Department of Pneumology, Hospital Virgen de la Salud, Toledo Hospital Complex, Toledo, SpainSpain
University Simon Bolivar, Caracas, VenezuelaVenezuela
Biomedical Research Unit Clinical, Hospital Clinico Universitario de Valladolid, Valladolid, SpainSpain
Department of Internal Medicine, General Hospital of Segovia, Care Complex Segovia, Se- govia, SpainSpain
Department of Neurology, Stroke Unit, University Hospital of Valladolid, Valladolid University, Valladolid, SpainSpain
Also available as PDF (figures and tables appear in the PDF).
Objective: Early detection of Diabetic Autonomic Neuropathy (DAN) could help prevent serious complications and mortality associated with this condition in type 2 diabetes. We aimed to determine the prevalence of Sudomotor Autonomic Dysfunction, Cardiac Autonomic Dysfunction (SAD, CAD) in the early stages of glucose metabolism alterations, ranging from risk categories for type 2 diabetes (prediabetes) to recently established type 2 diabetes. Research Design and Methods: It is a longitudinal, prospective and observational study (population consisting in 30 control subjects, 30 patients with increased risk for type 2 diabetes and 30 patients with type 2 diabetes ≤8 years of evolution. Study was carried out by designing a modified battery of Ewing. To study autonomic: resting Heart Rate (HR), deep inspiration, controlled breathing, 30/15, Valsalva maneuver, Sustained handgrip test (SHGT) and prolonged QTc indexes) and to study sudomotor: measurement of the Skin Conductance Response (SCR) deep inspiration, controlled breathing, standing to orthostasis, Valsalva maneuver and SHGT. The ECG and the Electrodermal response signal (EDR) was recorded while the patients execute the tests. Results: Results were statistically analyzed by taking into account the group the patients belonged to, their anthropometric variables (directly measured) and their results from blood tests. Obtained results allowed us to determine the order in which every autonomic index passes from normal to abnormal and the corresponding nerve fibers involved. Cardiac autonomic variables: resting HR: it is average value increases as the dysglicaemia progressed, significant differences were only found between the control and the type 2 diabetes group (p=0.041). Deep inspiration index: significant differences were only found between the increased risk group and the type 2 diabetes group (p=0.047). 42.9% of the control subjects, 39.1% of the increased risk patients and 59.3% of type 2 diabetes presented anomalous values for this index.
Diabetic Autonomic Neuropathy (DAN) belongs to the
group of diffuse Diabetic Neuropathies (DN), it is included in
peripheral secondary Autonomic Neuropathies (AN) and carries
a risk of vascular complications and sudden death, it is consid-
ered the most common AN in industrialized countries.
Characterized by Sudomotor Autonomic Dysfunction
(SAD) and Cardiovascular autonomic dysfunction (CVAD),
DAN is the most frequent Autonomic Dysfunction (AD) with
the greatest morbidity and mortality.2
Type 2 diabetes has a latency period estimated at 4-7
years, being in this time when the gluco-lipotoxicity on nerve
fibers is just a functional and reversible damage. This damage
progresses as type 2 diabetes evolves, passing through the stage
of subclinical organic damage until reaching the stage of estabtion made by several authors that in individuals with Oral Glu-
cose Intolerance (OGI), a decrease in nerve conduction is found 6thus presenting an added risk of distal small fiber neuropathy.
Not to mention the association found between the OGI and
the Quantitative Sudomotor Axon Reflex Test (QSART), which
1 seems to support the theory that the OGI can affect the function
of the autonomic small nerve fibers, and be the prelude of dia-
betic polyneuropathy11 dysfunction.
Despite EDR having been recently proposed as an in-
24,25 dicator in the evaluation of the diabetic foot, there are few
publications on SAD diagnosis in patients with type 2 diabetes
using SCR;26 and no studies in subjects with increased risk for
type 2 diabetes can be found in literature.
In this context, we designed a prospective study aimed
to determine the prevalence and types of autonomic neuropathy
in patients at different stages of the natural history of type 2 dia-
establish.
It is a longitudinal, prospective and observational study
designed at the beginning of 2009, carried out within the scope
of the “Servicio de Medicina Interna del Hospital Clínico Uni-
versitario de Valladolid” (HCUV), with the collaboration of
CARTIF´s Biomedical Engineering Division.
The ethical committee of the HCUV approved the de-
signed experimental protocol.
We included patients aged between 25 and 75 years
diagnosed with type 2 diabetes of ≤8 years of evolution or its
risk categories increased. Were excluded long-standing or severe
complications, those who presented polyneuropathy or dysauto-
nomia, acute heart disease, heart rhythm disorders and / or take
medications that may modify.
All members expressed their approval of the study by
signing the informed consent.
The study population consists in 30 control subjects, 30
patients with increased risk for type 2 diabetes and 30 patients
with type 2 diabetes ≤8 years of evolution, selected according to 1,27 ADA’s 2009 diagnostic.1,27
With the exception of those patients already diagnosed
with type 2 diabetes, patients underwent an Oral Glucose Tol-
erance Test (OGTT). The group to which each of the patients
belonged was established based on its results and those from
previous blood analysis.
Age, sex, height, weight, Body Mass Index (BMI),
waist and neck perimeter.
Epidermiologic variables were collected from the in-
formation provided by the participant.
Smoking: consumption: <5 packages/year =1 (light consump-
tion); 5-15 packages/year =2 (moderate); and >15 packages/year
= 3 (serious).
Alcoholic beverages: zero consumption = 0; 1 cup/day =1; 2
cups/day =2; and ≥3 glasses/day =3.
Physical activity was determined based on daily walk
at a pace that would prevent fluid talking while walking and the
weekly day’s physical exercise. A person was considered to ex-
ercise if walking lasted more than 1 hour and if it was executed
more than twice a week.
Hypertension: was established based on the measurements of
Blood Pressure (BP) and data recorded in the clinical history.
The recommendations of the 2007 guide of the European So-
ciety of hypertension and the European Society of Cardiology
state that, BP ≥140/90 mm Hg must be considered hypertension.
For patients with DM2, hypertension is diagnosed if BP ≥130/80
mm Hg according to the ADA in 2009.1
Dyslipidaemia: was used the criteria of The Third Report of the
Expert Panel on Detection, Evaluation, and Treatment of High
Blood Cholesterol in Adults (Adult Treatment Panel III) from
the National Cholesterol Education Program (NCEP), to deter-
minate the lipids plasma concentration.
Ischemic heart disease was established on the basis of
data provided by patients, data found in the clinical history and
through the ECG measured in this study.
Cardiovascular family history was established by the
presence of a family history of hypertension, hypercholester-
olemia and hypertriglyceridemia.
Two analytical determinations of each of the biochemi-
cal variables of interest were requested for our study in order to
obtain the mean of the recorded values. Blood and urine tests
were carried out under basal conditions and performed two days
prior to study entry.
Hyperinsulinemia was defined as basal levels of insu-
linemia ≥16 mU/L.
Insulin Resistance (IR) was quantified with the Ho-
meostatic model assessment index (HOMA-IR): multiplying the
mean basal insulinemia (mU/L) and basal glycaemia (mg/dl),
divided by 405. Border value for the Spanish population was set
at HOMA-IR ≥3,8.28
HbA1c: normal v <7%.
HDL-c: values were considered abnormal below 40 mg/dl in men
and 50 mg/dl in women according to the American Heart As-
sociation.
Micro-albuminuria: correlation albumin/creatinine of early
morning urine samples was determined. Anomalous values were
considered ≥30 mg/gr.
Uric acid: anomalous values were considered above 7 mg/dl in
males and 6 mg/dl in women.
Homocysteinemia: anomalous values considered above 15
µmol/L.
Two sensors with isotonic conductive gel were placed
on the fingertips of the second and third fingers of the non-dom-
inant hand for the registration of the responses associated with
distal innervation of the median nerve (SCR).24 Similarly, stan-
dard electrodes needed to capture a conventional ECG compris-
ing six bipolar derivations and three unipolar leads (V3, V4 and
V5-V6) were placed.
Once all electrodes were placed, the SCR signal was
monitored until its stabilization.
A BioPac MP 150 System® with a sampling frequency
of 1 kHz was used for the registration of the SCR and the ECG.
For the detection of events in the ECG, a proprietary
algorithm was developed in Matlab 7 , it automatically searches
for events by using a modification of the algorithm proposed by
Martínez. This generates a log that is stored in digital format
and was forwarded to CARTIF´s Biomedical Engineering Divi-
sion for reading and interpretation.
After waiting twenty minutes at rest and maintaining a
periodic breathing, Heart Rate (HR) was recorded and we then
proceeded to the execution of the autonomic testing battery,
based on DAN’s statement.30
Afterwards, the variables were analyzed and diagno-
sis of CAD was established if ≥2 indexes with anomalous value
31-33 were found.
The studied cardiac autonomic variables: were resting HR, deep
inspiration, controlled breathing, 30/15, Valsalva maneuver, Sus-
tained handgrip test (SHGT) and prolonged QTc indexes.
Resting HR: the average value the HR during the last 5 minutes
of the 20 that the subject remains at rest and prior to the start of
the battery. It was accounted in Beats per minute (BPM): normal
values: ≤90, borderline: 91-99, anomalous: ≥100.
Deep inspiration index: difference between maximum HR dur-
ing deep inspiration and the minimum HR within fifteen sec-
onds. It is a value in BPM: normal values: ≥15, borderline: 11-
Controlled breathing rate: difference between the average of the
HR during inspiration and average HR during exhalation regis-
tered during the controlled breathing maneuver. It is a value in
BPM: normal values: ≥15, borderline: 11-14, anomalous: ≤10.
th th 30/15 index: ratio between the 30th RR interval and the 15th RR
30s after standing up from rest to orthostasis. Normal values:
≥1.04, border: 1.01-1.03, anomalous: ≤1.00.
Valsalva index: ratio between the maximum RR interval reg-
istered within 45 seconds after the Valsalva maneuver and the
minimum RR interval during the 15 seconds of the maneuver.
Normal values: ≥1.21, border: 1.11-1.20, anomalous: ≤1.10.
SHGT index: we decided to determine the HR rather than the
diastolic ABP during isometric, sustained muscle contraction;
we then calculated the difference between the achieved maxi-
mum HR during this maneuver and the mean HR prior to the
maneuver. We established the anomalous value as ≤12 bpm, on 34-37 the basis of prior studies.
Prolonged QTc interval: we proceeded to measure QT intervals
during the ten minutes that the patient remained in dorsal decu- ® bitus. Martinez’s algorithm was used to measure the position of
the QRS complex.29 Farina´s DWT algorithm was used for the 38-40 correct measurement of the end of the T wave. These QT
intervals were corrected using Bazett’s formula41 to get the cor-
® rected QT interval (QTc) and finally, we calculated the average
QTc in miliseconds for each patient: normal between 300-440
ms in men and 300-450 ms in women, borderline: 440-470 ms
in men and 450-480 ms in women, abnormal: greater than 470
ms in men and 480 ms in women.
Measurement of the SCR is associated to a specific
stimulus; each response is different in each repetition of the
stimulus. We used the second response to a given stimulus for
having the best amplitude for the maneuver before habituation to
the stimuli occurred.
The following maneuvers can be associated with a
SRC: deep inspiration controlled breathing, standing to orthos-
tasis, Valsalva maneuver and SHGT; but the measurement of
30 the SCR associated with the standing to orthostasis had to be
discarded due to the electromyographic noise generated during
postural change.
A descriptive analysis of all collected variables was
made. Quantitative variables are presented with their mean and
standard deviation. The qualitative variables are exposed accord-
ing to the distribution of frequencies. The association between
ing the Pearson’s Chi-square test. In the event the number of cells
with expected value <5 would be higher than 20, Fisher’s exact
test was used. The Pearson correlation coefficient was used to
analyze the relationship between the SCR and the HR in various
autonomic stimuli. The comparison of quantitative values was
made through Student’s t-test or Mann-Whitney’s test in the case
of two groups. Anova or Kruskal-Wallis H test were used when
the number of groups was greater than 2. Test applied afterwards
include Fisher’s Least Significant Difference and Dunnett’s test.
P-values <0.05 have been considered as statistically
significant.
Data were analyzed using SPSS version 18.0 for Win-
dows.
(Minimum-maximum) (Minimum-maximum) (Minimum-maximum)
Age 47.4±7.30 53.7±13.2 56.4±8.4 0.075
(years) (31-61) (27-75) (28-67)
Male 49.4±7.4 48.5±13.3 54.9±10.6 -
Female 46.6±7.2 59.6±10.8 58.4±5.2 -
Height 1.60±0.10 1.60±0.10 1.60±0.10 0.992
(meters) (1.50-1.90) (1.50-1.90) (1.40-1.80)
Weight 76.7±27.4 77.6±18.8 81.1±17.7 0.733
(kg) (49.5-170.0) (46.0-128.0) (54.0-142.5)
BMI 28.1±7.3 28.3±4.9 29.7±4.4 0.510
(kg/m2) (21.1-53.7) (17.1-39.6) (23.8-43.8)
Waist 92.2±16.8 96.4±12.0 99.1±11.5 0.169
(cm) (70.0-140.0) (70.0-125.5) (87.5-120.5)
Neck(cm) 35.9±4.8 35.7±3.9 36.6±3.3 0.785
Basal Insulin 9.7±7.8 11.0±5.0 12.6±9.9 0.389
(mU/L) (3.0-39.0) (4.0-24.0) (4.0-47.0)
HOMA-IR 2.2±1.8 2.8±1.2 4.5±3.4 0.014+
(mU/mmol) (0.6-9.2) (1.1-6.0) (1.1-13.8)
HbA1c 5.7±0.3 6.0 ± 0.3 7.0 ± 1.1 <0.001#
(%) (5.0-6.0) (5.6 - 6.3) (5.5 - 10.0)
Total cholesterol 216.3±41.1 215.9±36.9 213.4±31.7 0.946
The overall prevalence of obesity was the 30.0% of the
population plus a 44.4% of overweight (74.4% with BMI 25 Kg/ 2).
m2). P-value (p=0.047) was found to be statistically significant
between groups. We did not find statistical significance for the
rest of the studied variables.
Statistical significance was found between the con-
trol and the type 2 diabetes group, both for the levels of HDL-c
Mean±SD Mean±SD Mean±SD p-value
(40-61) (27-74) (28-67)
(31-58) (43-75) (47-66)
(30.5-46.0) (30.0 - 44.5) (30.5 - 43.0)
(125.0-308.0) (163.0-353.0) (150.0-289.0)
HDL-c 56.4±17.5 50.3±13.4 45.5±15.8 0.033+
(mg/dl) (33.0-117.0) (33.0-90.0) (6.0-70.0)
HDL-c male 44.3±13.8 44.0±8.8 39.6±15.7 -
(md/dl) (33.0-71.0) (33.0-62.0) (6.0-67.0)
HDL-c female 61.5±16.6 57.6±14.2 51.9±13.7 -
(mg/dl) (43.0-117.0) (39.0-99.0) (25.0-70.0)
LDL-c 137.6±40.1 139.2±31.8 130.0±29.6 0.548
(mg/dl) (61.2 - 228.8) (66.0-226.0) (73.8-201.4)
Triglycerides 112.1±62.4 131.2±80.0 192.1±155.0 0.041+
(mg/dl) (45.0-334.0) (57.0-413.0) (51.0-781.0)
µalbuminuria 5.0±6.8 3.3±0.7 7.3±14.7 0.158
(mg/gr) (2.9-19.6) (2.9-5.6) (2.9-447.0)
Uric acid 4.4±1.4 5.0±0.9 5.4±1.5 0.028+
(mg/dl) (2.1-8.0) (3.4-7.5) (2.9-8.4)
Homocistein 9.3±2.8 9.6±1.5 10.8±5.2 0.241
(µmoles/l) (5.0-18.0) (7.0-12.0) (7.0-33.0)
BMI Normal 13 43.3 7
Overweight 12 40.0 15
Obesity 5 16.6 8
* : control - increased risk - type 2 diabetes + : control - type 2 diabetes # : increased risk - type 2 diabetes
Table 1. Anthropometric and biochemical variables results.
(p=0.033), triglycerides (p=0.041), uric acid (p=0.028), hyper-
tension, hypercholesterolemia and hypertriglyceridemia (p=
0.001) as well as for ischemic heart disease (p=0.005) and the
HOMA-IR (p=0.014). The highest average value of HOMA-IR
corresponded to the type 2 diabetes group.
No significant differences were found for the rest of the
variables studied.
Resting HR: it is average value increases as the dysglicaemia
progressed, significant differences were only found between the
control and the type 2 diabetes group (p=0.041).
Deep inspiration index: significant differences were only found
23.3 3 10.0
50.0 13 43.3
26.6 14 46.6
between the increased risk group and the type 2 diabetes group
(p=0.047).
Controlled breathing rate: a progressive decrease of its average
value was observed as dysglicaemia progressed, significant dif-
ferences were only found between the control group and the type
2 diabetes group (p=0.008). Significant differences were only
found between the control group and the increased risk group
(p=0.023).
No significant differences were found in the rest of the
indices studied.
Diagnosis of CAD: all patients who showed more than 2 in-
dexes with anomalous were diagnosed with CAD, and therefore
30.2% of the control group; 42.9% of the increased risk group
(Minimum-maximum) (Minimum-maximum) (Minimum-maximum)
Snuff consumption 1.3±0.9 1.5±1.3 1.8±1.2 0.138
Alcohol consumption 1.7±1.0 1.7±0.9 2.4±0.6 0.204
(a) (0-3)
No 12 40.0 9
Ex-smoker 6 20.0 14
Yes 12 40.0 7
No 24 80.0 21
Ex-alcoholic 2 6.6 5
Yes 4 13.3 4
<1 hour 14 46.6 12
≥1 hour 16 53.3 18
<2 days 18 60.0 16
≥2 days 12 40.0 14
Hypertension 3 10.0 7
Hypertension family history 16 53.3 11
High cholesterol 8 26.6 11
High cholesterol family history 15 50.0 15
High triglycerides 3 10.0 6
Ischemic cardiopathy 1 3.3 6
(a) Non consumption: 0; 1 glass wine/day: 1; 2 glasses wine/day: 2; ≥3 glasses wine/day: 3
Mean±SD Mean±SD Mean±SD p-value
(0-3) (0-3) (0-3)
(0-3) (0-3)
30 10 33.3
46.6 10 33.3
0.247 23.3 10 33.3
70.0 20 66.6
16.6 3 10.0 0.551
13.3 7 23.3
40.0 10 33.3
0.492 60.0 20 66.6
53.3 20 66.6
0.623 46.6 10 33.3
23.3 15 50.0 0.001
36.6 19 63.3 0.319
36.6 23 76.6 0.001
50.0 15 50.0 0.959
20.0 15 50.0 0.001
20.0 9 30.0 0.718
20.0 10 33.3 0.005
43.3 13 43.3 0.246
and 58.7% of the type 2 diabetes group, with a p-value =0.064.
SCR-HR: we found significant correlation between the sudomo-
tor response generated by the SHGT maneuver and the variation
of the HR generated by this autonomic stimulus (p=0.036) (Fig-
ure 1); not so for the remaining stimuli.
No significant differences were found in the rest of the
indices studied
Mean±SD Mean at 95% Mean±SD
(Minimum- (inferior limit- (Minimum-maxi-
maximum) superior limit) mum)
Resting HR 69.10±11.72 73.95±12.72 (64.55-73.64) (bpm) (46.12-92.88) (51.11-112.7)
14.00±8.97 16.61±11.85 ration index (10.52-17.47) (1.30-35.77) (4.31-54.07)
23.14±8.85 19.01±11.07 breathing (19.71-26.57) (4.29-41.00) (3.78-48.04)
Valsalva 1.54±0.37 1.56±0.35 (1.40-1.68) index (0.88-2.33) (1.13-2.52)
1.20±0.16 1.17±0.15 30/15 index (1.13-1.26) (1.00-1.63) (1.00-1.62)
SHGT index 7.58±6.58 9.78±5.92 (5.02-10.13) (bpm) (10.22-23.08) (2.54-24.09)
370±30 380±30 QTc (ms) (360-390) (300-420) (340-460)
(deep inspi- (0.20-0.39)
(controlled (0.10-0.25)
(Valsalva (0.14-0.32)
0.20±0.15 0.18±0.11 (SHGT ma- (0.14-0.26) (0.00-0.65) (0.05-0.40)
+: control - type 2 diabetes #: increased risk - type2 diabetes
Early detection of autonomic diabetic neuropathy could
help prevent serious complications and mortality associated with
this condition in type 2 diabetes patients. We aimed to determine
the prevalence of Sudomotor Autonomic Dysfunction and Car-
diac Autonomic Dysfunction (SAD, CAD) in the early stages
of glucose metabolism alterations, ranging from risk categories
for type 2 diabetes (prediabetes) to recently established type 2
diabetes.
The last adaptation on the classification of DN and data 4-11,42 revealed by recent studies suggest the presence of AD in the
stages prior to the diagnosis of type 2 diabetes, which justifies
our study.
Given that there is still no consensus on the use of cer-
(inferior limit- (Minimum-maxi- (inferior limit-
superior limit) mum) superior limit)
77.62±12.14 (68.31-79.59) (72.72-82.53) 0.041+ (49.88-98.04)
10.05±6.81 (11.49-21.74) (7.36-12.75) 0.047# (1.61-25.91)
14.97 ± 8.12 (14.10-23.92) (11.69-18.25) 0.008+ (2.98 - 28.07)
1.50±0.46 (1.42-1.70) (1.32-1.68) 0.874 (1.03-2.94)
1.15±0.07 (1.10-1.24) (1.12-1.17) 0.315 (1.03-1.31)
10.51±6.57 (7.15-12.40) (7.85-13.16) 0.223 (0.00-33.41)
380 ± 30 (370-400) (370-390) 0.721 (330-430)
(0.16-0.31) (0.21-0.39) 0.533
(0.09-0.19) (0.14-0.25) 0.475
(0.16-0.29) (0.20-0.45) 0.258
0.21±0.15 (0.13-0.23) (0.15-0.28) 0.734 (0.00-0.69)
tain standardized methodology, autonomic tests battery proposed
by Ewing et al. continue to be the gold standard for the diagnosis
of CVAD.31 This situation led to its use as a base from which we
developed the battery of autonomic tests for our study, which
was completed following the guidelines provided by the ADA in
its statement about for the diagnosis of CVAD.30
Before an autonomic stimulus, the loss of variation in
the HR is considered a Pathognomonic parasympathetic CAD
(PCAD) marker; while the registration of a fixed HR is an ac-
curate indicator of PCAD and Sympathetic CAD (SCAD).32
Regarding the deep inspiration index, the statistical significance
found for the average value between the type 2 diabetes and
increased risk for type 2 diabetes and the average value of the
type 2 diabetes group, approach to the abnormality, this reflects
a trend towards PCAD. Detection of anomalous values for the
30/15 index in the increased risk group indicates the presence of
PCAD.
Given the important influence that the respiratory rate
has on the variation of the HR, being its modulation almost in it
is entirely of vagal origin; finding anomalous values to the auto-
nomic stimulation of controlled breathing reflect the existence of
a functional compromise of the Parasympathetic Nervous Sys-
tem (PNS).
It is known that during SHGT there is a rise in HR, and
we would expect this rise to decrease as dysglicaemia progress-
es, being that HR is particularly sensitive to the dysfunction of
sympathetic fibers from the right stellate ganglion. Not hav-
ing registered null values for the various indexes, together with SHGT maneuver and the variation of the HR generated by this autonomic
responsible for the regulation of the heart’s chronotropism sym-
pathetic component can be established, at least in the increased
risk group. However, the fact finding participants with abnormal
values for the Valsalva index in the type 2 diabetes group, speak
in favour of a possible SCAD accompanying the PCAD already
present in this group.
Finally, the absence of participants with prolonged
QTc, reveals the integrity of left stellate ganglion sympathetic fi-
bers. However, there may be fiber injury without being reflected
in QTc prolongation. The heart acts as a syncytium and requires
global damage of the sympathetic component to be observed in
QTc.
The idea of using the controlled breathing index as a
screening test is strengthened. It is the first component of the
CAD related to altered dysglicaemia,33 after this first altered in-
dex, the following would be: deep inspiration, 30/15 index and
Valsalva index in order to establish the diagnosis of CAD based
on the presence of ≥ 2 abnormal indexes, as proposed by the
ADA and the AAN.31
The fact of finding control subjects with ≥ 2 abnormal
indexes for CAD, speaks in favour of other reasons beyond dys-
glicaemia; although it could also be participants with “hidden
pre-diabetes” not shown in the requested analytical determina-
tions.
For the study of the sympathetic component at periph- 34-37 eral level we used the SCR since the eccrine sweat glands pres-
ent at the fingertips react weakly to heat but intensely to auto-
postganglionic sympathetic fibers of the median nerve.
Since no significant differences among the studied
groups were found for any of the sudomotor responses gener-
ated by different autonomic stimuli; no presence of SAD can be
detected.
The presence of a low percentage of patients in every
group with null SCR values, can be related to a source of SAD
outside the dysglicaemia despite the preventive measures taken
before the study: hand washing, abundant use of isotonic con-
ductive gel, recording the signal in the non-dominant hand to
avoid neural mechanical wear of the nerve; without forgetting
that the detection of the SCR in the chosen fingertips, reflects
SAD in relation to a single nerve and distal level.
Considering parasympathetic preganglionic fibers, re-
sults from this study demonstrate the presence of PCAD, both
in the group of patients with increased risk and in the type 2
diabetes group.
Regarding the right stellate ganglion’s sympathetic fi-
bers, abnormal results found with the Valsalva maneuver show
a possible SCAD in the group of patients with short evolution
type 2 diabetes; while the group of patients with increased risk
we found no proof of SCAD.
Concerning left stellate ganglion sympathetic fibers,
the non-presence of patients with prolonged QTc interval shows
the integrity of the fibers.
SAD secondary to dysglicaemia cannot be detected in
connection to cholinergic postganglionic sympathetic fibers.
Signs make us suspect that SAD is not the first auto-
nomic injury and therefore does not precedes the PCAD already
present in patients with increased risk for type2 diabetes, and
followed by a possible SCAD in the group of patients with short
evolution type 2 diabetes.
In conclusion, signs indicating autonomic neuropathy
are already present in patients at risk for type 2 diabetes, being
its prevalence higher in patients with recently diagnosed type
2 diabetes. Whereas diabetic patient’s exhibit signs suggesting
parasympathetic and sympathetic involvement, prediabetic sub-
jects show only cardiac autonomic dysfunction, which supports
the notion, that parasympathetic fiber are the ones initially af-
fected by dysglicemia-related glycolipotoxicity. These findings
may contribute to optimise preventive strategies aimed to early
detect autonomic neuropathy in dysglicemic patients, even be-
fore they become diabetics.
This study was partially funded by the “Plan Nacional de
I+D+I”, through the projects DPI 2003-09309, “Sistema de
Soporte al Pronóstico y Diagnóstico de Complicaciones Mi-
crovasculares en Pacientes Diabéticos Tipo 1”, and DPI 2006-
14367, “Aplicación de Técnicas de Procesamiento de Señal para
el Desarrollo de Herramientas de Diagnóstico de la Neuropatía
Vegetativa”.
This work was executed in close collaboration with the Biomed-
ical Engineering Division of CARTIF Foundation and with the
“Servicio de Medicina Interna del Hospital Clínico Universita-
rio de Valladolid”.
F.J.P.B., P.V.R.F. and E.G.S. were responsible to develop the ar-
ticle, M.I.F.G., J.F.A. and J.P.T. Contributed to the data analysis
and writing the comments of the manuscript and M.F.M.M. the
statistical analysis
The authors declare not to have potential conflicts of interest.