You are on page 1of 10

The Laryiigoscope

Lippincott-Raven Publishers, Philadelphia

0 1997 The American Laryngological,
Rhinological and Otological Society, Inc.

Interaction Between Hypertension and

Diabetes Mellitus in the Pathogenesis of
Sensorineural Hearing Loss
Sigsbee W. Duck, MD; Jiri Prazma, MD, PhD; P. Scott Bennett, MD; Harold C. Pillsbury, MD

The purpose of this study is to support the hy- more prevalent, affecting more than 20% of the gen-
pothesis that diabetic end-organ damage of the eral population of the United States.1 These two con-
cochlea is augmented in the setting of hyperten- ditions, affecting millions of Americans, have been
sion. A historical perspective reviewing the effects shown to cause hearing loss in patients,ZJ as well as
of diabetes and hypertension as causative factors in cochlear damage in animal studies.435
the development of sensorineural hearing loss, as
well as the basic epidemiology and pathophysiol- Diabetes was first associated with hearing loss
ogy of the renal and vascular effects of diabetes and by Jordao6 in 1857 and since then has been shown to
hypertension, is presented. The results of audio- cause a slowly progressive, bilaterally symmetric,
logic findings in insulin-dependent diabetic pa- sensorineural hearing l0ss.7 Chronic hypertension
tients, both normotensive and hypertensive, were
analyzed and correlated with the results of animal has also been implicated in the development of hear-
studies to support the hypothesis that sensori- ing loss.33 Studies have documented that chronic
neural hearing loss in patients and cochlear hair hypertension potentiates noise-induced decreases in
cell loss in animal studies result from the effects of cochlear function and the development of histologic
hypertension in conjunction with insulin-depen- cochlear darnage.g.10 A significant relationship
dent diabetes mellitus. among hypertension, age, and hearing loss in an an-
Laryngoscope, 107:1696-1605,1997 imal model has also been confirmed.11
We hypothesize that diabetic end-organ damage
INTRODUCTION of the cochlea is augmented in the setting of hyper-
Over the years in our practice, we have seen di- tension. To our knowledge, no study to date has docu-
abetics with substantial hearing loss and others mented the effects of concomitant diabetes and hy-
with normal hearing. This discrepancy has triggered pertension on the inner ear. To examine the effects of
our curiosity to look for factors that may be respon- diabetes on the cochlea in the setting of hypertension,
sible for this difference. Therefore the question was we conducted a prospective analysis of the clinical au-
raised, what is the factor, either alone or in conjunc- diologic findings in normotensive and hypertensive
tion with insulin-dependent diabetes mellitus, that insulin-dependent diabetics and analyzed cochlear
is responsible for the differences in the audiometric hair cell losses in hypertensive diabetic rats, normo-
findings of these patients? tensive diabetic rats, and normotensive nondiabetic
Two of the most common chronic medical prob-
lems encountered by physicians are diabetes melli- MATERIALS AND METHODS
tus and hypertension. Conservative estimates of the
prevalence of diabetes mellitus in the general popu- Part A
lation are at least 1%, and hypertension is even Twenty-two patients with a history of insulin-depen-
dent diabetes mellitus participated in this study. They
were referred by internists for inclusion in this study. Pa-
Accepted with Honorable Mention as a Candidate's Thesis by the
Amtxrican Laryngological, Rhinological and Otological Society, Inc. tients were not considered as hypertensive candidates for
From the Division of Otolaryngology, School of Medicine, University this study unless they had been treated for hypertension
o f North Carolina a t Chapel Hill, Chapel Hill, North Carolina. for 2 or more years. Twelve of the patients were being
Send Reprint Requests to Sigsbee W. Duck, MD, Sagebrush Ear, treated for hypertension for 2 or more years, and 10 had
Nost. and Throat, P.O. Box 2500, Gillette, WY 82717, U S A . no history of hypertension. The average age of the pa-

Laryngoscope 107: December 1997 Duck et al.: Pathogenesis of Hearing Loss

tients, the duration of treatment with insulin, the use of ing and cutting tools fashioned from 30-gauge needles.
antihypertensive therapy, and other factors contributing The specimens were stained with 0.5% toluidine blue in
to hearing loss were recorded and evaluated. Patients 0.5% borax and mounted in glycerin on a slide.
with a history of noise exposure (i.e., from hunting or
heavy industrial exposure) and other extrinsic factors Hair cells were counted using light microscopy in
(i.e., aminoglycoside therapy) were excluded. All patients 200-ym segments, beginning a t the hook and continuing
were evaluated with complete audiometric evaluations in- toward the apex of the cochlea. The cochlea was divided
cluding airhone, speech reception threshold (SRT) and into four regions for comparison, including the hook, the
speech discrimination scores. The audiologist was blinded first turn, the second turn, and the third turn. The first
as to the hypertensive status of each of the 22 subjects. If and second turns were further divided into quarter turns
a significant difference (510 dB) was noted when evaluat- for comparisons between groups. Dividing the cochlea in
ing hearing in each ear, the subject was eliminated. this way allowed for a more complete and descriptive
analysis of the distribution of hair cell loss throughout the
The hearing of diabetic patients was analyzed using cochlea in the different study groups. For each segment
analysis of covariance (ANCOVA), a statistical technique the number of missing hair cells was recorded.
used to control for the influence of a confounding variable.
Confounding variables occur most often when subjects Experimental results collected from the diabetic and
cannot be assigned at random to different groups. In this normal rats were analyzed using nonparametric tests. Most
study hypertensive diabetics were older than normoten- frequently scientific data are analyzed using parametric
sive diabetics; because this age factor was not possible to tests such as analysis of variance (ANOVA) and Student’s
control, these data were analyzed by ANCOVA. t-test. However, parametric tests assume a normal distribu-
tion in experimental groups. Inspection of the raw data in-
dicated that the assumption of homogeneity of variance
Part B across treatments, which underlies parametric analysis,
This study used a total of 37 animal subjects consist- was not met; therefore analysis of effects was undertaken
ing of 11 LA/N-cp normotensive nondiabetic rats, 13 with nonparametric tests. In this study the distribution be-
WKY/N-cp diabetic normotensive rats, and 13 SHRIN-cp tween the samples was relatively large. For example, in hy-
spontaneously hypertensive diabetic rats. pertensive diabetics when comparing the distribution in the
first turn, third quarter (SD = 7.91) t o the distribution in
The W - c p normotensive nondiabetic rat was de- the second turn, second quarter (SD = 27.79), the distribu-
veloped by crossing the Albany/N strain with a hooded tion in the samples was large; therefore statistical evalua-
strain.12The WKY/N-cp diabetic normotensive rat was de- tion of the data was ranked and then analyzed using a two-
veloped from the Wistar-Kyoto rat strain as an animal way repeated-measure ANOVA. A P value of less than 0.05
model to study diabetic pathologic features. The SHRIN-cp was considered statistically significant.
spontaneously hypertensive diabetic rats were developed
at the National Institutes of Health (NIH) by establishing RESULTS
the corpulent cp gene from the obese Koletsky rat strains
into the SHRIN strains.12 The availability of these strains Part A
provides excellent models for the study of the effects of hy-
pertension and diabetes on the inner ear. All data are presented as a mean, with the stan-
dard error of the mean in parentheses. The average
All 37 rats were raised in hanging metal cages in a age of the entire group of patients was 55.7 years
noise-free environment. The animals were on a light cycle (24.39). The average age of normotensive insulin-
of 12 hours of light and 12 hours of dark controlled by an dependent diabetic patients was 47 years (+-5),as
automatic clock. The housing room had a controlled tem-
perature between 21°C and 25°C and humidity between compared with 62.4 years (23.78) of age for hyper-
40% and 50%. This study was performed in accordance tensive insulin-dependent diabetic patients. The av-
with the Public Health Service (PHS) Policy on Humane erage duration of therapy with insulin for normoten-
Care and Use of Laboratory Animals.13 The animals were sive diabetics was 13.4 years (23.72) and for
maintained on diets of 54% starch, 10% casein, 10% lac- hypertensive diabetics, 7.3 years (22.35). The average
talbumin, 5.9% cellulose, 4% beef tallow, 4% lard, 4% corn duration of hypertension requiring treatment was
oil, 4%) coconut oil, 1%salt mix, and 1%vitamin mix. They 15.1 years (22.49). The average SRT of normotensive
were sacrificed at 32 to 33 weeks of age. After sacrifice, the insulin-dependent diabetics was 11 dB (22.69) and
cochleae were fixed in a mixture of Bouin’s solution (a so- for hypertensive insulin-dependent diabetics, 26.67
lution of saturated aqueous picric acid, 10% formaldehyde dB (24.48). The average discrimination score of nor-
solution, and 5% acetic acid) and then stored in phos- motensive insulin-dependent diabetics was 98.8%
phate-buffered 1%paraformaldehyde at a pH of 7.4.
(20.8%)and for hypertensive insulin-dependent dia-
The bony capsule was decalcified with a 10% eth- betics, 95.45% (21.86%). A complete compilation of
lyenediamine-tetraacetic acid (EDTA)in phosphate buffer the audiometric results with the mean and standard
at a pH of 7.4. Using a surface preparation technique, the error of the mean of each particular frequency, SRT
cochleae were cut into halves along the long axis of the and speech discrimination scores, as well as the fac-
modiolus. The basilar membranes were removed under a
dissecting microscope by scooping out the stria and basi- tors of diabetes and duration of hypertension, is
lar membrane with subsequent dissection of the basilar shown in Tables I and 11. The results of the audio-
membrane from the stria, or by dissection of the basilar metric evaluations between the two is demonstrated
membrane from the stria in situ. The dissections were in Figure 1. In each frequency there is a significant
performed in a phosphate-buffered solution using scoop- increase in the hearing loss between normotensive

Laryngoscope 107: December 1997 Duck et al.: Pathogenesis of Hearing Loss

Raw Data, Mean, and Standard Error of Mean of All Studied Diabetic Hypertensive Patients.
Frequency (Hz) Speech Discrimination Duration (y)

Age AVG Blood Hyper-

Patient (y) Sex 250 500 1000 2000 4000 8000 SRT (dB) (Yo) Pressure tension Diabetes

AT 45 M 25 20 7.5 17.5 60 77.5 45 77.5 154/70 5 17

DM 66 M 30 20 22.5 20 42.5 65 55 96 130l70 20 1
BD 56 M 20 20 20 27.5 30 67.5 10 100 130180 20 3
DH 49 M 25 15 2.5 2.5 15 12.5 42.5 96 140183 10 3
IF 73 F 55 45 42.5 55 97.5 100 22.5 94 170190 10 5
DA 69 F 40 40 32.5 22.5 25 35 5 96 140170 15 1
DC 42 F 10 10 2.5 0 2.5 0 35 98 140190 10 1
VB 86 F 35 30 20 20 32.5 55 22.5 100 170188 24 3
MC 63 F 30 25 17.5 20 27.5 40 22.5 94 140190 15 1
RS 69 F 80 75 50 65 85 100 15 100 152160 2 13
CB 66 F 35 45 47.5 35 37.5 52.5 22.5 94 130170 31 20
AGE 65 F 20 15 15 20 35 40 22.5 100 160/80 20 20
Mean 62.42 33.75 30 21.83 25.42 40.83 53.75 26.67 95.45 146.3ff8.4 15.17 7.33
Standard 3.78 5.57 5.56 5.30 5.67 8.3 9.3 4.48 1.86 4.413.1 2.49 2.35

SRT = speech reception threshold; AVG = speech recognition if correct response; BP = blood pressure

and hypertensive insulin-dependent diabetics when nondiabetic rats; group 11, the WKY/N-cp diabetic
age factors are not taken into account. When both normotensive rats; and group 111, the SHR/N-cp
groups are reevaluated taking age factors into ac- spontaneously hypertensive diabetic rats. Outer
count and reevaluating the audiometric differences hair cell loss is expressed as mean hair cell loss per
between the two groups (Table III), a statistically sig- cochlear turn and per quarter of the first and second
nificant difference (P < 0.05) is still found between turns. The hook and third turn were counted and
frequency and group in the higher frequencies (4 to 8 analyzed as one unit without being divided into
kHz). quarters (Fig. 2). The results after summarizing
from quarters in the first and second turns are pre-
Part B sented in Figure 3. In group I (LALN-cp), the hair
The results of this study compare the three cell loss in the hook averaged 0.075 (20.21); cell loss
groups of rats: group I, the LA/N-cp normotensive in the first turn averaged 14.67 (22.04); in the sec-

Raw Data, Mean, and Standard Error of Mean of All Studied Diabetic Normotensive Patients.
Frequency (Hz) Speech Discrimination Duration (y)
Age AVG Blood
Patient (y) Sex 250 500 1000 2000 4000 8000 SRT(dB) (W Pressure Diabetes
GC 49 F 10 10 5 5 0 2.5 10 100 136184 22
EL 47 F 20 10 10 7.5 10 37.5 32.5 92 120180 5
CR 49 F 20 10 2.5 2.5 10 5 7.5 100 130190 11
EW 53 F 20 15 2.5 7.5 10 15 5 100 120180 2
ZR 70 F 35 35 25 37.5 50 55 5 100 100170 2
vz 37 F 25 15 0 0 0 0 2.5 100 1 18178 24
DS 45 F 30 25 2.5 2.5 2.5 0 10 100 130180 34
ET 62 F 15 15 5 15 27.5 32.5 5 100 134160 17
LC 45 F 15 10 25 5 17.5 10 17.5 100 120180 16
ZT 13 M 10 10 10 5 12.5 7.5 15 96 1OOl74 1
Mean 47 20 15.5 8.75 8.75 14 16.5 11 98.8 120.8177.6 13.4
Standard 5 2.72 2.77 3.05 3.62 5.05 6.26 2.69 0.8 4.2312.72 3.72

SRT = speech reception threshold; AVG = speech recognition if correct response; BP = blood pressure.

Laryngoscope 107: December 1997 Duck et al.: Pathogenesis of Hearing Loss

T I 50 -
I d
40- rr
I 30-
sg $0- f:c
z 20-

20- 8
g 10-
10 -

0 ,- I I I I I I I 1 I I I
250 500 lk 2k 4k 8k H 1-1 1-2 1-3 1-4 11-1 11-2 11-3 11-4 Ill

Fig. 1. Comparisons of two groups of diabetics: normotensive and Fig. 2. Mean outer hair cell loss in absolute values in three groups of
hypertensive. Depicted on horizontal axis are individually tested fre- rats: normal (control) LNN-cp rats, normotensive diabetic WKY/N-cp
quencies of 250 and 500 Hz and 1, 2, 4, and 8 kHz. Bars express rats, and hypertensive diabetic SHWN-cp rats. H = hook; I = first
mean hearing loss for tested frequency; vertical bars designate stan- turn; II = second turn; 111 = third turn. Numbers 1 to 4 represent the
dard error of mean. quarters of each turn; bars designate standard error of mean.

ond turn, the hair cell loss increased to 19.75 third turns between the groups. There was signifi-
(k2.48); and in the third turn, a decrease to 6 ( d . 1 6 ) cantly increased hair cell loss (P < 0.05) when com-
was noted (Fig. 3). In group I1 (WKYN-cp),hair cell paring turns I, 11, and I11 (P = 0.0125) and when
loss in the hook averaged 4.69 (21.06); loss in the comparing the quarter turns of turns I and I1 ( P =
first turn increased to 11.54 (kl.9); an increase in 0.00312). As can be seen in Figure 2, there was no
the second turn to 28.62 (27.54) was seen; and a de- significant hair cell loss within the hook region, turn
crease in the third turn to 1.08 (20.35) was shown. 111, and the fourth quarter of turn 11.
In group I11 (SHWN-cp),the hair cell loss was 6.17
This study reveals a highly significant outer
(k2.36) in the hook, 175.67 (d33.32) in the first
hair cell loss in diabetic rats that were also hyper-
turn, 123.5 (233.25) in the second turn, and 24.33 tensive. Most of the damage was localized to the
(28.81) in turn three. Examples of hair cell loss in first and second turns of the cochlea.
the first (LA/N-cp)and third groups (SHWN-cp)are
demonstrated in Figures 4 and 5, respectively.
There was significantly increased hair cell
loss in group I11 compared with groups I and I1 The results clearly support the hypothesis that
( P < 0.0001). insulin-dependent diabetes, in conjunction with hy-
pertension, has a synergistic effect on high-fre-
There was no statistical difference between the quency sensorineural hearing loss. In clinical and
first and second groups. Closer analysis of the dif- animal studies, respectively, there is a significant
ferences between the turns and the groups revealed high-frequency sensorineural hearing loss in pa-
a significant difference between the first turns tients (even when using correction factors for age)
(f= 37.32 and P < 0.0001). However, there was no and a definite adverse effect on the cochlea, result-
significant difference when comparing the hook and ing in hair cell loss.

TABLE 111.
Results of Covariance Statistical Evaluation of Two Groups of Patients Tested With Audiometric Hearing Thresholds.
~~ ~

Source df Sum of Squares Mean Square FValue PValue G-G H-F

Group 1 4062.81 1 4062.811 3.524 0.0759

Age 1 7250.155 7250.155 6.289 0.0214
Subject (group) 19 21904.289 1152.857
Frequency 5 38.766 7.753 0.088 0.9940 0.8954 0.9267
Frequency' group 5 1025.085 206.017 2.325 0.0487 0.1 188 0.1072
Frequency' age 5 385.779 77.156 0.875 0.5010 0.4144 0.4312
Frequency' subject (group) 95 8377.277 88.182
'Significant difference between the groups is a frequency group interaction highlighted in boldface

Laryngoscope 107: December 1997 Duck et al.: Pathogenesis of Hearing Loss


180 0-0 SHR


8 ti0

II Ill

Fig. 3. Outer hair cell loss in H and turns I. II, and 111. Horizontal bars
express mean of outer hair cell loss in absolute values; vertical bars Fig. 4. Three rows of outer hair cells without any loss in normal (con-
designate standard error of mean. Normal (control), normotensive trol) rats. The inner row of hair cells is out of focus. White horizontal
diabetic, and hypertensive diabetic rats are depicted. bar represents 25 prn.

A thorough review of the epidemiology and even more common in diabetics before the diagnosis
pathophysiology of the association between diabetes of diabetes, although there were no significantly
and hypertension helps to better understand the convincing data to support this conclusion. In 1981,
multisystem vascular and end-organ pathologic fea- Christlieb et a1.21 demonstrated a significant in-
tures associated with a combination of the two dis- crease in hypertension in juvenile diabetics as they
ease processes thereby affecting the cochlea. Dia- aged. Barrett-Connor et a1.22 found that there is a
betes is now the most common cause of end-stage consistent association between diabetes mellitus
renal failure in patients between the ages of 25 and and hypertension, with an adjustment for obesity,
65 years in the United States. As a result, more em- reducing its extent but not its prevalence. In con-
phasis is being placed on evaluating the role of hy- trast, Keen et al.23 cited a significant correlation be-
pertension in association with diabetes and their ef- tween glucose intolerance and hypertension that
fects on renal function.14 Epidemiologic studies of was independent of age or obesity.
the association between diabetes and hypertension
have demonstrated a clinical impression that hy- On histologic study it has been shown that the
pertension occurs with more frequency in the dia- changes of diabetic nephropathy occur many years
betic patient than the in general population.15 Esti- after the onset of microalbuminuria. Control of hy-
mates of the prevalence of hypertension in diabetics pertension has been shown to eliminate the mi-
vary between 10% and 80%, according to different croalbuminuria and slows the progression of renal
reports. These reports, however, are questioned be- failure.24 It appears that hypertension associated
cause of their methodology.16 with diabetes may be caused by metabolic factors

In 1954, Hamilton et al.17 observed that hyper-

tension was not significantly higher in diabetics
than in nondiabetics, except in the 70- to 79-year-old
age group. Keen et a1.18 found no systematic blood
pressure difference between diabetics and controls.
The study on London civil servants showed signifi-
cantly higher blood pressure in diabetics than in
controls.19 This study demonstrated that there was
a correlation between systemic blood pressure, dias-
tolic blood pressure, and glucose, which was inde-
pendent of body mass in men more than 40 years of
age. A 1967 study compared 662 employees of the
Dupont Company with matched nondiabetics (for
age, sex, and employment status) and found that the
prevalence of hypertension (systolic blood pressure
>150 mm Hg and diastolic blood pressure >94 mm
Hg) was higher in the diabetic group.20 Hyperten- Fig. 5. Three rows of outer hair cells with several hair cells (black ar-
sion increased as each category of body weight in- rowheads) in hypertensive diabetic rats. The inner hair cells are out
creased. It was also noted that hypertension was of focus. White horizontal bar represents 25 fim.

Laryngoscope 107: December 1997 Duck et al.: Pathogenesis of Hearing Loss

other than renal factors. Metabolic alterations found their normotensive counterparts. The finding of a
in the adipocytes of diabetic rats include the eleva- significant increase in glomerular basement mem-
tion of cellular cyclic adenosine monophosphate brane thickening in hypertensive as compared with
(AMP),both basal and norepinephrine stimulated, normotensive rats suggests that systemic blood
and higher beta-adrenergic receptor density.25226 It pressure may be an independent determinant of
has been found that, because of an increased sensi- glomerular basement membrane thickness.38~39
tivity to norepinephrine and angiotensin 11, much Early diabetic glomerular lesions reveal both
less norepinephrine and angiotensin I1 is needed in basement membrane thickening and augmentation
diabetics to achieve the same pressor effects in nor- of the mesangial matrix.40 Glomerular capillaries
moglycemic patients.27 Another possible contribut- are not normally surrounded circumferentially by
ing metabolic factor causing hypertension in stable the basement membrane. It can be seen in sections
nonazotemic diabetics is an increase in sodium ex- that the basement membrane of one capillary is
change.28 In the hypertensive diabetic, systolic blood fixed to the mesangium in two places. In a normal
pressure correlates with sodium exchange, resulting glomerulus these sites are side by side. With mesan-
in hypertension.29 A third factor could lie in genetic gial broadening the fixation sites are crowded out,
HLA type where the risk of developing insulin-de- but there is no reduction of the filtration surface or
pendent diabetes mellitus for the HLA-identical sib- marked decrease of the capillary lumen. Therefore
ling of an insulin-dependent diabetic patient is ex- in the early and intermediate stages of glomeru-
tremely high. Also, siblings with shared HLA losclerosis there is not very much reduction of the
specificities are at a greater risk of developing in- filtration surface and the capillary lumen. Ulti-
sulin-dependent diabetes mellitus.30 mately this process cannot continue, and large nod-
In benign hypertension there are arteriosclerotic ules form and are flattened, occluding capillaries at
changes with multiplication of the internal elastic the periphery. The nodules can then be in contact
lamina and thickening of the intima. In arterioles with and adhere to Bowman’s capsule. On histologic
there is hypertrophy of the media and subsequent study, type I diabetics with clinical nephropathy and
hyalinosis occurs. When combined with diabetes, the hypertension were found to have more frequent ex-
arterial changes are frequently demonstrated in the udative lesions, subcapsular fibrosis, and sclerotic
preglomerular afferent arterioles. The lumen of the glomeruli. There is also a significant diminution
blood vessels is narrowed, and muscles of the media with regard to open capillaries, endothelial cells,
are atrophic. This narrowing causes a decrease in and Bowman’s urinary space.41
glomerular perfusion and a decreased ability of the Hostetter et al.42 have conceived the hypothesis
muscle cells to react. The hyalinization in the pre- that glomerular hyperfiltration initiates and is re-
glomerular arterioles forms a barrier between the sponsible for the progression of diabetic nephropa-
jwtaglomerular cells and the lumen of the arteriole, thy. The hyperfiltration is stimulated by features of
which prevents renin release into circulation, re- the diabetic state (i.e., extracellular fluid volume
sulting in faulty coordination between the activity of expansion that is due to hyperglycemia, renal hy-
the juxtaglomerular apparatus and systemic arter- pertrophy, increased growth hormone, and glucagon
ial blood pressure.31-33 Studies in diabetic hyperten- secretion) or changes in vascular response to vary-
sives have shown that arteriosclerosis was nearly ing amounts of vasoactive hormones. The hyperfil-
always present in hypertensive patients.34135 In ad- tration increases transglomerular protein filtration,
dition, arteriosclerosis was also found in a remark- leading to albuminuria and mesangial deposition of
able percentage of normotensive diabetics. These circulating proteins, ultimately resulting in mesan-
studies illustrate that when considering the patho- gial expansion and glomerulosclerosis. The initial
physiology of arteriosclerosis in diabetics, hyperten- loss of functioning nephrons exerts a positive feed-
sion appears to be one of many contributing fac- back stimulus to compensatory hyperfiltration in
tors .36 less affected surviving glomeruli, thus contributing
Hypertension has been shown to potentiate to their eventual destruction.42
damages caused by diabetes. For example, diabetic Hypertension often becomes evident during
microangiopathy of renal cortical capillaries, char- the development of general glomerulosclerotic le-
acterized by basement membrane thickening, was sions without response t o diabetes mellitus. Per-
intensified in the setting of concomitant hyperten- haps this is the result of (or a n indicator of) ad-
sion.37 Diabetic nephropathy has been shown to be vanced glomerular lesions. However, as previously
accelerated and associated with increased glomeru- mentioned, this does not explain the fact that suc-
lar basement membrane thickening and proteinuria cessful treatment of hypertension in diabetics with
in hypertensive diabetic rats compared with nor- nephropathy can delay renal insufficiency for
motensive diabetic controls. Hypertension was years.43 This forms the view that hypertension plays
found to have an additive effect on glomerular base- an important role in the development of renal
ment membrane thickening, being increased in hy- changes in diabetics, accelerating the progression to
pertensive diabetic animals in comparison with renal insufficiency. Hypertension frequently ap-

Laryngoscope 107: December 1997 Duck et al.: Pathogenesis of Hearing Loss

pears only several years after the start of clinical with controls, the hearing impairment in diabetics
nephropathy, and thereafter, renal function deterio- was characterized by high-frequency sensorineural
rates at a predictably rapid rate. In diabetics, there hearing loss (after correction for age and sex). Both
is a slow increase in basement membrane thicken- cochlear and retrocochlear disease was found to ex-
ing and matrix augmentation that needs many ist in diabetics with hearing impairment.49
years to cause a noticeable diminution of the filtra- The clinical changes of inner-ear function in di-
tion surface and total function of glomerular capil- abetics seem to become evident as hearing loss of
lary lumina. Only in this advanced stage of the perception type with audiometric tracings being
glomerulosclerosis do further glomerular changes similar to those found in presbycusis (age-condi-
occur (i.e., arteriosclerosis and pericapsular and in- tioned hearing loss).50 PAS-positive thickened capil-
terstitial fibrosis). These changes play a significant laries were found in the cochlear stria vascularis
role that can lead to renoparenchymatous hyperten- that were consistent with diabetic changes found in
sion. Hypertensive changes may be superimposed other organs (i.e., the kidney and eye.)50 The thick-
on the diabetic glomerular changes, and further de- ening could potentially affect the function of the
terioration of renal function occurs.44 stria vascularis, ultimately resulting in decreased
Numerous studies have documented hearing hearing.50 It is hypothesized that the secretion of en-
losses in diabetics with abnormalities in audiometry dolymph and the building up of the electric potential
and brainstem auditory evoked responses.2,45-50 Fer- necessary for the cochlear microphonic are affected
rer et a1.45 concluded that type I diabetes mellitus by the decreased blood f l ~ w . ~ ODepending
-~~ on the
can cause mild sensorineural hearing impairment intensity and duration of these changes, it is possi-
that correlates with age and the duration of disease. ble that the sensory epithelium of the organ of Corti
Kurien et a1.2 have found that the diabetic popula- may ultimately be affected.50
tion has a poorer hearing threshold than the nondi-
Wackym and Linthicum54 studied the effects of
abetic population. All age groups of diabetics in both longitudinal and radial blood flow impairment
their study showed a high-frequency hearing loss as of the cochlea and suggested that diabetic sen-
compared with the control population. Although sorineural hearing loss results from microangio-
they found no relationship between the duration of
pathic involvement of the endolymphatic sac and/or
diabetes and hearing loss, poorly controlled and basilar membrane vessels. An impairment of longitu-
complicated diabetics have a significant high-fre- dinal blood flow affects the reabsorption of en-
quency hearing loss as compared with patients with
dolymph and the disposal of high molecular weight
well-controlled and uncomplicated diabetes.2
waste products and debris by the endolymphatic
Long-term insulin-dependent diabetes mellitus sac.54 Removal of higher molecular weight waste
also has an effect on auditory brainstem evoked re- products from the endolymph may occur by macro-
sponses. Even in the absence of symptoms consis- phagic activity of the endolymphatic sac55,56 or by
tent with diabetic neuropathy, 25% to 40% of dia- free-floating cells that may phagocytize these sub-
betic patients have been found to have retrocochlear stances and then migrate through the epithelium
impairment, as evidenced by the absence of wave I into the vascular bed.56,57 The effect of narrowed or
in auditory brainstem evoked response record- absent vascular endothelial tight junctional pores
ings.4"47 This is important for detecting desynchro- would limit macrophage or lymphocyte migration
nization of the auditory response that is indicative into or out of the endolymphatic sac. These changes
of neuropathy in the acoustic nerve.46 Axelsson and have been illustrated in diabetic microangiopa-
FagerberPH studied three separate age groups be- thy.58359 When the ability to effectively remove higher
tween ages 16 and 50 years (16 to 30 years, 30 to 39 molecular weight waste products has been jeopar-
years, and 40 to 50 years) and found that a definite dized, a toxic effect may be exerted on the hair cells,
degree of hearing loss of retrocochlear origin could thereby resulting in sensorineural hearing l0ss.64
be demonstrated in all three age groups (i.e., in
speech, Bekesy, and directional audiometry).48 In The impairment of radial flow may theoretically
another study, by Huang et a1.,49 Bekesy audiome- cause hair cell damage from microangiopathic
try, impedance audiometry with stapedius reflex changes in the stria vascularis. This is based on the
test, speech discrimination and the recording of inability of the thickened strial vasculature to ade-
electrocochleography, and brainstem auditory quately supply the hair cells with the necessary nu-
evoked potentials were performed on diabetic pa- trients to maintain the ionic character of the en-
tients and controls and it was found that the dia- dolymph.55 However, this is unlikely to be the
betics were abnormal. The results demonstrated primary mechanism for diabetic sensorineural hear-
that the average pure-tone thresholds, the subjec- ing loss, because diabetics in this study who had
tive click threshold, and the action potential reac- strial microangiopathy did not have a hearing loss.54
tive threshold, were all significantly elevated in di- Smith et a1.60 have quantitatively demon-
abetics. The average speech discrimination score strated basement membrane thickening consistent
was also decreased in diabetics. When compared with diabetic microangiopathy in the inner ear of

Laryngoscope 107: December 1997 Duck et al.: Pathogenesis of Hearing Loss

insulin-dependent diabetic rats. This finding sug- vascular or other factors is the most likely explana-
gests that inner-ear microangiopathy should be tion for the noise susceptibility of spontaneously hy-
considered as a possible cause of hearing loss in in- pertensive rats.10
sulin-dependent diabetic patients. It was also
demonstrated that noise exposure did not signifi- Gates et al.3 have shown that in hypertensive
cantly change basement membrane thickness in ei- men the age-adjusted high-frequency hearing loss
ther diabetic or control animals.60 Spontaneously was significantly greater (better ear, 24.7 vs 22.6
diabetic rats have also been shown to have a more dB hearing loss [HLI, P = 0.01; worse ear, 67.9 vs
pronounced cochlear hair cell loss when compared 59.3 dB HL, P = 0.01) than in normotensive men.
with nondiabetic controls. This loss was found in In hypertensive women, age-adjusted low-fre-
the midportion of the cochlea.61 Raynor et al.4 have quency hearing was significantly worse than in
also shown that consumption of a high-galactose nonhypertensive women (better ear, 20 vs 18 dB
diet induces diabetic-like changes in the inner ear. HL, P = 0.004).3
Hair cell damage in the Raynor study also occurred The combined results of this study support our
primarily in the midportion of the cochlea, with hypothesis that diabetic end-organ damage of the
only a small amount of damage found in the hook cochlea is intensified in the setting of concomitant
region.4 hypertension. This was verified in animal models
It has been shown in animal studies that there by the significant elevations of mean hair cell loss
is an increase in the permeability of the blood-brain noted throughout the cochlea in the hypertensive
barrier in adrenaline-induced hypertension in dia- and diabetic SHR/N-cp rat group when compared
with the diabetic normotensive WKYiN-cp and
betic rats.@It has also been shown that early-stage
general vascular disease is exacerbated (i.e., the el- nondiabetic normotensive LA/N-cp rat groups.
evation of the extracellular matrix compared with Clinical studies also show a statistically significant
hearing loss in the higher frequencies in insulin-
smooth muscle in arterial walls, marked suben-
dependent diabetic patients with hypertension
dothelial invasion of blood vessels with macrophage
when compared with patients with insulin-depen-
cell types) with combined diabetes and hyperten-
dent diabetes alone. The results of this study thus
indicate that either hypertension or a synergistic
It has also been suggested that insulin-depen- effect between hypertension and diabetes has a
dent diabetes mellitus may increase the hair cell more pronounced effect on hair cell loss in rats
loss caused by noise overstimulation. There was than does diabetes alone. The audiometric findings
found to be an increase in the number of hair cells presented also substantiate the clinical impression
lost in insulin-dependent, noise-exposed rats when that there is a potentiation of high-frequency hear-
compared with rats who had insulin-dependent dia- ing loss in patients with hypertension and insulin-
betes alone.10 dependent diabetes as opposed to insulin-depen-
dent diabetes alone.
In a comparative study of normotensive and
spontaneously hypertensive rats by Tachibana et
al.6 electrocochleographic studies showed that the CONCLUSION
function of the cochlea in the spontaneously hyper- The previously described findings support the
tensive rats declined with increasing age to a hypothesis that diabetic end-organ damage of the
greater extent than that of normotensive rats. The cochlea was intensified in the setting of concomitant
primary site of cochlear involvement, as docu- hypertension. This was verified in animal studies by
mented by electron microscopy, was the vascular the significant elevations of mean hair cell loss
strip followed by the organ of Corti.5 noted throughout the cochlea in the hypertensive
Borg and Viberglo state that the increased sus- and diabetic SHR/N-cp rat group when compared
ceptibility of spontaneously hypertensive rats to with the diabetic normotensive WKYN-cp and non-
noise-induced hearing loss may be attributed to the diabetic normotensive LA/N-cp rat groups. The sta-
spontaneous loss of hair cells. Normal, age-related tistically significant differences in hearing loss in
loss may also explain why old, spontaneously hyper- insulin-dependent diabetic and hypertensive pa-
tensive rats are somewhat more susceptible to noise tients when compared with the hearing of insulin-
than young rats. Also, the increased susceptibility of dependent diabetics who are normotensive also sub-
young, spontaneously hypertensive rats may be due stantiate our hypothesis. It has also been shown in
to a smaller number of hair cells at the start of noise this study that insulin-dependent diabetic patients
exposure or attributable t o the fact that remaining without hypertension have no significant hearing
hair cells are more susceptible to noise damage. In loss. These results support the hypothesis that hy-
older, spontaneously hypertensive rats there may be pertension is the essential factor, in conjunction
a smaller number of hair cells at the start of the with insulin-dependent diabetes mellitus, responsi-
noise exposure. Regardless of the age of the rats, the ble for high-frequency sensorineural hearing loss in
pre-noise exposure hair cell abnormality caused by patients and hair cell loss in laboratory animals.

Laryngoscope 107: December 1997 Duck et al.: Pathogenesis of Hearing Loss

BIBLIOGRAPHY 25. Chiappe de Cingolani GE. Cyclic AMP and glucose utilization by
diabetic rat fat cells. Arch Znt Physiol Biochem 1983; 91:l-8.
I . Isselbacher KJ, ed. Harrison’s Principles of Internal Medicine. 26. Chiappe de Cingolani GE. Beta-adrenergic receptors and
New York: McGraw-Hill; 1994:1117,1980. adenylate cyclase activity in diabetic rat fat cells. Diabetes
2. Kurien M, Thomas K, Bhanu TS. Hearing threshold in patients 1986;35:1229-32.
with diabetes mellitus. J Luryngol Otol 1989; 103: 164-8. 27. Weidmann P, Beretta-F’iccoli C, Trost BN. Pressor factors and
3. Gates G, Cobb JL, DAgostino RB, e t al. The relation of hear- responsiveness in hypertension accompanying diabetes
ing in the elderly to the presence of cardiovascular disease mellitus. Hypertension 1985;7(suppl 2):33-42.
and cardiovascular risk factors. Arch Otolaryngol Head 28. Beretta-Piccoli C, Weidmann P. Body-sodium blood volume
Neck Surg 1993;119:156-61. state in nonazotemic diabetic mellitus. Miner Electrolyte
4. Raynor EM, Robison WG, Garrett CG, e t al. Consumption of a Metab 1982;7:3642.
high-galactose diet induces diabetic-like changes in the in- 29. Weidmann P, Beretta-F’iccoli C, Keusch G, et al. Sodium-vol-
ner ear. Otolaryngol Head Neck Surg 1995;113:748-54. ume factor, cardiovascular reactivity and hypotension mech-
5. Tachibana M, Yamamichi I, Nakae S, et al. The site of involve- anisms of diuretic therapy i n hypertension associated with
ment of hypertension within the cochlea. Acta Otolaryngol diabetes mellitus. Am J Med 1979;67:779-84.
(Stockhi 1984;97:257-65. 30. Gorsuch AW, Spencer KM, Lister J, et al. Can future diabetes
6. Jordao AMD. Consideration sur un cas du diabete. Un Med be predicted? A study in families of affected children. Dia-
Paris 1857;11:447. betes 1982;31:862-6.
7. Jannulis GE, Delijannis G. Diabetes und Gicht als Ursache 31. Christleib AR. The hypertension of diabetes. Diabetes Care
van Kochlearisschadigung. Monatsschra Ohrenheilkund 1982;5:50-8.
Laringol Rino 1936;70:1504-8. 32. Ditscherlein G. Renal histology in hypertensive diabetics. In:
8. Makishima K. Arteriolar sclerosis as a cause of presbycusis. Gries FA, Weidmann P, eds. Diabetes and Hypertension.
Otolaryngology 1978;86:322-6. Berlin, Heidelberg: Springer Verlag;1988:39.
9. Axelsson A, Borg E, Hornstrand C. Noise effects on the 33. Bader H, Meyer DS. The size of the juxtaglomular apparatus
cochlear vasculature in normotensive and spontaneously in diabetic glomerulosclerosis and its correlation with arte-
hypertensive rats. Acta Otolaryngol 1983;96:215-25. riosclerosis and arterial hypertension: a morphometric light
10. Borg E, Viberg A. Age-related hair cell loss in spontaneously microscopic study on human renal biopsies. Clin Nephrol
hypertensive and normotensive rats. Hearing Res 1987;30: 1977;8:308-11.
111-8. 34. Ditscherlein G. Renal histopathology in hypertensive diabetic
1 1 . Borg E. Noise-induced hearing loss in normotensive and spon- patients. Hypertension 1985;7(suppl):29-32.
taneously hypertensive rats. Hearing Res 1982;8:117-30. 35. Ditscherlein G. Renal histopathology in hypertensive diabetic
12. Michaelis IV, Carswell N, Hansen CT, et al. A new genetic patients. Hypertension 1985;7(suppl2):29-32.
model of noninsulin-dependent diabetes and hypertension: 36. Ditscherlein G. Renal histology in hypertensive diabetics. In:
the spontaneous hypertensiveiNIH corpulent rat. In: Gries FA, Weidman P, eds. Diabetes and Hypertension.
Shafrir E, Renold AE,eds. Lessons from Animal Diabetes. Berlin, Heidelberg: Springer Verlag, 1988:40.
London: John Libbey; 1988:257-63 ( ~ 0 1 2 ) . 37. Junker U, Jaggi C, Bestetti G, Rossi GL. Basement membrane
13. National Institutes of Health. Office for Protection from Re- of hypothalamus and cortex capillaries from normotensive
search Risks: Public Health Service Policy on Humane Care and spontaneously hypertensive rats with streptomycin-in-
and Use of Laboratory Animals. Bethesda, MD: Office for duced diabetes. Acta Neuropathol 1985;65:202-8.
Protection from Research Risks, National Institutes of 38. Cooper ME, Allen TJ, O’Brien RC, et al. Effects of genetic hy-
Health; 1986. pertension on diabetic nephropathy in the rat: functional and
14. Rodby RA, Schwartz MM. Proteinuria, hematuria, hyperten- structural characteristics. J Hypertension 1988;6: 1009-16.
sion, and decreased renal function in a patient with dia- 39. Cooper ME, Allen TJ, Jerums G, Doyle AE.Accelerated pro-
betes for 9 years (clinical conference). Am J Kidney Dis gression of the diabetic nephropathy in the spontaneously
1992;20:658-67. hypertensive streptozotocin diabetic rat. Clin Exp Pharma-
15. Fuller JH. Epidemiology of hypertension associated with dia- col Physiol 1986;13:655-62.
betes mellitus. Hypertension 1985;7(suppl 1):3-7. 40. Osterby R. Early phases in the development of diabetic
16. Drury PL. Diabetes and arterial hypertension. Diabetologia glomerulopathy: a quantitative electron microscopic study.
1983;24:1-9. Acta Med Scand Suppl 1975;574:1-82.
17. Hamilton M, Pickering GW, Robert JAF, Sowry GSC. The aeti- 41. Ditscherlein G. Renal histology in hypertensive diabetics. In:
ology of essential hypertension. Part I. The arterial pressure Gries FA, Weidmann P, eds. Diabetes and Hypertension.
in the general population. Clin Sci 1954;17:11-54. Berlin, Heidelberg: Springer Verlag; 1988:38.
18. Keen H, Track NS, Sowry GSC. Arterial pressure in clinically 42. Hostetter TH, Helmut GR, Brenner BM. The case for in-
apparent diabetics. Diabetes Metab Rev 1975;1:15944. trarenal hypertension in the initiation and progression of
19. Jarrett RJ, Keen H, McCartney M, et al. Glucose tolerance and diabetic and other glomerulopathies. Am J Med 1982;72:
blood pressure in two population samples: their relation to 375-80.
diabetes and hypertension. Znt J Epidemiol 1978;7:15-24. 43. Mogensen CE. Antihypertensive treatment inhibiting the pro-
20. Pel1 S, DAlonzo CA. Some aspects of hypertension in diabetes gression of diabetic nephropathy. Acta Endocrinol (Copenh)
mellitus. JAMA 1967;202:104-10. 1980;94 (Suppl 238):l-82.
21. Christlieb AR, Warren JH, Krowelski AS, et al. Hypertension, 44. Ditscherlein G. Renal histology in Hypertensive diabetics. In:
the major risk in juvenile-onset insulin-dependent diabet- Gries FA, Weidmann P, eds. Diabetes and Hypertension.
ics. Diabetes 1981;3O(suppl2):90-6. Berlin, Heidelberg: Springer Verlag;1988:41.
22. Barrett-Connor E, Criqui MH, Klauber MR, Holdbrook M. Di- 45. Ferrer J, Biurrun 0, Lorente J, et al. Auditory function in
abetes and hypertension in a community of older adults. Am young patients with type 1 diabetes mellitus. Diabetes Res
J Epidemiol 1981;113:276-84. Clin Pract 1991;11:17-22.
23. Keen H, Chloveerakis C, Fuller JH, Jarrett FLJ. The concomi- 46. Martini A, Comacchio F, Magnavita V. Auditory brainstem
tants of raised blood sugar: studies in the newly detected and middle latency evoked responses in the clinical evalua-
hyperglycaemics. Part 11. Urinary albumin excretion, blood tion of diabetes. Diabet Med 1991;8:S74-7.
pressure and their relation to blood sugar levels. Guy’s Hosp 47. Parving A, Elberling C, Balle V. Hearing disorders in patients
Report 1969;118:247-54. with insulin-dependent diabetes mellitus. Audiology 1990;
24. Mauer SM, Steffes MW, Azar S, et al. The effects of Goldblatt 29: 113-21.
hypertension on development of the glomerular lesion of di- 48. Axelsson A, Fagerberg S-E. Auditory function in diabetics. Acta
abetes mellitus in the rat. Diabetes 1978;27:738-44. Otolaryngol 1968;66:49-64.

Laryngoscope 107: December 1997 Duck et at.: Pathogenesis of Hearing Loss

49. Huang Y, Pan CY, Gu R, et al. Hearing impairment in diabet- 61. Triana RJ,Suits GW, Garrison S, et al. Inner ear damage sec-
ics. Chin Med J 1992;105:44-8. ondary to diabetes mellitus. Arch Otolaryngol Head Neck
50. Jorgensen MB. The inner ear in diabetes mellitus. Arch Oto- Surg 1991;117:635-40.
laryngol 196 1;74:373-8 1. 62. Oztas B, Kucuk M. Influence of acute arterial hypertension on
51. Dohlmann G. Modern view on vestibular physiology. J Laryn- blood- brain barrier permeability in streptozotocin-induced
go1 1959;74:154-61. diabetic rats. Neurosci Lett 1995;188:53-6.
52. Omerod FC. The physiology of the endolymph. J Laryngol 63. Todd ME, Song MY, McNeill JH. Coexistence of diabetes and
1960;74:659-67. hypertension results in unique structural alterations in the
53. Mizukoshi 0. Some metabolic reactions in the cochlea. Jpn J renal artery in rats beyond that found with diabetes alone.
Otol 1 9 6 0 ; 6 3 ( ~ ~ ~ ~ 1 2 ) : 9 - 1 0 . Diabetes Clin Pract 1993;19:115-26.
54. Wackym PA, Linthicum FH. Diabetes mellitus and hearing
loss: clinical and histopathologic relationships. Am J Otol
55. Lundquist PG. Aspects on endolymphatic sac morphology and
function. Arch Otolaryngol 1976;212:231-40. During the review process several issues were
56. Lundquist PG, Kimura R, Wersall J. Experiments in endolym- raised concerning this very interesting report. Read-
phatic circulation.Acta Otoluryngol (Stockhi 1963;188:198-201. ers should note that, with regard to the analysis of
57. Rask-Andersen H, Stahle J. Immunodefense of the inner ear? results, the number of subjects is quite small in
Lymphocyte-macrophage interaction in the endolymphatic
sac. Acta Otolaryngol (Stockh) 1980;89:283-94. terms of reaching meaningful conclusions. All of the
58. Williamson JR, Kilo C. Current status of capillary basement hypertensive patients had been under treatment for
disease in diabetes mellitus. Diabetes 1977;26:66-75. 2 or more years (average, 15 years) before the study
59. Bloodworth JMB. Diabetic microangiopathy Diabetes 1963; began, and their blood pressure was controlled at
60. Smith TL, Raynor EM, Prazma J, et al. Insulin-dependent dia- the time of the study. The reliability of the analysis
betic microangiopathy in the inner ear. Laryngoscope 1995; of covariance is not clear in view of the age differ-
105:23640. ence between the two groups.

Laryngoscope 107: December 1997 Duck et al.: Pathogenesis of Hearing Loss