JOURNAL OF NEUROLOGY AND NEUROSCIENCE

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This article is available from: www.jneuro.com
Peripheral and central auditory
pathways function in patients
with type 2 diabetes mellitus
1 Department of Neurology and
Psychiatry, Assiut University Hospital,
Assiut, Egypt.
2 Department of Internal Medicine, Assiut
University Hospital, Assiut, Egypt.
3 Department of Audiology, Assiut
University Hospital, Assiut, Egypt.
Corresponding author:
hamed_sherifa@yahoo.com
Sherifa A. Hamed (M.D)
Consultant Neurology Professor
Department of Neurology and Psychiatry
Assiut University Hospital Assiut, Egypt zip
code: 71516
Sherifa A. Hamed
1*
(M.D.),
Mostafa A. Haridi
2
(M.D.),
Amal M. Elattar
3
(M.D.)
Abstract
This work aimed to investigate peripheral and central hearing function
(auditory pathways) in patients with diabetes mellitus (DM). This study
included 60 patients with mean age of 39.5713.89 years and dura-
tion of illness of 7.375.15 years. We did routine pure tone audiometry
(PTA) along with Auditory-Brainstem Response (ABR) at low and high
repetition rate frequencies and Event-Related Potentials (ERPs). Four-
teen patients (23.33%) had tinnitus and 18 patients (30%) had subjec-
tive hearing impairment. PTA reported peripheral auditory neuropathy
in 30% (18/60) or (30/120) of ears examined [versus 8.75% (7/80) for
control subjects] (P = 0.001). Of them, bilateral sensorineural hearing
impairment (SNHI) was reported in (72.22%; n = 13). The latency of
wave I was prolonged in 36.67% indicating auditory neuropathy. The
latency of wave III and I-III and III-V inter peak latencies (IPLs) were
delayed in 46.67% indicating impairment in the cochlear nucleus. The
latency of wave V and III-V and I-V IPLs were delayed in 30% without
impairment in wave I or III, indicating impairment in the activity in the
nuclei of lateral lemniscus. Compared to control subjects, patients had
higher hearing threshold at different frequencies (250-8000 Hz) (P =
0.0001), prolonged absolute latencies of waves I, III and V and I-III, III-V
and I-V IPLs at 90dBHL low and high repetition frequencies and N100,
N200, P200 and P300 components of ERPs (P = 0.0001) and reduced
amplitudes of P200 and P300 (P = 0.0001). No signicant differences
were identied among different audiologic variables between patients
with type 1 (T1DM) and type 2 (T2DM) diabetes mellitus. Patients who
were uncontrolled on anti-diabetic medications had prolonged I-V IPLs
at 90dBHL low (right: P = 0.025; left: P = 0.041) and high (right: P =
0.047; left: P = 0.036) repetition frequencies and reduced amplitudes
JOURNAL OF NEUROLOGY AND NEUROSCIENCE
2014
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doi: 10.3823/343
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of P300 (right: P = 0.050; left: P = 0.052). signicant correlations were
identied between many audiologic variables and demographic- clini-
cal- and laboratory- variables In multivariate analysis and after adjust-
ment of other risk factors, there were increase in the odds for latency
of wave III (OR 1.90; 95% Cl 1.02 to 3.55, P = 0.044); I-III (OR 2.36;
95% Cl 0.95 to 5.81; P = 0.06) and III-V (OR 2.36; 95% Cl 0.95 to
5.81; P = 0.06) IPLs and amplitude of P300 (OR 2.36; 95% Cl 0.95
to 5.81; P = 0.06) in relationship to the degree hyperglycemia. We
conclude that, patients with DM have higher frequency of peripheral
and central hearing impairment (i.e. acoustic nerve, auditory pathway
throughout the brainstem till the auditory cortex). The degree of hear-
ing impairment was signicantly correlated with glycemic control. This
knowledge is important for specialists serving those patients.
Key words: Diabetes mellitus, auditory function, Auditory-Brainstem
Response, Event Related Potentials.
Introduction
Diabetes mellitus (DM) comprises a group of meta-
bolic disorders and several distinct types that are
characterized by abnormalities in carbohydrate me-
tabolism and chronic hyperglycemia. These meta-
bolic disorders are results of complex interaction of
genetic, environmental and life style factors [1]. The
two main types of DM are type-1 (T1DM) or insulin
dependent DM (IDDM) and type-2 (T2DM) or non-
insulin dependent DM (NIDDM). T2DM comprises
90% of DM [2]. T2DM is gradual in onset and oc-
curs mainly in the middle age and elderly subjects.
T2DM is predominantly due to insulin resistance (IR)
with relative insulin deciency or insulin secretion
defect [3]. Many organ systems are adversely af-
fected by the metabolic dysregulation associated
with DM, particularly with T2DM as the nervous
system, heart, retina and kidney [4]. Evidence from
several human and animal studies indicated that the
prevalence rates of diabetic complications are pro-
portionately related to the magnitude and duration
of antecedent hyperglycemia. Diabetic neuropathy
are recognized as the most common nervous sys-
tem complications caused by DM worldwide [4-10].
Auditory neuropathy or sensorineural hearing im-
pairment (SNHI) has been reported to be one of
the common complications of DM. However, its fre-
quency varies between studies and ranges between
completely asymptomatic electrophysiological ab-
normalities to manifest SNHI [11-15]. Central delay
in neural conductance along the auditory pathway
was also reported with DM and assessed by sev-
eral means, for example: a) auditory brainstem re-
sponses (ABRs) (short- and middle-latencies) which
reect auditory pathway function starting from
the auditory nerve and throughout the brain stem.
While long-latency evoked response or known as
Event Related Potentials (ERPs) reects the function
within the auditory cortex [16-22]. ABR and ERPs
are simple, non-invasive procedures to detect early
impairment of auditory pathways even in the ab-
sence of specic symptoms. For ABR, wave I and
II represent activity in cochlear nerve, wave III in
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cochlear nucleus, wave V represents activity in nu-
clei of lateral lemniscus and I-III and I-V interpeak
latencies (IPLs) are regarded as auditory conduc-
tion time within the brainstem, and b) Transient
(TEOAEs) and distortion product (DPOAEs) evoked
otoacoustic emissions [23, 24]. Otoacoustic emis-
sions (OAEs) testing permits sensitive assessment
of cochlear function from any cause and objective
monitoring of dynamic changes in cochlear respon-
siveness before functional and signicant hearing
loss occur. OAEs amplitude indicates the summed
activity of outer hair cells (OHCs). Minimal amounts
of cochlear damage may cause measurable changes
in OAE responses and as scattered OHC loss accu-
mulates, OAE amplitude decreases prior to signi-
cant changes in pure-tone thresholds [25].
Results from animal and human studies indicate
that diabetic neuropathy is due to degeneration
of nervous system cells as a result of vasculopathy
(microangiopathy, macroangiopathy) and direct or
indirect effects of hyperglycemia with resultant hy-
poxia and oxidative stress [26-28]. Thus advances in
understanding the spectrum of neurological com-
plications and the physio-pathological mechanisms
of damage to the nervous system as a result of
DM are highly important in current neurological and
therapeutic researches.
Aim of the work
This work aimed to investigate peripheral and cen-
tral hearing function (auditory pathways) in patients
with DM using routine diagnostic audiometry along
with Auditory-Brainstem Response (ABR) at low and
high repetition rate frequencies and Event-Related
Potentials (ERPs). We investigated the relationship
between audiologic variables and demographic
(age and gender), clinical [type of DM, duration of
illness and associated comorbid medical problems
(as hypertension and hypercholesterolemia/dyslipid-
emia) and the degree of control on anti-diabetic
medications]. Multivariate analysis was done to de-
termine the relationship between hyperglycemia
and cochlear and auditory functions variables after
controlling of related confounders.
Materials and methods
This is a cross-sectional case-control study. It includ-
ed 60 patients with DM. The diagnosis of DM was
done according to the World Health Organization
Expert Committee on DM, Geneva [29]. Diabetics
met one or more of the following criteria: 1) had
a fasting glucose value greater than 125 mg/dl on
two separate occasions; 2) had a 2 hours glucose
value greater than 200 mg/dl during a 75 gram oral
glucose tolerance test (OGTT); or 3) had a prior di-
agnosis of DM, and were being treated with hypo-
glycemic agents and/or diet and exercise. Patients
were randomly recruited from the Internal Medicine
and Neurology departments of Assiut University
Hospital, Assiut, Egypt. Patients were classied ac-
cording to type of DM into T1DM and T2DM, and
the degree of control on anti-diabetic medications
into controlled and uncontrolled. Forty age-, sex-,
and socioeconomic status- matched subjects were
included as healthy controls for comparison. Control
subjects were recruited from the general population.
Excluded from the study were subjects with: a) pre-
vious history of otological or labyrinthine disorders,
b) systemic or metabolic diseases associated with
hearing loss other than DM and its associated hy-
percholesterolemia/dyslipidemia, hypertension, in-
sulin resistance and obesity (as renal insufciency,
gout, hypothyroidism or active gastrointestinal dis-
ease), c) history of hypoglycemic coma or complica-
tions of DM (other than peripheral neuropathy) (as
nephropathy, retinopathy, etc.) d) clinical evidence
of postural hypotension, e) history of stroke or
transient ischemic attacks, f) history of head injury,
g) reported exposure to unsafe noise, h) previous
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use of ototoxic drugs, i) family history of deafness,
and j) use of medication which might be expected
to interfere with the functioning of central nervous
system (e.g. methyldopa, reserpine, anticonvulsants,
antipsychotic and antidepressants).
The protocol of this study was in conformity with
the local ethics guidelines and informed written
consent was obtained from each participant.
All study participants underwent a standardized
interview questionnaire regarding vascular risk fac-
tors.
Methods:
1) Data collection:
Demographic and clinical data were collected as fol-
low: age, gender, type of DM, duration of illness,
type of treatment, duration of treatment, degree of
control on anti-diabetic medications, systolic blood
pressure, diastolic blood pressure, weight, height,
body mass index (BMI), degree of obesity. BMI was
calculated as follow: BMI [weight (kg)/height (m2)].
Normal was dened if BMI was >20 to <25 kg/m2,
over weight if BMI was equal or >25 to <30, obese
if BMI was equal or >30 to <35 and morbidly obese
if BMI was >35 [30].
2) Specimen collection and analysis:
Venous blood samples were drawn from patients
at 8.00 am. Routine hematology tests

were done
and included: fasting blood glucose (FBG), com-
plete blood count (CBC), renal function, lipogram
[serum total cholesterol (TC), triglycerides (TG), low
density lipoprotein cholesterol (LDL-c), high density
lipoprotein cholesterol (HDL-c)] and uric acid. Serum
levels of TC, TG, HDL-c and LDL-c were measured
by enzymatic colourimetric method using the auto-
analyzer Hitachi 911 (Boehinger, Mannheim, USA).

Serum uric acid was determined by colorimetric US
plus kit, supplied by Roche diagnostics, (GmbH,
D-68298 Mannheim, USA).
3) Basic audiolgical evaluation:
All participants underwent basic audiological evalu-
ation which included: a) initial otoscopic examina-
tion, b) standard pure tone air and bone conduc-
tion audiometry (PTA): which were conducted using
dual channel clinical audiometer (Madson OB822,
Assens, Denmark). Pure tone audiometric thresh-
olds were measured from 250 to 8000 Hz (250,
500, 1000, 2000, 4000 and 8000 Hz) and pure
average thresholds for the right and left ears were
obtained, c) speech audiometry: which was done
to identify the hearing level at which subjects un-
derstood and repeated at least 90% of a set of 10
monosyllables, d) tympanometry: which was done
using Middle Ear Analyzer Interacoustics (Az26, As-
sens, Denmark). Speech audiometry, tympanometry
and acoustic reex were done to exclude pathologic
conditions of the external or middle ear. Hearing
thresholds were determined in decibel hearing level
(dB HL). The examined ears were dened as normal
if no absolute threshold level > 20 dB was measured
over the whole frequency range. Threshold shifts in
PTA were considered to be signicant if they showed
at least 10 dB change in more than two consecu-
tive frequencies, or if a threshold greater than 20
dB was observed in any audiometric range. Hearing
loss was calculated for each ear separately as the
amount of threshold shifts above the standard au-
diometric zero, and the average hearing loss of both
ears was calculated. Grading of hearing impairment
was adopted according to Northern and Downs

[31]

into: mild, moderate, moderately severe and severe
impairment and are dened as average threshold
between 25-40dB, 41-55dB, 56-70dB and 71-90dB
respectively.
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4) Auditory brainstem response (ABR)
recording:
ABR was done by (Nicolet Spirit) OS/2 version 3.
ABR was performed using alternating clicks at 0.1
seconds, time window was 10 millisecond and lter
settings were 150 Hz-3 kHz. The stimuli were de-
livered at 90 dBHL with repetition rate of 11.1-51.1
pulse/second. Each response reected an average of
1500 stimuli presentations. The absolute latencies
of waves I, III and V and interpeak latencies (IPLs)
of I-III, III-V and I-V were recorded from both ears.
5) Event-Related Potentials (ERPs) testing:
ERPs testing was done on a separate day. It takes
at least one and half hour to administer (as rep-
etition of testing was needed to assure accuracy).
ERPs are series of scalp

waves that are extracted

from the electroencephalogram (EEG) by time do-
main analysis and averaging of EEG activity

follow-
ing multiple stimulus repetitions. They were elicited
with an auditory discrimination task paradigm by
presenting a series of binaural 1.000 Hz (standard)
versus 2,000 Hz (target) tones at 70 dB with a 10
millisecond rise/fall and 40 millisecond plateau time.
Tones were presented at a rate of 1.1 per second,
with target tones occurring randomly with a 0.2
probability. Subjects were sitting with their eyes
closed and were instructed to mentally count the
number of the target but not the frequent tones,
and then asked to report the number of target
tones counted at the end of each run. Potentials
were recorded from scalp electrodes placed at Cz
and were referred to linked ears. Filter settings were
0.5 and 70 Hz. Responses to 30 target and 120
non-target tones were obtained in each trial. Sepa-
rate averages for target and non-target tones were
obtained. Before recording, subjects were familiar-
ized with the two tones and instructed to press a
button when they heard target tones. The obtained
ERPs were subdivided into early or sensory-evoked
components

(e.g. P100, N100, P200, N200), which

emerge within the rst 100-200 millisecond after
stimulus

onset and basically reect stimulus detec-
tion and auditory evoked brainstem potentials, and
later or

cognitive-related components (e.g. P300).
Latencies of each event-related component (N100,
P200, N200 and P300) were measured. P300 laten-
cy was measured as the major positive peak after
N200, within a range of 250-500 milliseconds. The
amplitudes of N200 and P300 were measured as
peak to peak from the negative component just be-
fore the wave to the maximum positive peak of the
wave. P300 is believed to index stimulus signicance
and the

amount of attention allocated to the elicit-
ing stimulus event,

being maximal to task-relevant
or attended stimuli and being

absent or small to
task-irrelevant or unattended stimuli [32].
Statistical analysis
Calculations were performed using SPSS, version
12.0. Data were presented as mean SD (standard
deviation). Independent two-sided Students t test
was used for comparison between groups. Pear-
sons r was used to assess correlations. Multivari- Multivari-
ate analysis was done by stepwise forward logistic
regression based on the probability ratios. The de-
pendent variable was audiologic variables. Variables
that showed signicant association with audiologic
variables in the simple linear regression analysis
(i.e. p<0.05) were used as independent variables
for multiple logistic regression analysis. Multivariate
odds ratio (OR) for risk factors and 95% condence
interval (CI) were calculated. For all tests, p<0.05
was considered

statistically signicant.

Results
This study included 60 patients with DM (T1DM
= 16, T2DM = 44; male = 21; females = 39), with
mean age of 39.5713.89 years and duration of
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illness of 7.375.15 years. Nearly 48.33% of the
patients were uncontrolled on anti-diabetic treat-
ment. Demographic and clinical characteristics of
the studied group were shown in Tables 1. Four-
teen patients (23.33%) had tinnitus and 18 patients
(30%) had subjective hearing impairment (unilateral
= 6 or 33.33%; bilateral = 12 or 66.67%). PTA re-
ported peripheral auditory neuropathy or SNHI in
30% of patients (18/60) [T1DM = 5 (31.25% or
5/16); T2DM = 13 (29.55% or 13/44)] or (30/120)
of ears examined [versus 8.75% (7/80) for control
subjects] (P = 0.001). Bilateral SNHI was reported
in (72.22%; n = 13). Mild, moderate and severe
SNHI was identied in 40% (12/30), 33.33% (10/30)
Table 1. Demographic, clinical and laboratory characteristics of the studied groups.
Demographic and Clinical
characteristics
Patients
(n = 60)
Control subjects
(n = 40)
P-value
Male/female 21/39 12/28 -
Age; years 20-55 (39.5713.89) 20-50 (30.257.40) 0.380
Duration of illness; years 1-25 (7.375.15) - -
Type of DM
Type 1 DM
Type 2 DM
16 (26.67%)
44 (73.33%)
Type of treatment
Oral hypoglycemic
Insulin and oral hypoglycemic
38 (63.33%)
22 (36.67%)
-
-
-
-
Duration of treatment; years 1-25 (7.275.11) - -
Degree of control on treatment
Controlled
Uncontrolled
31 (51.67%)
29 (48.33%)
-
-
-
-
Degree of obesity; # (%)
normal
Overweight
Obese
Morbidly obese
BMI; kg/m2
37 (61.67%)
12 (20.00%)
8 (13.33%)
3 (5.00%)
17.0-40.0 (27.295.25)
18 (45.00%)
12 (30.00%)
6 (15.00%)
4 (10.00%)
15.20-53.50 (29.336.75) 0.564
Blood Pressure; mmHg
Systolic blood pressure
Diastolic blood pressure
Number of patients with
hypertension
70-140 (121.8413.02)
65-110 (77.049.01)
32 (56.14%)
100.00-130.00 (120.00.00)
60.00-85.00 (80.00.00)
0
0.456
0.760
Fasting blood sugar; mmol/l 3-26 (11.325.41) 3.10-5.40 (4.300.71) 0.0001
Lipid prole
TC; mg/dl
LDL-c; mg/dl
TG; mg/dl
HDL-c; mg/dl
Number of patients with dyslipidemia
135.00-295.00
190.0043.39
41.00-196.00
100.0231.88
42.00-450.00
187.60109.34
23.00-79.00
45.0413.24
37 (64.91%)
124.00-195.00
168.107.10
170.00-270.00
115.3025.40
49.00-128.00
92.108.20
35.00-48.00
43.901.20
0
0.052
0.289
0.007
0.750
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Kidney function tests
Urea; mmol/l
Creatinine; mol/l
0.90-8.00
4.111.08
37.80-130.00
66.5922.60
3.00-7.00
4.400.30
45.00-110.00
74.705.00

0.850

0.855
Uric acid; mg/dl 3.991.71 4.610.99 0.670
Data are expressed as mean SD; number (%).
TC, total cholesterol; TG, triglycerides; LDL-c, low density lipoprotein cholesterol; HDL-c, high density lipoprotein cholesterol.
Table 2. Results of Pure Tone Audiometry (PTA) thresholds, Auditory-brainstem response (ABR) at 90 dB
HL with low and high repetition rate frequencies and Event-Related Potentials (ERPs) components.
Audiologic variables
Patients Controls
P1-value P2-value
Right Left Right Left
Frequency [Hz] PTA
250 14.383.34 14.821.49 10.513.80 11.031.50 0.0001 0.0001
500 18.172.34 17.883.97 6.621.56 7.063.10 0.0001 0.0001
1000 16.334.36 17.003.65 9.052.67 8.992.87 0.0001 0.0001
2000 18.834.99 19.722.07 8.193.25 7.191.15 0.0001 0.0001
4000 22.083.79 24.505.91 12.814.57 11.912.57 0.0001 0.0001
8000 25.176.49 25.505.49 11.002.27 10.001.47 0.0001 0.0001
ABR
ABR at 90dBHL low
repetition:
Wave latencies:
I
III
V
Interpeak latencies:
I-III
III-V
I-V
1.950.19
3.890.27
5.980.27
2.960.24
1.950.25
4.020.41
1.950.27
3.820.20
5.970.29
2.990.25
1.900.25
3.970.32
1.240.18
3.040.62
5.290.74
1.980.21
1.240.23
3.090.39
1.800.15
3.040.74
5.060.61
2.080.21
1.290.23
3.090.62
0.0001
0.0001
0.0001
0.0001
0.0001
0.0001
0.0001
0.0001
0.0001
0.0001
0.0001
0.0001
ABR at 90dBHL high
repetition:
Wave latencies:
I
III
V
Interpeak latencies:
I-III
III-V
I-V
1.820.27
3.930.48
6.130.35
2.970.23
2.110.22
4.880.31
1.920.28
4.000.49
6.010.62
2.750.35
2.800.26
4.140.31
1.280.18
3.020.14
5.300.42
2.040.25
1.070.35
3.070.60
1.250.11
3.050.13
5.050.24
2.030.18
2.000.16
3.130.13
0.0001
0.0001
0.0001
0.0001
0.0001
0.0001
0.0001
0.0001
0.0001
0.0001
0.0001
0.0001
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and 26.67% (8/30) of ears involved, respectively.
The latency of wave I was prolonged in 36.67% (n
= 22) of patients with DM indicating impairment
of auditory or acoustic nerve transmission till the
level of cochlear nucleus. The latency of wave III
and I-III and III-V IPLs were delayed in 46.67% (n
= 28) of patients with DM (without impairment in
wave I or V) indicating impairment in the cochlear
nucleus. The latency of wave V and III-V and I-V
IPLs were delayed in 30% (n = 18) with DM without
impairment in wave I or III, indicating impairment in
activity in the nuclei of lateral lemniscus. Table 2
showed results of PTA thresholds, ABR at 90 dB HL
with low and high repetition rate frequencies and
ERPs components. Compared to control subjects,
patients with DM had higher hearing threshold at
different frequencies (250-8000 Hz) (P = 0.0001
for all), prolonged absolute latencies of waves I, III
and V and I-III, III-V and I-V IPLs at 90dBHL low and
high repetition frequencies of ABR and N100, N200,
P200 and P300 components of ERPs (P = 0.0001
for all) and reduced amplitudes of P200 and P300
components of ERPs (P = 0.0001 for all). Table 3
and 4: showed results of PTA thresholds, ABR at 90
dB HL with low and high repetition rate frequencies
and ERPs components according to the type of DM
and the degree of control on anti-diabetic drugs.
No signicant differences were identied among
different audiologic variables between patients with
T1DM and T2DM. Patients who were uncontrolled
on anti-diabetic medications had prolonged I-V IPLs
at 90dBHL low (right: P = 0.025; left: P = 0.041) and
high (right: P = 0.047; left: P = 0.036) repetition
frequencies and reduced amplitudes of P300 (right:
P = 0.050; left: P = 0.052).
Correlations between audiologic variables and de-
mographic, clinical and the degree of control on
anti-diabetic medications showed signicant asso-
ciations between: 1) age at presentation and latency
of wave III at low repetition rate frequencies (r =
0.335, P = 0.035) and P300 latency (r = 0.401, P
= 0.005), 2) duration of DM and latency of wave
V at low repetition rate frequencies (r = 0.358, P
= 0.023), 3) systolic blood pressure and hearing
threshold at 8000 Hz (r = 0.383, P = 0.007) and
latency of wave III at high repetition rate frequencies
(r = 0.372, P = 0.018), 4) diastolic blood pressure
and hearing threshold at 4000 Hz (r = 0.393, P =
0.005); latency of wave III (r = 0.354, P = 0.023),
5) TC level and latency of wave III (r = 359, P =
0.023), III-V IPLs at low repetition rate frequencies
(r = 0.324, P = 0.042) and P300 latency (r = 455, P
= 0.001); LDL-c level and hearing threshold at 8000
Hz (r = 0.341, P = 0.016); TG level and hearing
threshold at 4000 Hz (r = 0.302, P = 0.035) and III-
V (r = 0.388, P = 0.013), I-V (r = 0.353, P = 0.027)
IPLs at low repetition rate frequencies and latency
ERPs
N
100
latency (msec) 128.3138.60 129.8434.30 112.1825.71 112.0025.08 0.0001 0.0001
N
200
latency (msec) 246.0845.71 244.4966.60 242.1229.33 231.8819.92 0.0001 0.0001
P
200
latency (msec) 177.5631.57 182.6428.66 162.4124.51 169.9426.66 0.0001 0.0001
P
200
amplitude (mv) 6.824.11 7.033.21 9.113.67 9.103.45 0.0001 0.0001
P
300
latency (msec) 343.5933.67 346.3832.82 325.1223.96 311.9430.75 0.0001 0.0001
P
300
amplitude (mv) 8.114.24 8.434.03 9.962.72 10.912.27 0.0001 0.0001
Data are expressed as mean SD.
P1- and P2-values: signicance versus controls subjects (right and left sides) respectively.
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Table 3. Results of Pure Tone Audiometry (PTA) thresholds, Auditory-brainstem response (ABR) at 90 dB
HL with low and high repetition rate frequencies and Event-Related Potentials (ERPs) components
according to the type of diabetes mellitus.
Audiologic
variables
T1DM T2DM
P1-
value
P2-
value
P3-
value
P4-
value
P5-
value
P6-
value
Right Left Right Left
Frequency
[Hz]
PTA
250 13.442.18 17.132.66 16.131.92 14.842.07 0.304 0.347 0.727 0.774 0.360 0.502
500 18.752.02 19.382.81 19.521.96 17.331.87 0.009 0.072 0.019 0.194 0.787 0.550
1000 15.631.82 16.881.88 17.421.54 17.581.76 0.067 0.022 0.007 0.011 0.456 0.785
2000 17.811.99 18.942.61 19.841.89 20.002.50 0.002 0.009 0.0001 0.001 0.465 0.770
4000 21.884.16 23.754.91 24.032.41 23.872.58 0.172 0.098 0.011 0.071 0.657 0.980
8000 30.317.96 32.198.76 23.232.74 22.262.59 0.100 0.071 0.036 0.333 0.411 0.291
ABR
ABR at
90dBHL
low
repetition:
Wave
latencies:
I
III
V
Interpeak
latencies:
I-III
III-V
I-V
1.960.18
3.790.27
5.820.24
2.830.20
2.830.31
4.360.26
1.950.22
3.830.27
5.950.26
2.720.21
1.980.21
3.940.32
1.250.21
3.200.28
5.270.29
2.050.27
1.220.23
3.280.48
1.250.29
3.010.16
5.250.26
2.080.30
1.090.27
3.040.32
0.0001
0.0001
0.0001
0.0001
0.0001
0.0001
0.0001
0.001
0.0001
0.0001
0.0001
0.0001
0.0001
0.0001
0.0001
0.0001
0.0001
0.0001
0.0001
0.001
0.0001
0.0001
0.0001
0.0001
0.944
0.993
0.570
0.800
0.356
0.526
0.965
0.777
0.232
0.649
0.297
0.452
ABR at
90dBHL
high
repetition:
Wave
latencies:
I
III
V
Interpeak
latencies:
I-III
III-V
I-V
2.830.22
3.950.63
6.970.43
2.970.20
2.880.18
4.810.24
2.920.28
4.090.33
5.741.25
2.700.46
2.010.17
4.800.41
1.850.33
3.200.49
6.140.35
2.160.24
2.080.23
4.250.35
1.900.26
3.030.23
5.080.29
2.120.35
1.230.31
4.130.27
0.0001
0.0001
0.0001
0.0001
0.0001
0.0001
0.0001
0.0001
0.0001
0.0001
0.0001
0.0001
0.0001
0.0001
0.0001
0.0001
0.0001
0.0001
0.0001
0.0001
0.0001
0.0001
0.0001
0.0001
0.823
0.448
0.812
0.952
0.737
0.615
0.249
0.629
0.419
0.646
0.853
0.823
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ERPs
N
100
latency
(msec)
116.8138.60 130.0031.64 136.8342.53 131.4835.60 0.0001 0.0001 0.0001 0.0001 0.101 0.886
N200
latency
(msec)
245.4419.07 230.6965.47 246.3461.13 249.9776.39 0.0001 0.0001 0.0001 0.0001 0.942 0.379
P
200

latency
(msec)
175.8826.15 182.5633.39 190.1740.03 184.4824.94 0.0001 0.0001 0.0001 0.0001 0.156 0.842
P
200

amplitude
(mv)
7.411.38 6.040.79 6.810.69 6.340.46 0.0001 0.0001 0.0001 0.0001 0.704 0.747
P
300

latency
(msec)
347.2827.37 343.3925.35 344.1034.62 348.4035.05 0.0001 0.0001 0.0001 0.0001 0.737 0.585
P
300

amplitude
(mv)
8.981.01 8.401.03 8.480.79 8.420.75 0.0001 0.0001 0.0001 0.0001 0.696 0.989
Data are expressed as mean SD.
T1DM, type 1 diabetes mellitus; T2DM, type 2 diabetes mellitus.
P1- and P2-values: T1DM versus controls (right and left sides) respectively.
P3- and P4-values: T2DM versus controls (right and left sides) respectively.
P5- and P6-values: T1DM versus T2DM (right and left sides) respectively.
of wave III at high repetition rate frequencies (r =
0.442, P = 0.004); HDL-c level and hearing thresh-
old at 250 Hz (r = -0.327, P = 0.022) and latency
of wave III at low (r = -0.357, P = 0.024) and high
(r = -0.478, P = 0.002) repetition rate frequencies
and P300 latency (r = -0.393, P = 0.006), and 6)
blood sugar level and hearing threshold at 4000 Hz
(r = 0.302, P = 0.035) and 8000 Hz (r = 350, P =
0.007), latency of wave III (r = 399, P = 0.011), wave
V (r = 0.445, P = 0.005), I-III (r = 0.456, P = 0.004),
III-V (r = 0.321, P = 0.044) and I-V (r = 0.355, P =
0.003) IPLs at low repetition rate frequencies, I-III (r
= 0.543, P = 0.001) and III-V (r = 0.456, P = 0.002)
IPLs at high repetition rate frequencies; and latency
(r = 0.467, P = 0.002) and amplitude (r = -0.530, P
= 0.001) of P300. In multivariate analysis and after
adjustment of other risk factors, there were increase
in the odds for latency of wave III (OR 1.90; 95% Cl
1.02 to 3.55, P = 0.044); I-III (OR 2.36; 95% Cl 0.95
to 5.81; P = 0.06) and III-V (OR 2.36; 95% Cl 0.95
to 5.81; P = 0.06) IPLs and amplitude of P300 (OR
2.36; 95% Cl 0.95 to 5.81; P = 0.06) in relationship
to the degree hyperglycemia.
Although it is not our aim, 38 patients (63.33%)
had bilateral sensory/sensorimotor peripheral neu-
ropathy and all also had peripheral (n = 18) and/or
central (n = 20) auditory neuropathy.
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Table 4. Results of Pure Tone Audiometry (PTA) thresholds, Auditory-brainstem response (ABR) at 90 dB HL with
low and high repetition rate frequencies and Event-Related Potentials (ERPs) components according to
the degree of control on anti-diabetic drugs.
Audiologic
variables
Controlled patients Uncontrolled patients
P1-
value
P2-
value
P3-
value
P4-
value
P5-
value
P6-
value
Right Left Right Left
Frequency
[Hz]
PTA
250 16.582.59 17.633.23 14.261.80 14.221.69 0.686 0.357 0.023 0.307 0.468 0.358
500 20.002.29 17.892.79 18.701.97 17.881.86 0.006 0.174 0.138 0.507 0.671 0.998
1000 17.371.96 19.212.33 16.301.55 16.111.59 0.014 0.007 0.142 0.338 0.670 0.280
2000 21.321.91 21.052.77 17.782.04 18.812.60 0.0001 0.005 0.042 0.061 0.212 0.559
4000 22.112.71 25.003.44 24.443.15 23.703.28 0.036 0.061 0.002 0.106 0.576 0.786
8000 23.953.23 22.633.30 27.595.14 28.525.49 0.009 0.171 0.001 0.026 0.552 0.363
ABR
ABR at
90dBHL
low
repetition:
Wave
latencies:
I
III
V
Interpeak
latencies:
I-III
III-V
I-V
1.970.19
3.830.17
5.800.32
2.910.19
1.980.20
4.900.56
1.980.25
3.770.19
5.920.26
2.940.29
1.860.31
4.820.37
1.250.21
3.010.31
5.170.25
2.100.27
1.210.28
4.270.32
1.240.29
3.240.19
5.020.26
2.120.27
1.360.21
4.460.27
0.0001
0.0001
0.0001
0.0001
0.0001
0.0001
0.0001
0.0001
0.0001
0.0001
0.0001
0.0001
0.0001
0.0001
0.0001
0.0001
0.0001
0.0001
0.0001
0.0001
0.0001
0.0001
0.0001
0.0001
0.841
0.678
0.727
0.241
0.339
0.025
0.663
0.225
0.260
0.423
0.232
0.041
ABR at
90dBHL
high
repetition:
Wave
latencies:
I
III
V
Interpeak
latencies:
I-III
III-V
I-V
1.930.36
3.990.55
6.170.31
2.180.29
2.070.16
4.870.38
1.940.31
4.070.19
5.820.98
2.110.40
1.940.35
4.880.30
1.290.26
3.160.52
6.130.42
2.140.18
2.100.26
4.140.29
1.230.26
3.030.30
5.030.31
2.170.38
1.230.21
4.040.22
0.0001
0.0001
0.0001
0.0001
0.0001
0.0001
0.0001
0.0001
0.0001
0.0001
0.0001
0.0001
0.0001
0.0001
0.0001
0.0001
0.0001
0.0001
0.0001
0.0001
0.0001
0.0001
0.0001
0.0001
0.236
0.468
0.732
0.635
0.642
0.050
0.927
0.596
0.267
0.706
0.406
0.052
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Discussion
The results of this study indicate the followings:
1) patients with DM had higher frequency of pe-
ripheral hearing impairment. 2) Patients with DM
had higher frequency of central hearing impairment.
3) Vascular compromise with reduced blood ow
to the cochlea and/or direct effect of hyperglycemia
has been suggested as possible etiologies of audi-
tory dysfunction in patients with DM.
FIRST, the ndings indicate that DM is associated
with high frequency of auditory neuropathy. Nearly
30% of patients with DM had higher hearing thresh-
olds indicating peripheral auditory neuropathy or
SDHI which appeared at different frequencies (250-
8000 Hz) [11-14] particularly high frequencies and
regardless the type of DM (T1DM versus T2DM) and
the degree of control on anti-diabetic medications.
This is also supported by the nding that 36.67%
had prolonged absolute latency of wave I of ABR
(which indicate impairment of auditory or acoustic
nerve transmission till the level of cochlear nucleus)
[16, 17, 19-22]. Studies evaluated the frequency and
distribution of risk factors among populations with
idiopathic sensorineural hearing loss revealed that
DM is among the frequent vascular metabolic risk
factors (Latent: 63.8%, manifest diabetes: 6.6%)
followed by hyperuricemia (35.9%) and hyperlipo-
proteinemia (24.2%) [33].
SECOND, the results of this study conrmed that
patients with DM reported a higher frequency of
central impairment of auditory pathways as evi-
ERPs
N
100

latency
(msec)
121.2946.77 129.2433.53 134.5937.63 133.4434.46 0.0001 0.0001 0.0001 0.0001 0.331 0.842
N
200

latency
(msec)
250.8235.43 218.8425.60 242.8858.61 257.5238.61 0.0001 0.0001 0.0001 0.0001 0.578 0.223
P
200

latency
(msec)
181.3537.16 181.8225.05 187.3036.56 187.3027.77 0.0001 0.0001 0.0001 0.0001 0.607 0.533
P
200
amplitude
(mv)
8.27345 7.893.68 9.184.36 8.433.99 0.0001 0.0001 0.0001 0.0001 0.447 0.280
P
300

latency
(msec)
342.4420.40338.4435.07 347.6734.22 352.0535.22 0.0001 0.0001 0.0001 0.0001 0.593 0.091
P
300

amplitude
(mv)
5.662.42 5.232.02 8.025.13 6.692.83 0.0001 0.0001 0.0001 0.0001 0.047 0.036
Data are expressed as mean SD.
P1- and P2-values: controlled patients versus controls (right and left sides) respectively.
P3- and P4-values: uncontrolled patients versus controls (right and left sides) respectively.
P5- and P6-values: controlled versus uncontrolled patients (right and left sides) respectively.
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denced by prolongation of wave III and I-III, III-V
and I-V IPLs indicating delayed transmission at the
level of brainstem [19-22]. We also reported abnor-
malities in P300 component of ERPs (a long-latency
auditory evoked response) in the form of delayed
latencies (indicating demyelination) and reduced
amplitudes (indicating axonapathy and degenera-
tion) which further conrm central involvement of
auditory pathway (i.e. auditory cortex) [18]. THIRD,
the possibilities that vascular compromise with
reduced blood ow to the cochlea and/or direct
effect of hyperglycemia as a possible etiology of
auditory dysfunction in our patients, are highly sug-
gested, as evidenced by the following: 1) It is well
known that the cochlea is a vascular region pro-
vided with terminal capillary bed. The high meta-
bolic demands of the inner ear and the inherited
properties of the cochlea making it unable to form
collateral vessels that could restore blood ow in
the ischemic regions resulting in high sensitivity to
minimal blood ow reduction [34] and appearance
of clinical manifestations even before evidence of
macrovascular complication [35]. In support, SNHI
was observed at higher frequencies (2000-8000 Hz)
[23, 24]. High frequency loss has been found to
be related to outer hair cells (OHCs) degeneration
along base-to-apex gradient or mainly in the basal
turns of the cochlea that follows reduced function
of the stria vascularis, a highly vascular epithelium
[36]. This is commonly attributed to atherosclerosis-
related microcirculatory disturbances of the cochlear
vasculature [14, 35]. DM might decrease the func-
tion of the stria vascularis and OHCs loss in a similar
manner involved in other related metabolic vascular
diseases as hyperchlosterolemia/dyslipidemia [9, 26,
28] and hyperuricemia [37]. 2) We reported that
63.33% had bilateral sensory/sensorimotor periph-
eral neuropathy and all also had peripheral and/or
central auditory neuropathy. Vascular compromise
of the vasa nervorum (which are small arteries that
provide blood supply to peripheral nerves) has been
suggested as the pathologic lesion responsible for
SNHI with DM. In support, the absence in signi-
cant difference in hearing impairment regardless of
type and duration of DM but the correlation with
the blood sugar level is in support to the notion that
the degree of hyperglycemia is the main cause of
hearing impairment with DM. In fact, studies indi-
cated that diabetic neuropathy is a dynamic process,
both degeneration and regeneration occurs simulta-
neously [26-28], however a shift of the balance be-
tween degeneration and regeneration toward more
degeneration may occur overtime [27]. Impairment
of regenerative capacity of nervous system cells
may occur as a result of hyperglycemia, reduction
of nerve blood ow and hypoxia, impairment of
cellular scavenging activity against oxidative stress
[38], abnormal fatty acid metabolism [9, 27], ATPase
activity, depletion of myoinositol [39], increase in
platelet aggregation [40] and loss of growth factor
systems [41, 42].

Despite the importance of the results of this study,
there are some limitations which include: 1) rela-
tively small number of patients, and 2) due to the
cross-sectional design of this study; the temporal
relation between appearances of auditory dysfunc-
tion in patients with DM is unknown.
Conclusions
Patients with DM have higher frequency of periph-
eral and central hearing impairment (i.e. acoustic
nerve, auditory pathway throughout the brainstem
till the auditory cortex). The degree of hearing im-
pairment was signicantly correlated with glycemic
control. This knowledge is important for specialists
serving those patients and thus frequent evaluation
by audiometric tests in DM patients is recommend-
ed for controlling hearing disorders by therapeutic
and rehabilitation procedures. Future related re-
searches are also important and have to include the
following: a) longitudinal studies that prospectively
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assess the relation of the disease process over time
on auditory functioning of patients with DM, and
b) randomized clinical trials that prospectively com-
pare auditory function in response to different treat-
ment modalities including anti-diabetic medications,
vasodilator, antioxidants versus a control group of
DM patients.
Conict of interests
We declare that this work has no conict of inter-
ests. There is no involvement of sponsor for this
work design, data collection, analysis, interpreta-
tion, drafting, nor the decision to submit this paper
for publication. All are authors responsibility.
Abbreviations
DM, diabetes mellitus; T1DM, type 1 diabetes melli-
tus; T2DM, type 2 diabetes mellitus; IR, insulin resis-
tance; BMI, body mass index; PTA, pure tone audi-
ometry; CHI, conductive hearing impairment; SNHI,
sensorineural hearing impairment; ABR, Auditory-
Brainstem Response; ERPs, Event Related Potentials;
TC, total cholesterol; TG, triglycerides; LDL-c, low
density lipoprotein cholesterol; HDL-c, high density
lipoprotein cholesterol.
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