normalization when insulin was added at a
physiological dose. Since our observations are restricted
to two subjects, however, conclusions must be cautious.
Delayed gastric emptying is a feature of diabetic
autonomic neuropathy [27], but may also be a consequence of hyperglycaemia itself, according to recent
observations [28]. Our patients had no signs of neuropathy, but the possibility cannot be ruled out that
different time courses of gastric emptying in control
and diabetic subjects contributed to a minor degree to
the observed differences in MSA responses to glucose
intake. The high plasma glucose level in the diabetic
subjects and the weak and transient increase in MSA
corroborates and reinforces previous observations that
hyperglycaemia itself does not stimulate MSA [3,16].
The increase in MSA after food intake is believed to be
a compensatory phenomenon, preventing a fall in blood
pressure during the post-prandial redistribution of
blood [4,24]. Our control subjects displayed a slight
increase in blood pressure, which was not observed
in the diabetic patients, but the blunted increase in
MSA in the latter group was not accompanied by any
detectable fall in blood pressure. In subjects with
autonomic neuropathy, MSA is scarce and difficult to
detect [29]. In this situation the MSA response (and
presumably sympathetic outflow to other vessel beds) to
both injected insulin and food ingestion is likely to be
defective, thereby contributing to post-insulin and postprandial hypotension [30,31].
The diabetic patients were selected to have intact
peripheral and autonomic nerve function, and MSA at
rest did not differ between the diabetic and control
subjects. Hoffman et al. [32] reported a lowered burst
frequency in diabetic subjects without overt polyneuropathy, and interpreted this as a subclinical sign of
polyneuropathy (an interpretation that might be
questioned [33]). The peripheral nerve function of our
patients, documented in detail, was within normal limits.
With a rigorous interpretation, the fact that the patients’
conduction velocities were 0.7–1 S.D. below the age- and
height-weighted normal values might be regarded as a
slight tendency towards reduced nerve function. If so,
resting MSA would be expected to be decreased in our
patients to conform with the quoted results [32], but we
were unable to confirm this observation.
In conclusion, the present study shows that there is a
dual stimulation of MSA after food intake, and that the
total response is reduced by about one-half in the absence
of endogenous insulin secretion. It is also concluded that
MSA at rest is similar in healthy subjects and in those
with type I diabetes without polyneuropathy.
ACKNOWLEDGMENTS
This work was supported by the Swedish Medical
Research Council (grant no. 10839), and by grants from
the Ernfors Foundation for Diabetes Research, the
Research Fund of the Swedish Diabetes Association, and
Novo Nordisk, Sweden.
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Received 1 November 1999/14 January 2000; accepted 11 February 2000
# 2000 The Biochemical Society and the Medical Research Society