Redistribution of Sudomotor Responses Is an Early Sign of Sympathetic Dysfunction in Type 1 Diabetes
Robert D. Hoeldtke,
Kimberly D. Bryner,
Gabriella G. Horvath,
Robert W. Phares,
Lance F. Broy, and
Gerald R. Hobbs
From the Department of Medicine (R.D.H, K.D.B., G.G.H., R.W.P., L.F.B.)
and the Departments of Community Medicine and Statistics (G.R.H.), West
Virginia University, Morgantown, West Virginia.
Address correspondence and reprint requests to Robert D. Hoeldtke, MD, PhD,
Department of Medicine, WVU Medical School, P.O. Box 9159, Morgantown, WV
26506-9159. E-mail:
rhoeldtke{at}hsc.wvu.edu
.
 |
ABSTRACT
|
---|
Patients with diabetic neuropathy typically have decreased sweating in the
feet but excessive sweating in the upper body. Previous studies of sudomotor
function in diabetes have included patients with long-standing disease. The
present study was designed to test for the early presence of sudomotor
dysfunction and to characterize its relation to glycemic control and other
aspects of peripheral nerve function. A total of 37 patients (10 males, 27
females) enrolled in a longitudinal study, in which autonomic function was
evaluated annually for 3 years. Patients enrolled 2-22 months after the
diagnosis of type 1 diabetes. Forty-one age- and sex-matched healthy control
subjects were also studied. Sweat production in response to acetylcholine
stimulation was dramatically increased in the forearm at the time of the first
evaluation (1.67 ± 0.24 µl/cm2 in the diabetic patients
vs. 1.04 ± 0.14 µl/cm2 in the control subjects,
P < 0.05). Likewise, the ratio of sweating in the forearm to
sweating below the waist was higher in the diabetic patients (0.553 ±
0.07 µl/cm2) than in the control subjects (0.385 ± 0.04
µl/cm2, P < 0.05). Forearm sweat was negatively
associated with the renin-to-prorenin ratio and vanillylmandelic acid (VMA)
excretion (P < 0.025), tests of sympathetic nerve function. The
ratio of sweating in the forearm to sweating in the foot was likewise
increased in diabetic patients with poor glycemic control. We interpret this
redistribution of sudomotor responses to be indicative of sympathetic nerve
injury and conclude 1) that the sympathetic nervous system is
especially vulnerable to the adverse effects of chronic hyperglycemia and
2) that sympathetic dysfunction can be detected very early in type 1
diabetes.
 |
INTRODUCTION
|
---|
It is widely recognized that sympathetic denervation leads to decreased
sudomotor responses, atrophy of sweat glands, and eventually anhidrosis
(1,2).
Paradoxically however, sympathetic nerve injury can also cause hyperhidrosis,
which is a common complication of sympathectomy
(3,4).
Hyperhidrosis in patients with sympathetic dysfunction may occur adjacent to
an anhidrotic lesion or at a remote location. Decreased sweating in the feet
of patients with diabetic neuropathy is typically associated with excessive
sweating elsewhere, most often in the face or neck
(1). Although it seems as if
the remaining sweat glands are excessively active to compensate for those that
have been denervated or atrophied, this theory has been difficult to test, and
the pathophysiology of compensatory hyperhidrosis remains obscure.
Previous studies of sudomotor function in diabetes have been performed on
patients with longstanding disease, many of whom had overt neuropathy and
sudomotor dysfunction. The early natural history of sudomotor function,
particularly its relation to other aspects of autonomic function and glycemic
control, has not yet been described.
The purpose of the present research was to determine whether sudomotor
dysfunction could be detected early in type 1 diabetes in patients with intact
somatosensory and cardiovascular autonomic nerve function. Patients were
recruited <2 years after the onset of diabetes and studied longitudinally
for 3 years. Patients had a comprehensive annual evaluation of cardiovascular
autonomic and sudomotor function. We were also interested in comparing
sudomotor function, a cholinergic sympathetic activity, with adrenergic
sympathetic events known to be affected by diabetes. Because the adrenergic
nervous system is the major site of norepinephrine synthesis, we measured
vanillylmandelic acid (VMA) excretion, which is an index of norepinephrine
production and known to be decreased in patients with autonomic neuropathy
(5,6).
The sympathetic nervous system also promotes the processing of prorenin and
the synthesis and secretion of renin; therefore, we measured the plasma
renin-to-prorenin ratio, which is known to be diminished in diabetic autonomic
neuropathy
(7,8).
 |
RESEARCH DESIGN AND METHODS
|
---|
Patients. A total of 37 patients (10 males, 27 females) with type 1
diabetes enrolled 2-22 months after diagnosis in a longitudinal study of
autonomic nerve function (Table
1). Patients with symptoms of neuropathy, other systemic
illnesses, or excessive alcohol consumption (an average of more than two
drinks per day) were excluded from the study. All patients were taught to
monitor their glucose levels at home and to adjust their insulin doses as
necessary to maintain optimal glycemic control. HbA1 was measured
one to four times a year for 3 years. A total of 36 patients underwent three
annual evaluations, and 1 patient withdrew after the second year. None of the
patients complained of decreased sweating or hyperhidrosis.
The diabetic patients were admitted to beds designated for research at West
Virginia University Hospital to control their dietary intake, activity, and
glucose before and during the annual autonomic function testing. Glucose was
monitored before each meal and snack and at 3:00 A.M., and insulin adjustments
were made as needed. Patients were administered a weight-maintaining diet
containing 130 mEq sodium daily. Caffeine, aspirin, and cigarettes were not
allowed on the morning of the tests because of possible effects on autonomic
function.
Autonomic function tests were also performed in 41 age- and sex-matched
healthy control subjects to provide a basis of comparison with the diabetic
patients. The control subjects were also admitted to the hospital,
administered the same diet, and subjected to the same restrictions.
The research protocol was approved by the Institutional Review Board of
West Virginia University Hospital, and informed consent was obtained from the
participants.
Cardiovascular autonomic function
Beat-to-beat variation with deep breathing. Patients were
studied in the supine posture after relaxing comfortably for at least 10 min.
Heart rate was monitored electrocardiographically while they breathed slowly
(5 s inspiration/5 s expiration), as deeply as possible, for 5 min. The
difference between the maximum and minimum instantaneous heart rates reflects
the integrity of the parasympathetic innervation of the heart
(9). In addition, vector
analysis of the instantaneous heart rate was performed, and mean circular
resultant was determined. This alternative index of heart rate variability
minimizes error introduced by variation in intrinsic heart rate or ectopic
cardiac beats (10).
Heart rate response to the Valsalva maneuver. Heart rate was
monitored electrocardiographically while patients were supine and instructed
to expire into a sphygmomanometer until a pressure of 40 mmHg was maintained
for 20 s. The Valsalva ratio was calculated by dividing the maximal
instantaneous heart rate during the maneuver by the minimal heart rate
observed after release (11).
The test was performed twice and the average result calculated. A normal
response (ratio >1.15) indicates that the baroreceptor reflex and the
efferent limb of the sympathetic nervous system are intact.
Small fiber somatosensory function. Quantitative sensory testing was
used to assess small and thinly myelinated A delta fibers, which convey cold
sensation, and C fibers, which convey heat. The hot and cold stimuli were
applied to the dorsal aspect of the feet and the wrist, and participants were
asked to distinguish between progressively small thermal stimuli until they
were no longer able to detect the change in temperature
(12). Specific thermal
thresholds were then determined by a microprocessor-controlled forced-choice
technique (Neurolink, East Lyme, CT). Thresholds were determined on two
separate days, and the average performance was calculated for each of the four
parameters of interest (heat-threshold feet, cold feet, heat wrist, and cold
wrist).
Sudomotor function. Sudomotor function was assessed with the
quantitative sudomotor axon reflex test (QSART)
(13). Sweat production was
quantitated in a circular sweat cell connected to the sudorometer (Abrams
Instrument, Okemos, MI). The sweat cell was applied to the skin; an inner air
chamber was connected to a dry nitrogen gas (2-5% absolute humidity); and
acetylcholine (10%) was placed in an outer chamber from which it was applied
to the skin by iontoelectrophoresis using a constant-current (1 mA for 5 min)
generator (World Precision Instruments, Sarasota, FL). Sweating was
quantitated by measuring the change in relative humidity of the nitrogen
flowing through the inner chamber. Chart recordings proportional to relative
humidity were integrated with respect to time, using a HiPad digitizer
(Houston Instruments, Austin, Tx) and a Bioquant II Computer Analysis Program
(R and M Biometrics, Nashville, TN). Four sweat capsules were used. One was
placed on the left forearm, 25% of the distance from the pisiform bone to the
ulnar epicondyle; one was placed over the anterior surface of the distal left
leg; one over the proximal left leg; and one over the proximal left foot, over
the extensor digitorum brevis muscle. Total sweat was calculated by taking the
sum of sweat produced in the four sites.
Biochemical measurements
HbA1. HbA1 was measured by agar gel
electrophoresis (14). The
reference range for the nondiabetic population was 4.7-7.3%.
Renin and prorenin. Active renin was measured as the rate of
conversion of renin substrate to angiotensin I by plasma collected in EDTA
(15). Total renin (active plus
inactive) was prepared in a separate 1-ml aliquot of plasma by preincubating
the latter for 1 h with 10 µg trypsin from porcine pancreas (Sigma, St.
Louis, MO). Total and active renin were then assayed by determining
angiotensin I by radioimmunoassay using 125I-labeled angiotensin I
(INCStar, Stillwater, MN). Prorenin was calculated as the difference between
total and active renin (16).
To avoid the confounding effect of ovarian prorenin, blood sampling was
rescheduled for women who were menstruating at the time of their annual
evaluation (17).
Vanillylmandelic acid. Urinary VMA was measured by high-performance
liquid chromatography and coulometric detection using isoVMA as an internal
standard (18).
Statistical analysis. Analysis of variance was used to test
differences between diabetic patients and control subjects and differences
between years in the longitudinal study
(19). Association between
biochemical parameters and sudomotor function was assessed using regression
analysis (20).
 |
RESULTS
|
---|
None of the diabetic patients developed signs or symptoms of neuropathy,
microvascular disease, or other diabetic complications during the course of
this study. One patient developed hypertension. Of the 37 patients, 20
maintained their HbA1 concentrations within American Diabetes
Association guidelines (<1% above the upper limit of normal for patients
without diabetes). Patients with good control had the same age and sex
distribution as those with poor control.
Cardiovascular autonomic function in the diabetic patients was similar to
that in the control subjects. Heart rate variability with deep breathing was
slightly greater in the diabetic patients than in the control subjects during
the first and second evaluations (Table
2). At the time of the third evaluation, the post-Valsalva R-R
interval was 1.83 ± 0.07, significantly lower (P < 0.05)
than that of control subjects (2.02 ± 0.06).
The renin-to-prorenin ratio of the diabetic patients was
50% that of
the control subjects at each evaluation (P < 0.01 each year)
(Table 2). Urinary sodium had a
negative correlation with plasma renin, a positive correlation with prorenin,
but no correlation with the renin-to-prorenin ratio. VMA excretion was
decreased in the diabetic patients only at the third evaluation (2.43 ±
0.17 vs. 3.01 ± 0.19 mg/g creatinine, P < 0.05).
Sweat production in response to acetylcholine iontophoresis was
dramatically increased in the forearms of the diabetic patients at the first
evaluation (1.67 ± 0.24 vs. 1.04 ± 0.14 µl/cm2 in
the control subjects, P < 0.05)
(Table 3). Smaller increases at
other sites during the first patient evaluation were not significant, but
total sweat was increased (5.09 ± 0.54 µl/cm2 in the
diabetic patients vs. 3.90 ± 0.41 in the control subjects, P
< 0.05). Forearm and total sweat were normal in the diabetic patients
during subsequent evaluations. Sweating in the feet and sweating below the
waist were not different in the diabetic versus the nondiabetic patients.
However, the ratio of sweating in the forearm to sweating below the waist was
dramatically increased at the time of the first evaluation (0.553 ±
0.07 vs. 0.385 ± 0.04 µl/cm2, P < 0.05).
Sweat production tended to be greater in the males than in the females for
both the control subjects and the diabetic patients, but the effect of sex was
not statistically significant (Table
4). The female diabetic patients produced sweat at rates equal to
or greater than that of the nondiabetic males. Age had no effect on sweat
production.
To assess the effect of glycemic control on sweat production, we divided
patients according to whether their average HbA1 was above or below
the median for all patients. The average HbA1 for those in the low
HbA1 group (14 female, 6 male) was 7.66 ± 0.16%, whereas the
average HbA1 for those in the high HbA1 group (13
female, 4 male) was 10.0 ± 0.28%. The excessive forearm and total sweat
production at the time of the first patient evaluation was more pronounced in
those with poor control. In the forearm, sweat production in the poorly
controlled diabetic patients was 2.10 ± 0.41 µl/cm2,
greater than that of the well-controlled diabetic patients (1.30 ± 0.26
µl/cm2, P < 0.01) and greater than that of the
control subjects (1.04 ± 0.14 µl/cm2, P <
0.001) (Fig. 1). In the feet,
however, the opposite pattern was seen. At the second evaluation, sweat
production in the feet of the diabetic patients with good versus poor control
was 1.05 ± 0.18 vs. 0.676 ± 0.13 µl/cm2,
respectively (P < 0.05) (Table
5). At the third evaluation, sweat production was 1.36 ±
0.29 µl/cm2 in those with good control and 0.86 ± 0.18
µl/cm2 in those with poor control (P < 0.025).
However, sweating in the feet of the poorly controlled diabetic patients was
not different from that of the control subjects at any time point. The ratio
of forearm sweat to foot sweat was greater (P < 0.01) in patients
with poor control than in patients with good control throughout the study
(Table 5). At the time of the
first evaluation, the ratio of forearm sweating to below-the-waist sweating
was 0.703 ± 0.14 µl/cm2 in the diabetic patients with
poor control, significantly different from those with good control (0.426
± 0.07 µl/cm2) and the control subjects (0.385 ±
0.04 µl/cm2) (P < 0.01). The ratio of forearm to
below-the-waist sweat was significantly greater (P < 0.01) in
patients with poor control than in patients with good control throughout the
study (Fig. 1). Analysis of the
forearm sweat to total sweat and HbA1 as continuous variables
confirmed an association, although it was only of borderline significance
(P < 0.06).

View larger version (26K):
[in this window]
[in a new window]
|
FIG. 1. Effect of glycemic control on forearm sweat, total sweat, and ratio of
sweating above the waist to sweating below the waist. Mean results for
patients whose HbA1 values were below ( ) or above ( ),
respectively, the median for the group, versus that of the control subjects
( ). Forearm sweat is expressed as microliters per square centimeter,
whereas total sweat is expressed as microliters per 4 cm2.
*Different from controls, P < 0.001; different
from diabetic patients with low HbA1, P < 0.01;
different from controls, P < 0.005; different from
controls, P < 0.01; ||different from diabetic patients with low
HbA1, P < 0.01; and ¶diabetic patients with high
versus low HbA1 across all years were different (P <
0.01).
|
|
Sweat production was negatively associated with heart rate variability with
deep breathing. The average total sweat production for each patient during the
3-year study was inversely correlated with their average beat-to-beat
variation with deep breathing (P < 0.05)
(Fig. 2). Weak negative
associations with heart rate variability were noted for sweat production in
the forearm (P < 0.1), the foot (P < 0.05), and below
the waist (P < 0.1). Similar weak negative associations were noted
for the heart-rate response to the Valsalva maneuver and sweat production, but
these were significant only in the foot (P < 0.05).

View larger version (14K):
[in this window]
[in a new window]
|
FIG. 2. Average heart rate variability with deep breathing versus average total
sweat production. The beat-to-beat variation is expressed as the maximum heart
rate during deep breathing minus the minimum heart rate during deep breathing.
Total sweat is expressed as microliters per 4 cm2 of skin. The
average heart-rate variability with deep breathing for each patient during the
3-year study was inversely associated with their average total sweat
production (P < 0.05).
|
|
Thermal threshold detection did not differ between the diabetic patients
and the control subjects (Table
2). There was no correlation between sudomotor function and
thermal threshold detection in the upper extremities. In the feet, thermal
thresholds for cold correlated with sweating at the time of the second
evaluation (P < 0.025). At the third evaluation, the association
approached significance (P = 0.065). The average thermal threshold
for cold in the feet over the entire study was negatively correlated with the
average sweat production in the foot (P < 0.05)
(Fig. 3).

View larger version (15K):
[in this window]
[in a new window]
|
FIG. 3. Average thermal threshold for cold in the feet versus average sweat
production in the foot. The cold threshold is expressed in degrees centigrade.
Sweat production is expressed as microliters per square centimeter. The
average cold threshold for each patient during the 3-year study was inversely
associated with average sweat production in the foot (P <
0.05).
|
|
The renin-to-prorenin ratio was inversely correlated with sweat production.
Forearm sweat production showed a significant negative association with the
renin-to-prorenin ratio for years 1 (P < 0.025)
(Fig. 4) and 3 (P <
0.05) and for the average of years 1, 2, and 3 (P < 0.01). Total
sweat production showed a significant negative association with the
renin-to-prorenin ratio for years 1 (P < 0.01)
(Fig. 4) and 3 (P <
0.05) and for the average of years 1, 2, and 3 (P < 0.05).

View larger version (12K):
[in this window]
[in a new window]
|
FIG. 4. Plasma renin-to-prorenin ratio versus forearm sweat and total sweat at
the first evaluation. Plasma renin and prorenin are both expressed as
nanograms of angiotensin I formed per milliliter of plasma per hour. Forearm
sweat is expressed as microliters per 4 cm2. Forearm and total
sweat were negatively associated with the renin-to-prorenin ratio (P
< 0.025 for both measures of sweat).
|
|
VMA excretion was also inversely associated with sweat production. Forearm
sweat was negatively associated with VMA excretion for year 1 (P <
0.025) (Fig. 5). Total sweat
was negatively associated with VMA for years 1 (P < 0.01)
(Fig. 5) and 2 (P <
0.025) and for the average of years 1, 2, and 3 (P < 0.05).

View larger version (10K):
[in this window]
[in a new window]
|
FIG. 5. VMA excretion versus forearm sweat and total sweat at the first
evaluation. VMA is expressed as milligrams per gram creatinine. Forearm sweat
is expressed as microliters per square centimeter and total sweat as
microliters per 4 cm2. Forearm sweat and total sweat were
negatively associated with VMA excretion (P < 0.05 and P
< 0.01, respectively).
|
|
The renin-to-prorenin ratio was decreased in the well-controlled diabetic
patients as well as in the poorly controlled diabetic patients, but the
changes were more pronounced in the poorly controlled diabetic patients
(Table 6). VMA excretion was
decreased only in the poorly controlled diabetic patients at the third
evaluation (Table 6). The
post-Valsalva R-R interval ratios were lower in the poorly controlled diabetic
patients than in the well-controlled diabetic patients or in the control
subjects (Table 6).
 |
DISCUSSION
|
---|
This study was designed to test for the presence of sympathetic neuropathy
in early type 1 diabetes. In experimental diabetes, sympathetic dysfunction
develops rapidly (21), and
studies of pupillary light reflexes in humans have suggested that this also
occurs in clinical diabetes
(22). In the present study, we
observed a redistribution of sympathetic sudomotor responses at the time of
the first patient evaluation, which was within the first 2 years after
diagnosis. Increased sweating was observed in the forearm, and the ratio of
forearm sweating to the sum of sweating in three sites below the waist was
increased (Table 3) (Fig. 1). A similar
redistribution pattern was observed at the second and third evaluations,
although the ratios of sweating in the forearm to sweating below the waist or
sweating in the feet in poorly controlled diabetic patients were not different
from the ratios in control subjects. Nevertheless, the ratio of sweating in
the forearm to sweating in the foot was higher in the poorly controlled versus
the well-controlled diabetic patients throughout the study
(Table 5). At the second and
third evaluations, the ratio was increased in the poorly versus the
well-controlled diabetic patients because the hyperglycemic group had less
sweat production in the feet than the well-controlled diabetic patients.
Because it is well documented that patients with overt neuropathy have
decreased sweating in the lower extremities and increased sweating in the
upper trunk, head, and neck
(1,2),
we interpret the presently observed redistribution of sudomotor responses as
evidence of sympathetic dysfunction. It is unlikely that the excessive forearm
sweating should be interpreted to mean that sudomotor function is
paradoxically healthier in the diabetic patients than in the control subjects.
The redistribution of sudomotor responses was seen primarily in the diabetic
patients with poor glycemic control (Fig.
1) (Table 5), and the
latter is known to damage the autonomic nervous system
(23). Accordingly, Cardone and
Dyck (21) observed that the
early development of sudomotor dysfunction was evident only in poorly
controlled diabetic rats. In addition, the negative associations between
forearm sweating and biochemical measures of the integrity of the sympathetic
nervous system, VMA excretion and the plasma renin-to-prorenin ratio, also
suggest that excessive sweating at the time of the first evaluation was
indicative of sympathetic nerve injury (Figs.
4 and
5). Moreover, excessive
sweating was associated with worse heart-rate variability with deep breathing,
suggesting that the pathological process taking place in the sympathetic
nervous system was also showing early effects on parasympathetic function
(Fig. 2).
We also tested the function of small somatosensory nerves by measuring
thermal threshold detection. Performance of the diabetic patients was not
different from that of the control subjects on this test. Thus, it appears
that sympathetic nerves are more vulnerable to the adverse effects of chronic
hyperglycemia than other small nerves. Generally, there was little or no
correlation between thermal threshold detection and sudomotor responses.
However, high cold thresholds in the feet were associated with decreased
sweating in the feet (Fig. 3).
This indicates that the decreased sudomotor function in the feet previously
described in patients with chronic diabetes and overt neuropathy begins to
develop early in the disease.
Although decreased sweating in the feet is the anticipated response to
sympathetic dysfunction, the excessive sweating in the forearm is not as
easily explained. Excessive sudomotor responses to acetylcholine have also
been observed in individual diabetic patients, raising the question of
denervation hypersensitivity
(24). There is no evidence,
however, that a damaged sympathetic nerve is hypersensitive to administered
acetylcholine or that the sweat gland is hypersensitive to the acetylcholine
released by the neuron
(13,21,25,26).
In fact, the opposite has been observed; namely, that sympathetic nerve damage
decreases its response to acetylcholine stimulation, and decreased sweating is
the usual consequence (13).
Thus, we feel it is unlikely that the increased sweating in the forearm in
early diabetes is indicative of denervation hypersensitivity.
Could the increased sweating in the forearm in early diabetes reflect a
compensatory response to sympathetic nerve injury elsewhere in the body
(1)? The phenomenon of
compensatory hyperhidrosis is a well-documented consequence of regional
sympathectomy
(3,4,27).
Moreover, there are other instances in which decreased sympathetic activity in
one part of the body is associated with excessive activity elsewhere in the
body. Nondiabetic patients with orthostatic tachycardia have decreased
autonomic surface potentials and other evidence of sympathetic dysfunction in
the feet, yet they have increased increments in plasma norepinephrine (a large
fraction of which derives from forearm sympathetic neurons) when they undergo
orthostatic stress (28).
Finally, diabetic patients with overt sympathetic neuropathy in the lower
extremities may have increased sweating in upper body and face, typically
after eating (29). Thus, it is
reasonable to postulate that increased sweating in the forearm reflects
sympathetic hyperactivity, which in turn is a compensatory response to
sympathetic nerve injury elsewhere in the body. However, there are problems
with this interpretation of our data. Because there was no sign of decreased
sweating below the waist at the time of the first patient evaluation, it is
necessary to postulate that any compensatory increase in sweating in the
forearm was the result of sympathetic injury suffered by neurons we did not
test. The decreased renin-to-prorenin ratios at the time of the first patient
evaluation, especially in the poorly controlled diabetic patients
(Table 6), provides indirect
evidence for the early onset of sympathetic injury that may have been missed
at the time of the first evaluation by the QSART, which was only performed on
a very small fraction (4 cm2) of the total surface area of the
body. Sweating in the feet, the renin-to-prorenin ratios, and the
post-Valsalva R-R interval ratios were all decreased in the poorly controlled
versus the well-controlled diabetic patients at the time of the second and
third evaluations.
An alternative explanation of our findings is that compensatory
hyperhidrosis may be a local process, whereby partially denervated sweat
glands are reinnervated by multiple regenerating neurons
(30), which transiently leads
to an exaggerated response to cholinergic stimulation. Kennedy et al.
(30) have documented in
rodents that denervated sweat glands are quickly reinnervated by regenerating
sympathetic neurons, and it is possible that this occurs clinically early in
diabetes and caused the transient increase in the acetylcholine-induced
forearm sweating and total sweating that we observed. However, the excessive
sweating was seen only at the first evaluation, presumably because persistent
hyperglycemia continues to damage both new and preexisting sympathetic
neurons.
Although we are unable to prove the validity of the above mechanistic
speculations, our results are nevertheless consistent with the large body of
literature that indicates that diabetes-related sudomotor disturbances reflect
sympathetic nerve injury
(1,2,3,4,28,29,30).
These studies support the broad interpretation of our current data, namely
that redistribution of sudomotor responses in diabetic patients is an adverse
consequence of chronic hyperglycemia and is definitely pathological. In this
regard, our results provide a new perspective of the natural history of
diabetic autonomic neuropathy. Although it is a common belief that
parasympathetic abnormalities develop early in diabetes and that sympathetic
dysfunction develops late
(31), this dogma may be
invalid because it is based on comparisons of sensitive tests of
parasympathetic function, such as the heart rate variability with deep
breathing, and insensitive tests of sympathetic function, such as the
hemodynamic response to orthostatic stress or isometric hand grip. However,
the QSART, a much more sensitive test of postganglionic sympathetic neurons
than older methods
(32,33),
has made it possible to demonstrate that sympathetic involvement occurs very
early in poorly controlled type 1 diabetes and may be the first detectable
feature of peripheral neuropathy.
In summary, we observed a relative increase in forearm sweating and a
relative decrease in sweating below the waist, especially in the feet, early
in poorly controlled type 1 diabetes. Increased sweating in the forearm at the
time of the first evaluation showed a negative association with plasma
renin-to-prorenin ratio and VMA excretion, two independent measures of the
integrity of the sympathetic nervous system. The renin-to-prorenin ratio was
decreased throughout the study in the diabetic patients, and VMA excretion was
decreased at the time of the third evaluation; both parameters were more
significantly affected in the poorly controlled diabetic patients. Thus,
multiple lines of evidence indicate sympathetic nerve dysfunction in our
patients. Because small-fiber somatosensory function and cardiac
parasympathetic function were normal during the first few years of diabetes,
our results indicate that the sympathetic nervous system is especially
vulnerable to the adverse effects of chronic hyperglycemia.
 |
ACKNOWLEDGMENTS
|
---|
This study was supported by National Institutes of Health Grant DK-32239
(to R.D.H.) and the Compton Nutrition Foundation.
 |
FOOTNOTES
|
---|
QSART, quantitative sudomotor axon reflex test; VMA, vanillylmandelic
acid.
Received for publication March 16, 2000
and accepted in revised form October 16, 2000
 |
REFERENCES
|
---|
-
Goodman JI: Diabetic anhidrosis. Am J Med41
: 831-835,1966[Medline]
-
Fealey RD, Low PA, Thomas JE: Thermoregulatory sweating
abnormalities in diabetes mellitus. Mayo Clin Proc64
: 617-628,1989[Medline]
-
Shelley WB, Florence R: Compensatory hyperhidrosis after
sympathectomy. N Engl J Med263
: 1056-1058,1960
-
Moran KT, Brady MP: Surgical management of primary hyperhidrosis.
Br J Surg 78:279
-283, 1991[Medline]
-
Kopin IJ, Polinsky RJ, Oliver JA, Oddershede IR, Ebert MH: Urinary
catecholamine metabolites distinguish different types of sympathetic neuronal
dysfunction in patients with orthostatic hypotension. J Clin
Endocrinol Metab 57:632
-637, 1983[Abstract]
-
Hoeldtke RD, Cilmi KM: Norepinephrine secretion and production in
diabetic autonomic neuropathy. J Clin Endocrinol Metab59
: 246-252,1984[Abstract]
-
Keeton TK, Campbell WB: The pharmacological alteration of renin
release. Pharmacol Rev 31:81
-277, 1981
-
Hoeldtke RD, Bryner KD, Komanduri P, Christie I, Ganser G, Hobbs
GR: Decreased prorenin processing develops before autonomic dysfunction in
type 1 diabetes. J Clin Endocrinol Metab85
: 585-589,2000[Abstract/Free Full Text]
-
Ewing DJ, Cambell IW, Clarke BF: Assessment of cardiovascular
effects in diabetic autonomic neuropathy and prognostic implications.
Ann Int Med 92:308
-311, 1980[Medline]
-
Genovely H, Pfeifer MA: R-Rvariation B: the test of choice
in diabetes. Diabetes Metab Rev4
: 255-271,1988[Medline]
-
Baldwa VS, Ewing DJ: Heart rate response to Valsalva manoeuvre:
reproducibility in normals, and relation to variation in resting heart rate in
diabetics. Br Heart J 39:641
-644, 1977[Medline]
-
Jamal GA, Hanser S, Weir AL, Ballatyne JP: The neurophysiologic
investigation of small fiber neuropathies. Muscle
Nerve 10:537
-545, 1987[Medline]
-
Low PA, Caskey PE, Tuck RR, Fealey RD, Dyck PJ: Quantitative
sudomotor axon reflex test in normal and neuropathic subjects. Ann
Neurol 14:573
-580, 1983[Medline]
-
Menard LA, Dempsey MD, Blankstein LA: Agar gel electrophoresis
determination of glycosylated hemoglobin: effect of variant hemoglobins,
hyperlipidemia, and temperature. Clin Chem27
: 472,1981[Abstract/Free Full Text]
-
Sealey JE, Atlas SA, Laragh JH, Oza NB, Ryan JW: Activation of a
prorenin-like substance in human plasma by trypsin and urinary kallikrein.
Hypertension 1:179
-189, 1979[Medline]
-
Kotchen TA, Guyenne TT, Corvol P, Menard J: Enzymatic activation of
renin in plasma in normal and uraemic subjects. Clin
Sci 67: 365-368,1984[Medline]
-
Blankestijn PJ, Derkx FH, Van Geelen JA, De Jong FH, Schalekamp MA:
Increase in plasma prorenin during the menstrual cycle of a bilaterally
nephrectomized woman. Br J Obstet Gynaecol97
: 1038-1042,1990[Medline]
-
Matson WR, Langlais P, Volicer L, Gamache PH, Bird E, Mark KA:
N-electrode three-dimensional liquid chromatography with electro-chemical
detection for determination of neurotransmitters. Clin
Chem 30:1477
-1488, 1984[Abstract/Free Full Text]
-
Winer BJ: Multifactor experiments having repeated measures on the
same elements. In Statistical Principles in Experimental
Design. 2nd ed. NY, McGraw-Hill, 1979, p.514
-603
-
Snedecor GW, Cochran WG: Statistical
methods. 6th ed. Ames, IA, Iowa University Press,1967
, p. 172-195
-
Cardone C, Dyck PJ: A neuropathic deficit, decreased sweating, is
prevented and ameliorated by euglycemia in streptozocin diabetes in rats.
J Clin Invest 86:248
-253, 1990.[Medline]
-
Hreidarsson AB: Acute reversible autonomic nervous system
abnormalities in juvenile insulin dependent diabetes.
Diabetologica 20:477
-481, 1981
-
The DCCT Research Group: The effect of intensive therapy on the
development and progression of neuropathy. Ann Int Med122
: 561-569,1995[Abstract/Free Full Text]
-
Levy DM, Reid G, Abraham RR, Rowley DA: Assessment of basal and
stimulated sweating in diabetes using a direct-reading computerized
sudorometer. Diabet Med 8:S78
-S81, 1991[Medline]
-
Hayashi H, Nakagawa T: Functional activity of the sweat glands of
the albino rat. J Invest Dermatol41
: 365-367,1963
-
Janowitz HD, Grossman MI: The response of the sweat glands to some
locally acting agents in human subjects. J Invest
Dermatol 14:453
-458, 1950
-
Voris HC: Symposium on techniques and procedures in surgery:
thoracolumbar sympathectomy for hypertension. S Clin North
Am 35: 255-264,1955
-
Hoeldtke RD, Dworkin GE, Gaspar SR, Israel BC: Sympathotonic
orthostatic hypotension: report of four cases.
Neurology 39:34
-40, 1989[Abstract]
-
Odel HM, Roth GM, Keating FR: Autonomic neuropathy simulating the
effects of sympathectomy as a complication of diabetes mellitus.
Diabetes 4:92
-97, 1955
-
Kennedy WR, Navarro X, Kamei H: Reinnervation of sweat glands in
the mouse: axonal regeneration versus collateral sprouting. Muscle
Nerve 11:603
-609, 1988[Medline]
-
Bennett T, Hosking DJ, Hampton JR: Cardiovascular control in
diabetes mellitus. Br Med J 2:585
-587, 1975[Medline]
-
Low PA, Zimmerman BR, Dyck PJ: Comparison of distal sympathetic
with vagal function in diabetic neuropathy. Muscle
Nerve 9: 592-596,1986[Medline]
-
Riedel A, Braunee S, Kerum G, Schulte-Monting J, Lucking CH:
Quantitative sudomotor axon reflex test (QSART): a new approach for testing
distal sites. Muscle Nerve 22:1257
-1264, 1999[Medline]