Glycative Stress Research
Online edition : ISSN 2188-3610
Print edition : ISSN 2188-3602
Received : September 3, 2020
Accepted : September 17, 2020
Published online : September 30, 2020
doi:10.24659/gsr.7. 3_240

Review article

Glycative stress and the inner ear disorder
Junko Tsuda, Kazuma Sugahara, Hiroshi Yamashita
Department of Otolaryngology, Yamaguchi University Graduate School of Medicine, Yamaguchi, Japan

Abstract

Sensorineural hearing loss is reported to be frequently associated with diabetic patients; however, it has not been widely
recognized as a complication. Renal disorders are well known as one of the three major complications of diabetes, and the renal
glomerulus has a histological similarity to the cochlear stria vascularis of the inner ear. It is well known that ototoxicity andnephrotoxicity are common adverse events in administration of aminoglycoside antibiotics and platinum-based antineoplastic
agents. As just described, the relationship between inner ear disease and renal disease has been pointed out before. In order toelucidate the mechanism of the onset of hearing loss in diabetes, we conducted a study using Tsumura Suzuki Obese Diabetes(TSOD) mouse, a type 2 diabetes mellitus (T2DM) model. It was confirmed that TSOD mice developed deafness earlier thanthose of the control, and histopathologically, a significant reduction in the capillary distribution density was observed in the stria
vascularis. This is considered to be a finding of diabetic microangiopathy in the inner ear. In order to prevent hearing loss causedby diabetes, caloric restriction and Kampo administration (Bofutsushosan and Daisaikoto) were conducted with TSOD mice,
resulting in the hearing loss being significantly ameliorated and the cochlear blood flow being maintained. On the other hand, theadministration of metformin, drawing attention in the field of anti-aging medicine, was not effective in TSOD mice, while, in thepresbycusis model DBA/2, the hearing loss was suppressed from the early stage in an interesting issue. The background of T2DM
is often associated with the metabolic syndrome caused by excessive accumulation of visceral fat. Various factors are involved inits pathogenesis in a complicated manner. Further studies are needed to clarify the mechanism of diabetic inner ear disorder.

KEY WORDS: diabetes mellitus type 2, hearing loss, auditory brainstem response, cochlea, stria vascularis, metformin

Introduction

Anatomy of the inner ear

Due to changes in lifestyle, such as diet and exercise, thediabetic population in Japan has been increasing; however,sensorineural hearing loss is not widely recognized as adiabetic complication. Deafness induced by diabetes, often
early onset from past epidemiologic studies, impairs the low
and mid range, which is important for conversation, and thus
significantly reduces quality of life (QOL). In recent reports,
it has been shown that hearing loss is a risk of dementia inthe elderly and, with growing public interest in this issue,
attention is being paid to prevention as well as treatment
for hearing loss. Based on our study using type 2 diabetes
mellitus (T2DM) model mice, this article describes changesof the inner ear in diabetes-induced auditory disorder and its
prevention.

The structure of the ear consists of the outer ear, middle
ear, and the inner ear, which contains the cochlea, which
controls auditory sense, and the vestibular and semicircular
canals, which control the balance sense. The cochlea is aperipheral auditory sensory organ with a two-and-a-halfturn snail-like structure. The cross section of the cochlea isdivided into three sections. The central section is called thecochlear canal, with the endolymph fluid inside and the outer
section includes scala vestibule and scala tympani with theperilymph fluid inside. The composition of perilymph is ahigh Na + and low K + concentration similar to extracellular
fluid, while the composition is different in the endolymph
with high K+ and low Na+ as well as intracellular fluid.
The sound that is input to the outer ear as air vibrations

Corresponding to: Professor Hiroshi Yamashita, MD, PhD
Department of Otolaryngology, Yamaguchi University Graduate School of Medicin
1-1-1 Minamikoogushi, Ube-shi, Yamaguchi 755-8505, Japan
TEL : +81-836-22-2281 e-mail: hiro-shi@yamaguchi-u.ac. jp
Co-authors: Tsuda J, tjunko@yamaguchi-u.ac.jp;
Sugahara K, kazuma@yamaguchi-u.ac.jp_ 240 _

Glycative Stress Research 2020; 7 ( 3) : 240-247(c) Society for Glycative Stress Researche1

Glycative Stress Researchvibrates the eardrum and auditory ossicles of the middle
ear and vibrates the labyrinthine fluid in the cochlea of theinner ear, followed by conversion into electrical energy as
the action potential of neurons, and then is transmitted fromthe cochlear nerve afferently to the central nervous system.
Similarities exist between the inner ear cochlear striatum andrenal glomeruliis region that supplies the energy required forconversion.
The cochlear stria vascularis, rich in capillaries, islocated on the outer wall of the cochlear duct and spirally
surrounds the cochlea, producing an endolymphatic potential
of + 80 to + 90 mV (Fig. 1 ) 1).

Similarities between the cochlear stria
vascularis and the renal glomeruli

The kidney includes one million units called nephrons,
which are composed of glomeruli and renal tubules. The
glomerulus consists of inside capillaries with a thread-balllike structure and outer surrounding Bowman's capsule witha bag structure. The blood in the capillaries is filtered by theglomerulus and Bowman's capsule receives the primitive
urine filtrated. NaCl, Ca2 +, and Mg2 + are reabsorbed fromthe glomerulus to the proximal tubule and then NaCl, Ca2 +,and water are reabsorbed by the distal tubule, followed by,further in the collecting duct, the reabsorption of Na+, water,
K+ and the secretion of H+. The cochlear stria vascularis
also has many ion transporters, i.e., K+ channels and Na, Cl,

K cotransporters. K+ in the endolymph is said to be recycled,
where K+ that has flowed into the auditory hair cells circulate
from the stria vascularis to the endolymphatic space.

Relationship between labyrinth disease andrenal disease

The relationship between labyrinth disease and renal
disease has been pointed out before. Alport's syndrome is adisease that causes progressive hereditary nephritis, which is
caused by mutation of type 4 collagen gene in the glomerularbasement membrane. This disease is known to be often
associated with progressive bilateral sensorineural hearing
loss. It is also well known that ototoxicity and nephrotoxicity
are common adverse events when aminoglycoside antibiotics
or platinum-based antineoplastic agents are administered.
These reports suggest a similarity between the inner ear andthe kidney.
Quick CA et al. 2) showed in their pathological study that
anticochlear antibodies react with renal tubular epithelium inrats and guinea pigs, and that anti-renal glomerular basement
membrane antibodies react with the cochlear stria vascularisand the capillaries of spiral ligament (ligamentum spirale
cochleae).
Arnold W et al. 3) demonstrated, using a rat
glomerulonephritis model induced by an anti-basement
membrane antibody, that both stria vascularis and renal
glomeruli were impaired in basement membrane and

The lateral wall of the cochlea(Scala vestibule)(Scala media)

Stria vascularis

Tectorial membrane

Inner spiral tunnel
InnertunnelBasilar membrane

Hair cells
Cochlear nerve(Scala tympani)Fig. 1. Cross section of cochlear.

The stria vascularis is located on the lateral wall of the cochlea and is involved in endolymph production and maintenanceof electric potential. It is rich in capillaries and composed of three types of cells: marginal cells, intermediate cells, andbasal cells. Quoted from reference 1).

_ 2 41 _Glycative Stress and the Inner Ear Disorder

endothelial cells. It is considered that the inner ear, especiallystria vascularis, and the renal glomeruli have similar
antigenicity.
Typical histopathological changes in diabetic nephropathy
include the glomerular basement membrane thickening,mesangial enlargement, tubular basement membranethickening, interstitial enlargement, and microvascularexudative lesions. It has been reported that this cause ispersistent hyperglycemia exposing to endothelial cells in
microcirculation, i. e., glomerular capillaries, peritubular
capillaries, and arterioles 4).
The cochlear stria vascularis has a structure composedof epithelial cells and capillaries and is rich in vascularity.
Therefore, if there are factors that affect the vasculature, thetissue may be vulnerable to disability

Diabetes and hearing loss
The number of people with diabetes in Japan has been
increasing since 1997 5), and according to the results of the
National Health and Nutrition Survey conducted by the
Ministry of Health, Labour and Welfare (MHLF) in 2017,
the prevalence of diabetes was 18.1% for men and 10.5 %for women, with an estimated 10 million people. Although
retinopathy, neuropathy, and nephropathy are well known
as the three major complications of diabetes, sensorineural
hearing loss is not recognized as a major complication.
Hearing loss may actually be underestimated.
A meta-analysis by the Lancet International Commission
team reported that hearing loss was a significant risk factor
for dementia in all three studies, with a high combined
relative risk of 1.94 (95% confidence intervals [CI ]: 1.382.73) 6). In 2017, the Commission recognized hearing loss as
the first factor that could prevent the onset and developmentof dementia with medical interventions, and it quickly
gained worldwide attention. The WHO guideline 2019
“ Risk reduction of cognitive decline and dementia” also
recommends early response and intervention to hearing loss 7).
The prevalence of hearing loss in patients with diabetes
has been extensively reported, including in the 2008 US
Large Scale Epidemiologic Survey. According to this report,
the prevalence of auditory disorder is significantly higher indiabetic adults, and the risk of hearing loss is higher not onlyin the high range but also in the mid and low range 8). A largescale epidemiological survey was conducted at the National
Center for Geriatrics and Gerontology in 2010, and therelationship between diabetes and auditory disorder wasinvestigated in 2,306 middle-aged and elderly local residents.
As a result, it was reported that diabetes has a significant
negative effect on audibility, and its effect is more pronounced
in middle-aged than in elderly 9). Therefore, it is suggested
that hearing loss due to diabetes develops from an early age,and the low- and mid-frequency range, which is important for
conversation, is also impaired, which significantly reduces
QOL.
Morphological changes in the cochlea due to diabetes
have been studied so far using human temporal bones andanimal models. However, there still remain many unclear
points, not reaching a common conclusion.
Fukushima H et al. 10) examined the human temporalbone pathology and pointed out that the cochlea with

T2DM had a significantly thickened capillary wall of thestria vascularis compared with the non-diabetic case. They
concluded that this is a finding of diabetic microangiopathy
in the cochlea.
As an animal model, Smith TL et al. 11) reported athickening of the basement membrane of capillaries of thestria vascularis in streptozocin–treated rats, which is thought
to be involved in diabetic microangiopathy. Leptin genedeficient ob/ob mice are considered to be T2DM models.
Lee HS et al. 12) investigated auditory sense using this model,
and pointed out that the threshold of the auditory brain stem
response (ABR) increased from the earlier stage than that ofcontrol, and histologically degeneration of outer hair cells
and disappearance of ganglion spiral cochleae cell.
Thus, many studies suggest that diabetes causes hearing
loss early in life with aging, and microangiopathy occurs in
the cochlea. However, because many factors are involved indiabetes, auditory assessment and histological changes in the
inner ear are not consistent among models and reporters. It
can be said that diabetic inner ear disorder is a complicatedpathogenesis in which various findings are mixed.

Study of hearing loss in T2DM model
TSOD mouse

The TSOD (Tsumura Suzuki Obese Diabetes) mouse weused is a T2DM model mouse established by sibling matingof male ddY mice that exhibits obesity and diabetes 13).
Manifestation of this model includes overeating, severe
obesity, hyperglycemia, hyperinsulinemia, and hyperlipidemia,
and as a diabetic complication, peripheral neuropathy has
also been reported. Thickening of the glomerular loop wall,
enlargement of the mesangial region, and nodule formation
have been reported in the kidney. Dyslipidemia has also
been confirmed, in addition to elevated total cholesterol andtriglyceride levels, and hyper-LDL-cholesterolemia. Fromthe examination of CT images, model rats showed a relatively
small amount of subcutaneous fat, but excessive accumulationof visceral fat, which was accompanied by visceral fat typeobesity, impaired glucose tolerance, hyperlipidemia, andhypertension. Therefore, this mouse is considered tocorrespond to the metabolic syndrome model.
Using TSOD mice and a control strain, TSNO (Tsumura
Suzuki Non-obesity) mice, we measured body weight, blood
glucose level and auditory brainstem response (ABR) overtime as an evaluation of auditory sense 14). Furthermore, eachtemporal bone was excised and examined histopathologically.
In TSOD mice, body weight and blood glucose levels
significantly increased from 2 months of age, and weresignificantly higher than those of TSNO (Fig. 2). The ABRthreshold, an assessment of hearing, significantly increasedin TSOD mice from 8 months of age, resulting in early
hearing loss ( Fig. 3 ). Histopathologically, in TSOD mice,narrowing of the stria vascular capillaries on the lateral wallof the cochlea was observed, and the additional vascular
staining revealed reduction of the blood vessel density
compared to that of TSNO ( Fig. 4 ). These findings are
considered to be diabetic microangiopathy in the cochlea,
suggesting a chronic decrease in blood flow in the diabetic
inner ear. As mentioned above, the stria vascularis is richin capillaries, so it is considered to be morphologically_ 242 _Glycative Stress Research

a)

b)

70

**

**

**

300

**

50
40
30
20
10
0

2

**

250

Glucose (mg/dL)

Body weight (g)

60

**

**

*

5

7

10

200
150
100
50
0

13

2

5

Months of age

7

10

13

Months of age
TSOD

TSNO (control)

Fig. 2. Changes in body weight and blood glucose level in TSOD and TSNO mice.

a) Body weight. Diabetic model TSOD mice showed significant weight gain from 2 months of age, and exhibited severe
obesity of more than 60 g at 5 to 10 months of age. Significant weight gain was observed compared to control TSNO mice.

b) Diabetes model TSOD mice showed a blood glucose level of over 200 mg/dL from 2 months of age, and hyperglycemia

persisted up to 10 months of age. Results are expressed as mean ± SEM, * p < 0.05, ** p < 0.01 vs. TSNO (control), n = 5.
TSOD, Tsumura Suzuki Obese Diabetes; TSNO, Tsumura Suzuki Non-obesity = control for TSOD; SEM, standard error
mean. Quoted from reference 14).

TSOD
0

ABR threshold (dBSPL)

20

40

*
60

*

80
TSOD
TSNO (control)

100
120
0

1

2

3

4

5

6

7

8

9 10 11 12 13 14Months of Age

Fig. 3. Auditory evaluation in TSOD and TSNO mice.

Auditory sense was evaluated by measuring the threshold of auditory brainstem response (ABR) at 8 kHz. Diabetes model
TSOD mice showed a significant threshold increase from 10 months of age, and hearing loss occurred with aging earlier
compared with control TSNO mice. Results are expressed as mean ± SEM, * p < 0.05 vs. TSNO (control), n = 5. TSOD,
Tsumura Suzuki Obese Diabetes; TSNO, Tsumura Suzuki Non-obesity = control for TSOD; SEM, standard error mean.
Quoted from reference 14).

_ 2 43 _Glycative Stress and the Inner Ear Disorder

Vascular area in the lateral wall of the cochleaa)b)

TSNO (control)
9 months of age****

17 months of age

Vascular area (%)

50

TSOD
9 months of age

17 months of age

40
30
TSOD

20

TSNO

10
0

9
17
Months of age

Fig. 4. Evaluation of blood vessel area of outer wall of cochlea by blood vessel staining (India ink) in TSNO
and TSOD mice.

a) At 9 and 17 months of age, capillaries in the cochlear stria vascularis were observed by blood vessel staining. In
TSOD mice, a decrease in the distribution density of capillaries was observed. b) When the blood vessel area wasevaluated using the image processing software “ImageJ,” the TSOD mice showed a significant reduction in the vessel
area at any age compared to the TSNO mice. Results are expressed as mean ± SEM, ** p < 0.01 vs. TSNO (control), n = 2.
TSOD, Tsumura Suzuki Obese Diabetes; TSNO, Tsumura Suzuki Non-obesity = control for TSOD; SEM, standard error
mean. Quoted from reference 14).

susceptible to microangiopathy. In the 1970s, based on
pathological findings in the cochlea, Schuknecht HF 15)
classified senile deafness into four types as follows: 1) Sensory
presbycusis, 2) Neural presbycusis, 3) Strial presbycusis,
and 4) Cochlear conductive presbycusis. TSOD mice areconsidered to belong to 3) Strial presbycusis. As mentioned
above, the outer wall of the cochlea mainly composed of stria
vascularis has the function of maintaining the homeostasisof the ion concentration in the inner ear. Therefore, oncedamaged, hair cells are thought to be unable to function
normally and produce sensorineural hearing loss.
Concurrently, gene expression analysis of visceral fat
in TSOD mice (12 months of age) revealed high expressionof TNF-α and IL-6, inflammatory cytokines 16). We also
performed gene expression analysis in the cochlea of TSOD
mice (14 months of age) and found that 176 gene expression
increased and 345 gene expression decreased (n = 3, p < 0.01,
expression ratio > 1.5 [ = Log2 ratio > 0.585] and expression
ratio < 0.66 [= Log2 ratio < 0.585]). There were, in addition
to Igf1, decreased expression of many growth factors andreceptors such as Igfbp6, Tgf b2, Fgfr2, Fgfr2, Ctgf, Fgf 7,
Fgf12, and increased expression of many inflammatory
cytokines such as IL1a and Icam4. From the above findings,
it was confirmed that TSOD mice, a T2DM model, had an
early hearing loss with aging, and in the cochlea, chronic
blood flow failure due to diabetic microangiopathy wasconfirmed as in the human temporal bone specimen. Genecomprehensive analysis suggested that chronic inflammation
may be involved in the cochlea.

Anti-aging medical trials for the inner ear
As an attempt to protect the inner ear against hearing
loss in T2DM model mouse TSOD, we administered calorie
restriction and traditional Chinese medicine (Kampo)
using Bofutsushosan and Daisaikoto 17). The experimental
animals were divided into 4 groups with 10 animals in eachgroup. In the control group, TSOD mice were fed an ad
libitum standard solid diet. In the calorie restricted group,
the solid feed was administered every other day. Boththe Bofutsushosan group and the Daisaikoto group wereraised by allowing the animals to freely ingest a solid feed
containing 3 % each component. ABR test was performed
periodically to evaluate auditory sense, and the cochlea was
excised and examined histopathologically. As a result, weightgain was significantly suppressed in the calorie-restrictedgroup, and blood glucose level was decreased in the calorierestricted group and the Kampo group (Bofutsushosangroup, Daisaikoto group). Compared with the control group,
the ABR threshold increase was suppressed and the agerelated hearing loss was ameliorated in the calorie restrictedgroup and the Kampo group. Similarly, in the histologicalexamination, the distribution density of capillaries on the_ 244 _Glycative Stress Research

DBA/2

100
90

TSOD

80

0

ABR thresold (dBSPL)

Control

ABR threshold (dBSPL)

Bofutsushosan

20

Daisaikoto

40
60
80

*

*

70

**

60

**

50
40
30

Control
Control

20

100

Metformin
Metformin

10

120

0
6

7

8

9

10

11

5

11

15

19

Weeks of Age

Months of age

Fig. 5. Auditory evaluation of Kampo administration to
TSOD mice.

Fig. 6. Auditory evaluation of metformin
administration to DBA/2 mice.

Auditory sense was evaluated by measuring the thresholdof auditory brainstem response (ABR) at 8 kHz.
Compared with the control group, the increase in ABRthreshold with age was ameliorated in the group treatedwith Kampo medicine: Bofutsushosan and Daisaikoto.
Results are expressed as mean ± SEM, * p < 0.05 vs.
control (without Kampo medicine), n = 10. TSOD, Tsumura
Suzuki Obese Diabetes; SEM, standard error mean. Quoted
from reference 17).

outer wall of the cochlea was well maintained in the calorierestricted group and the Kampo group as compared with thecontrol group, suggesting that the blood flow failure in the
inner ear due to diabetes improved (Fig. 5 ).
Additional studies were conducted using the antidiabetic
drug “metformin.” Metformin has been widely used asa therapeutic agent for T2DM widely in the world sincethe 1950s, and furthermore, many longevity effects andantitumor effects have been reported in recent years,
and anti-aging effects have been attracting attention. It
is reported that long-term administration of metformin
mixed feed to C57BL/6 mice showed a lifespan extension
effect of 5.83% as compared with the control group 18). In
addition, 78,241 diabetic patients treated with metformin
had a 15 % reduction in mortality compared to 90,463 nondiabetic patients 19). Therefore, a mixed feed of metformin
was administered to TSOD mice (T2DM model) for a longterm from 4 to 30 weeks of age, and a comparison was madewith the control group. Administration was also performedin the same manner in presbycusis model mice C57BL/6J
and DBA/2. As a result, in TSOD mice, there was no
significant difference in the ABR threshold between themetformin group and the control group. On the contrary, in
the C57BL/6 mouse for presbycusis, although there was no
significant difference in the metformin group, the increase

Auditory sense was evaluated by measuring thethreshold of auditory brainstem response (ABR) at
8 kHz.
Compa red with the control group, the ABRthreshold was significantly lower in the metformina d m i n ist ere d g roup f rom 11 we ek s of age,
indicating a protective effect. Results are expressed
as mean ± SEM, ** p < 0.01 vs. control (without
metformin medicine), n = 5. DBA/2, presbycusis
model; SEM, standard error mean.

in ABR threshold tended to be lower than that in the control
group at early stage of 10 weeks of age. Furthermore, in the
DBA/2 mouse, the ABR threshold was significantly lower
in the metformin group from 11 weeks of age, and the inner
ear protective effect was observed (Fig. 6 ). An additional
histological study of the cochlea in DBA/2 mice showing
a significant improvement revealed that ganglion spiralcochleae cells and hair cells under the tectorial membrane
were retained well in the metformin group compared to thecontrol group. Observation of SA-β-gal activity, a marker ofcellular aging, in various organs throughout the body showed
reduced activity in the metformin group at the liver, lungs
and brain compared with the control group, suggesting that
cellular aging is suppressed (Fig. 7 ).
It is reported as a mechanism of the anti-aging effectof metformin that AMP-activated protein kinase (AMPK)is activated to suppress the aging-promoting signal mTOR
(mammalian target of rapamycin) and to activate eNOS
(endothelial nitric oxide synthase) in vascular endothelial
cells, thus increasing NO production and resulting in the
improvement of vascular function 20). AMPK is also a K
channel regulator in outer hair cells and is involved inprotection of the inner ear from acoustic damage. It is possiblethat the administration of metformin activated AMPK in
the inner ear and exhibited a protective effect, which is_ 2 45 _Glycative Stress and the Inner Ear DisorderSA- -gal staining
DBA/2
Kidney

Liver

Lung

Brain

Control-1

Control-2

Metformin-1

Metformin-2

Fig. 7. Histological evaluation of metformin administration to DBA/2 mice by SA-β-gal staining ofvarious organs.
The SA-β-gal activity, a marker of cellular senescence, was observed in various organs throughout the body. The
stained cells turn blue. In the liver, lung, and brain, the findings suggestive of reduced activity in the metformingroup compared with the control group.

necessary for further study. On the other hand, a protective
effect was exhibited in the presbycusis model mouse, while
not in the T2DM model mouse. As our speculation, since
TSOD mice are a model of metabolic syndrome associatedwith hyperlipidemia, it is possible that oral administrationof metformin alone was insufficient to suppress hearing loss
associated with severe arteriosclerosis.

Summary
Hearing loss is not widely recognized as a diabetic
complication; however, it is often reported that hearing loss
occurs with age earlier in patients with diabetes. Hearing
impairment occurs in the low and mid range, which isimportant for conversation, and thus significantly deteriorates
QOL. In our examination of T2DM model mouse TSOD,
hearing loss was observed from an early stage with aging,and histologically, narrowing of the capillary lumen in the
stria vascularis of the lateral wall of cochlea, suggesting
the presence of chronic blood flow failure due to diabetic
microangiopathy in the inner ear. Administration of Kampo
medicine (Boufutsushosan and Daisaikoto) and calorie
restriction significantly suppressed age-related hearing

loss with maintained cochlear blood flow. Metformin
administration was not effective in TSOD mice with severe
inner ear vascular disease in the metabolic syndrome model,
but in the presbycusis model DBA/2, the hearing loss was
suppressed earlier. Metformin administration was noteffective in TSOD mice, a metabolic syndrome model, withsevere inner ear vascular disease, while in DBA/2 mice,the hearing loss was ameliorated from the earlier stage. Its
mechanism was confirmed to have protective effects oncochlear hair cells and spiral ganglion cells.

Conflict of Interest Statement
The authors claim no conflict of interest in this study.

Acknowledgment
This work was supported by JSPS KAKENHI Grant
Number 15K1075 and 18K09321. Part of this study waspresented at the Training Session, Japanese Society of Antiaging Medicine on March 10, 2019, Osaka, Japan.

_ 246 _Glycative Stress Research

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