Cochlear, auditory brainstem responses in type 1 diabetes: relationship with metabolic variables and diabetic complications
A. Lasagni1, P. Giordano2, M. Lacilla2, A. Raviolo1, M. Trento1, E. Camussi3, G. Grassi1, L. Charrier3, F. Cavallo3, R. Albera2, M. Porta1, M. M. Zanone1
1Department of Medical Sciences, 2Department of Surgical Sciences, and 3Department of Public Health and Pediatric Sciences, University of Turin, Turin, Italy.
Running Head: Auditory function in type 1 diabetes. Word count: 3132
Disclosure statement: the authors have nothing to disclose What's new?
Auditory function involves the cochlea and neural transmission, making the ear a potential “window” to evaluate microvascular and neurological abnormalities associated with chronic hyperglycemia.
We tested the presence of auditory alterations in young adults with long term type 1 diabetes. We detected a qualitative auditory dysfunction, reflecting cochlear dysfunction.
Otoacoustic emission alterations are associated with higher blood pressure, indicating a possible role for vascular mechanisms. A delay of acoustic nerve transmission and presence of somatic or autonomic neuropathy is observed.
In young adults with type 1 diabetes, abnormalities of auditory perception might reflect neuropathic and/or vascular alterations.
Corresponding author: Dr Maria M. Zanone
Department of Medical Sciences University of Turin
Corso Dogliotti 14, 10126 Torino, Italy.
Phone: +39 011 6335540, Fax: +39 011 6334515 e-mail: mariamaddalena.zanone@unito.it
Aims. Few studies have analyzed the presence of hearing abnormalities in diabetes. Objective. We assessed the presence of subclinical auditory alterations and their possible association with early vascular and neurological dysfunction in young adults with type 1 diabetes of long duration.
Methods. Thirty-one people with type 1 diabetes (mean age 33 ± 2.3 years, disease duration 25.7 ± 4.2 years) and 10 healthy controls underwent Pure Tone Audiometry (PTA), Distortion Product Otoacoustic Emission (DPOAE) and Auditory Brainstem Response (ABR) analyses. Associations with metabolic variables and chronic complications were explored.
Results. Compared to healthy participants, people with diabetes had significantly higher mean hearing thresholds, though still within the normoacusic range. DPOAE intensities at medium frequencies (2.8 to 4 kHz) were significantly lower in diabetic people. In ABR, in addition to waves I, III and V, we observed the appearance of a visible wave IV in diabetes compared to controls (prevalence 61% vs 10%, p < 0.05), and its appearance was related to a prolonged I-V interval (4.40 ms ± 0.62 vs 4.19 ms ± 0.58, p < 0.05). Diastolic blood pressure was higher in patients with abnormal DPOAEs (p < 0.05), whereas systolic blood pressure correlated with wave V and interpeak I-V interval latencies. A trend towards association between evidence of wave IV and presence of somatic neuropathy or abnormal cardiovascular autonomic tests was observed.
Conclusions. Young adults with long-term type 1 diabetes have subclinical abnormalities of qualitative auditory perception, despite normal hearing thresholds, which might reflect neuropathic and/or vascular alterations.
Introduction
Diabetes is associated with chronic vascular and neurological complications. Studies (1–7) and recent meta-analyses based on pure tone audiometry (8, 9) suggest an association between hyperglycaemia and impaired auditory function with sensorineural hearing loss. However, most studies were heterogeneous in terms of methodology and patients’ characteristics and resulted in discordant reports on possible pathogenic mechanisms and associations of abnormalities at the cochlear level (2, 10, 11) or acoustic neural pathway (1, 2, 4, 5, 9, 12–14) with chronic complications,.
Auditory function in diabetes has been mainly assessed by Auditory Brainstem Response (ABR) registration. Most studies reported either increased ABR latencies at peripheral (wave I) and/or central (waves III-V) level (1, 12) or isolated delays in absolute wave latency (2, 5, 6, 15). These observations were interpreted as evidence of neuropathy, central and/or peripheral, at the basis of auditory dysfunction. Availability of methods to directly investigate cochlear function suggested possible impairment also for this organ (2, 10). The recording of otoacoustic emissions allows a direct, objective and noninvasive evaluation of outer hair cells (OHC) function in Corti’s organ. Studies in people with diabetes have shown more pronounced loss or degeneration of OHC compared to inner hair cells (IHC) (2, 16, 17), suggesting a role also for microangiopathy in auditory dysfunction. This is supported by evidence of basement membrane thickening of the vessels within the stria vascularis, which occupies the lateral wall of the cochlea and is responsible for production of endolymph and generation the endocochlear potential, and of the basilar membrane, both in experimental animal models of diabetes and autoptic studies of the human temporal bone (16, 17).
Involvement in auditory function of both the cochlea, with its abundance of blood capillaries (16), and neural transmission along the auditory pathway to the brainstem, makes the ear a potential “window” to simultaneously evaluate microvascular and neurological abnormalities associated with chronic hyperglycemia.
The aim of this study was to evaluate subclinical sensorineural auditory alterations in a cohort of young adults with type 1 diabetes of long duration and no manifest hearing impairment, as detected by classic audiometric threshold test. We also aimed at identifying possible vascular and neurological dysfunction in association with auditory function, metabolic variables and presence of chronic diabetic complications.
Materials and methods
Participants
Thirty-one people with type 1 diabetes, belonging to a cohort previously monitored in longitudinal studies of chronic complications (18), agreed to participate. In the original study, 112 adolescent patients with type 1 diabetes were recruited (T0) and prospectively followed 4 years (T4) and 16 years (T16) later to assess the development of cardiac autonomic neuropathy and the predictive value of circulating autoantibodies to autonomic nervous structures. Autonomic, motor and distal sensory function symptoms were identified by a structured questionnaire, designed according to Dyck (19). According to the good practice recommendations of the Italian Society of Diabetes 2010, peripheral somatic neuropathy was assessed by clinical and neurological examination, including foot inspection, 10g Semmes-Weinstein monofilament, deep tendon knee and ankle reflexes and recording of vibratory perception threshold at the tip of the great toe, using a biothesiometer (Biomedical Instruments Co, Newbury, Ohio. Mean of three readings used). Somatic neuropathy was defined by presence of signs and symptoms; it was confirmed by electrodiagnostic study in 3 patients agreeing to undergo full assessment. Autonomic neuropathy was assessed between 8.00 and 12.00 am, by four standard cardiovascular (CV) tests on an automated, computer-integrated system and consisting of: deep breathing test, lying to standing heart rate change, heart rate change during Valsalva manouvre, postural systolic blood pressure decrease on standing. Age-related index values (18) were used to establish abnormality of the tests. Consumption of food and caffeine-containing beverages and smoking was restricted for 2 hours before testing.
Diabetic nephropathy was assessed by performing standard urine test, serum creatinine and albumin excretion rate (urinary albumin-to-creatinine ratio, A/C) dosage; microalbuminuria was defined as A/C > 30 mg/g, confirmed within 6 months.
All patients underwent fundus examination by 2-field, 45° digital colour photography using a Canon CR6-45NM fundus camera (Canon Inc, Ochigiken, Japan). Diabetic retinopathy was
classified as absent if corresponding to ETDRS standard 10 (20), background if corresponding to ETDRS 20-47, and severe if ETDRS ≥53 or previously lasered. To assign retinopathy severity, grading of the worst eye was considered in each patient.
In the present study, auditory function was assessed within 1 year from T16 and metabolic measurements (HbA1c and lipid profile) were updated. Blood pressure was measured and calculated as the mean of three readings performed after at least 10 minutes rest, using Omron blood pressure recorder. All people with a defined history of hypertension were on therapy with ACE-inhibitors or angiotensin II receptor blockers.
Their clinical characteristics and metabolic measurements are summarized in Table 1. Diabetic complications were assessed and quality of life investigated as previously described (18). Ten healthy participants [Males= 70%, age 32 ± 1 years, BMI 23.9 ± 1.5 kg/m2, systolic and diastolic blood pressure 123 (116-125) mmHg and 78 (71-80) mmHg], age-matched and without family history of diabetes, acted as controls. The study was approved by the local Ethics Committee and informed consent was obtained from all participants prior to the procedure, in accordance with Helsinki Declaration.
Assessment of hearing impairment
The auditory system was studied by performing a preliminary comprehensive ear nose and throat visit. Exclusion criteria were history of other chronic diseases, occupational exposure to noise and presence of ear transmission disease.
All participants underwent pure tone audiometry (PTA), distortion product otoacoustic emissions (DPOAE) and auditory brainstem response (ABR). Pure tone audiometry was performed using an audiometer (Amplaid 455, Amplifon, Milan, I) in a sound-proof room, and participants wore a headphone to receive pure tone stimuli at the frequencies of 0.25 kHz, 0.5 kHz, 1 kHz, 2 kHz, 3 kHz, 4 kHz, 6 kHz and 8 kHz. The hearing threshold for each frequency was recorded and
all thresholds were then averaged. An average audiometric threshold < 25 dB in the worst ear was considered normal.
Distortion product otoacoustic emissions, a direct, objective exam measuring the function of the outer hair cells in the Corti’s organ which modulate auditory reception, were recorded using a 92 ILO Otodynamic Analyzer (version 1:35, Otodinamics Ltd, Hatfield, Herts, UK). DPOAEs are responses generated when the cochlea is stimulated simultaneously by two pure tone frequencies whose ratio is between 1.1 to 1.3. Their presence is the expression of the fine contractile function of the OHCs that enhance cochlear sensitivity and frequency selectivity. Participants wore a headphone providing the stimuli and recording responses. The acoustic stimuli were couples of tones delivered simultaneously through a probe. Two primary tones of different intensity (f1 = 70 dB, f2 = 60 dB) and frequency ratio f2/f1=1.22, were used to generate the DPOAE. The distortion product with frequency 2xf1- f2 was selected to measure the DPOAE amplitude, expressed in dB SPL. The cochlear region was stimulated at five frequencies (1, 2, 2.8, 4, and 6 kHz). Both ears were tested separately at baseline, sending a broadband 60 dB noisy signal to the each ear. The otoacoustic emission was considered present if it was 3 dB greater than the background noise. The result was then interpreted both qualitatively, as presence/absence of an OHC response, and quantitatively by reading the dB level of the emitted response.
Auditory brainstem response testing is an objective test, evaluating the integrity of the hearing system from the cochlea up through the lower brainstem. Auditory brainstem responses (ABR) were measured by an Amplaid MK 22 PLUS OTO 2011 (Amplifon). The test was carried out in a sound-proof room, with the participant at rest, delivering the stimuli as clicks through headphones. The nerve signal is detected by three electrodes, the positive vertex placed on the forehead, the negative on the ear to be tested (lobe, or preauricular mastoid space) and the 'ground' on the opposite side. Clicks of alternating polarity were used as acoustic stimuli, with a frequency of 11 stimulations per second, duration of 100 µseconds and 12 msec analysis time. The nervous pathway signal detected was recorded in the form of five waves (I - V), the latencies of which are evaluated in milliseconds.
The waveform refers to specific anatomical points along the auditory neural pathway: cochlear nerve and nuclei (waves I and II), superior olivary nucleus (wave III), lateral lemniscus (wave IV), and inferior colliculi (wave V).
Statistical analysis
The results of the descriptive analysis are presented as absolute and relative frequencies for qualitative variables, and mean ± standard deviation (SD) and/or median and interquartile range (IQR) for quantitative variables. Each ear [right (R), left (L)], otherwise stated, was analysed separately.
The Shapiro-Wilk test was performed to verify normality of distribution of quantitative variables. Univariate analysis was carried out to assess differences in audiological tests between people with diabetes and healthy participants. Only among diabetic people univariate analysis was done to assess differences in clinical variables between participants with and without alterations in audiological tests. In both cases, comparisons were conducted using chi-square or Fisher's exact test for qualitative variables, and Student t-test or a nonparametric test (Mann Whitney) for quantitative variables. Correlations between variables were analysed by Pearson’s test or Spearman's test. P values less than 0.05 were considered significant. Data were analyzed using Stata 13 software (StataCorp LP, TX, USA).
Results
Hearing assessment
All people with diabetes had normal otoscopic examination and a normal hearing threshold. However, the patients’ hearing threshold was significantly higher than in the normal participants (R 14.3 ± 4.6 dB vs 9.9 ± 2.5 dB, L 13.0 ± 3 dB vs 9.9 ± 2.6 dB, p < 0.05) (Figure 1A).
DPOAE could not be detected in at least one frequency in approximately one third of the patients (R 11/31, 35%, L 12/31, 39%). DPOAE intensity was reduced at all frequencies compared to normal controls, the difference reaching statistical significance at frequencies between 2.8 and 4 kHz (p < 0.05) (Figure 1B).
ABR analysis did not show differences in the absolute latencies of individual waves or I-III and I-V intervals between patients and control participants. However, 6 patients (20%) had absent waves in one ear, requiring further investigation by magnetic resonance scans, which did not show either neurinoma or demyelinating disease. Furthermore, a wave IV was detected on the ABR pattern of more than half the patients with a higher prevalence than that of normal controls (R 17/31, 55%, L 19/31, 61.3% in patients, vs R 1/10, L 1/10, 10.0% in control participants, p < 0.05). Patients with wave IV pattern had a longer I-V interval than those without wave IV (4.40 ms ± 0.62 vs 4.19 ms ± 0.58, p < 0.05). Wave IV is usually embedded in wave V (Figure 2A) and was presumably unmasked by the prolonged I-V interval.
Associations with metabolic variables, diabetic complications and quality of life
There were no significant correlations between DPOAE or ABR variables and present/past HbA1c levels or lipid profile nor with presence of retinopathy or microalbuminuria. However, people with diabetic retinopathy showed lower DPOAE intensity at all frequencies compared to people without retinopathy, although the difference did not reach statistical significance (Table 2).
Trends were detected towards associations between presence of wave IV and somatic neuropathy (6/7, 86% in people with somatic neuropathy vs 11/24, 46% in people without somatic
neuropathy, p = 0.07) and altered cardiovascular tests (11/13, 85% in people with altered test vs 9/18, 50% in people with normal test, p = 0.04).
Diabetic people with any DPOAE alterations had higher diastolic blood pressure compared to those without alterations [85 (78-85) mmHg vs 75 (70-80) mmHg, p < 0.05], and this was detected at both ears. People with detectable wave IV had higher systolic blood pressure compared to those without wave IV [130 (127-130) mmHg vs 120 (115-126) mmHg, p < 0.05]. Finally, systolic blood pressure values correlated with wave V latency and with I-V interpeak interval, reaching statistical significance at one side (wave V latency r = 0.47, p < 0.05; I-V interpeak interval r = 0.36, p < 0.05) (Figure 2B).
There was no correlation between quality of life variables and audiological measurements.
1 0
Discussion
In this study, we detected a subclinical auditory dysfunction in a group of young adults with type 1 diabetes of long duration, lasting acceptable glycaemic control and with a varied range of chronic complications. Despite being within the normal range for PTA, the average hearing thresholds among people with diabetes were significantly higher than those of healthy participants, confirming previous reports (4–6). Potentially, a cochleopathy may lie underneath such hearing dysfunction, as DPOAE intensity in our study was reduced at all frequencies, reaching statistical significance at the 2.8-4 kHz frequency range. Discrepancies in the range of significantly reduced frequencies with two recent studies (21, 22), may be related to differences in the population studied (children and adolescents), patient stratification according to glycaemic control in those two studies, as well as patient numerosity.
Corti’s organ is the sensorineural end hearing organ within the cochlea. It includes polarized epithelial cells (hair and supporting cells), a specialized basement membrane with a matrix layer called basilar membrane, nerve endings and the tectorial membrane. There are two types of hair cells, inner and outer, inner ones (IHC) being the true sensory cell type sending impulses via the auditory nerve, and outer hair cells (OHC) enhancing cochlear performance both qualitatively – by increased selectivity – and quantitatively – by increased sensitivity (23). All cells in the sensory epithelium are differentiated, an unusual feature in epithelial tissues, which accounts for inability of hair cells to be replaced, once lost. Vascular cochlear partition is relevant to the symptoms of hearing loss due to vascular causes. The close dependency of the endolymphatic potential on the stria vascularis explains the vulnerability of otoacoustic emission to ischemia. In fact, the initial phase of auditory transduction depends on cochlear micromechanics, related to contraction of the OHC of Corti’s organ. Contractions of the OHC are effective only when amplified and this amplification is ensured by the stria vascularis which generates the high endolymphatic potential (24). Cochlear ischemia is followed almost immediately by hearing loss.
Otoacoustic emissions reflect the function of cochlear OHC, responsible for qualitative sound perception. Hence, their damage could result in subclinical hearing dysfunction, as detected in our study, though not yet affecting social relations and quality of life.
A recent meta-analysis of 13 eligible studies (8), indicates that no data were provided on the prevalence of diabetic complications, not allowing analyses with hearing alterations. A link between acoustic dysfunction and presence of microvascular complications was not detected in our study, possibly reflecting the prevalence of background retinopathy in our cohort. In line with this, DPOAE alterations were detected in a cohort of adolescent patients without chronic diabetic complications (22), while a recent smaller study describes the most disordered audition in 4 patients with proliferative retinopathy (25), although without providing statistical analysis. However, a trend towards more reduced DPAOE in presence of diabetic retinopathy is suggested also in our study.
ABR recordings did not exhibit longer latencies, either at wave or interpeak interval levels, suggesting normal auditory pathways in the patients, as previously reported (2). However, in 60% of the patients a wave IV pattern could be detected, associated with a longer interpeak I-V interval. These data suggest subclinical delay of acoustic nerve transmission, in agreement with previous studies reporting abnormally increased latencies and/or significant wave V delay suggesting acoustic neuropathy (1,5,10,12,15). Differences in the populations studied and glycaemic control, which was overall acceptable in our patients, may account for the lack of evident abnormalities in our case series. Nevertheless, we detected a trend towards an association between peripheral neuropathy and/or cardiac autonomic dysfunction and the presence of wave IV. The latter may suggest early damage of small nerve fibers within the auditory pathway at the pons and midbrain level – lateral lemniscus and inferior colliculi –, in line with evidence that small nerve fibres may be affected first in diabetic neuropathy (26, 27). Our data build on recent research detecting an association with distal symmetric polyneuropathy (2, 25). In contrast, Rance et al (25) could not detect an association with small fibre neuropathy. However in that small study only 8 out of 10
1 2
patients completed cardiac small fibre investigation, which included only blood pressure response on tilt table test, and not full assessment with four cardiovascular tests.
Although a link between acoustic dysfunction and presence of microvascular complications was not detected in this study, the association between DPAOE alterations and blood pressure levels suggests a possible role for vascular mechanisms. This is in line with studies in which the combined deleterious effects of diabetes and hypertension were studied. Duck et al. did a prospective analysis of audiologic findings in normotensive and hypertensive people with type 1 diabetes and also analyzed cochlear hair cell loss in hypertensive diabetic rats, normotensive diabetic rats and normotensive nondiabetic rats, concluding that hypertension may be the driving factor responsible for high-frequency sensorineural hearing loss in patients and for hair cell loss in laboratory animals (28). Post-mortem data from people with both type 1 and type 2 diabetes show atrophy of the stria vascularis and thickening of the basilar membrane in human temporal bones (16, 17, 29). Furthermore, associated hypertension intensifies diabetic end-organ damage in the cochlea, with a synergistic effect on hair cell loss (16, 28). Finally, Loader et al. reported higher plasma SDF-1a concentrations, a biomarker of microangiopathy, in type 2 diabetic people with higher pure-tone audiometry thresholds compared with nondiabetic participants (30).
A correlation was also detected between wave V latency and blood pressure, in agreement with reports of progressively more severe abnormalities of nerve microvasculature in association with mild to severe diabetic neuropathy (31) and of hypertension as a risk factor for cardiac autonomic neuropathy (32), suggesting a role for microangiopathy in the genesis of diabetic nerve damage also in the ear.
An association with glycaemic control could not be detected, in accordance with other studies (8, 21, 22, 25, 33). Oxidative stress, metabolic injury, as well as glycaemic excursions, may be independent risk factors for cardiovascular disease (34) and play a pathogenetic role in ear disturbances. Furthermore, the DCCT indicates that hyperglycaemia has a less robust relationship with diabetic autonomic neuropathy than with other complications, as deficiency in neurotrophic
factors and essential fatty acids, advanced glycosylation products and autoimmune damage could all be involved (18).
This paper has strengths, such as a standardized methodology and strict patient characterization, which allowed to identify the presence of subclinical hearing abnormalities in diabetes and their possible associations with other complications. Among its limitations is that the study was run in a sub population of patients investigated in a previous survey of diabetic neuropathy (18) that had not been specifically designed to address hearing problems. Since only a fraction of the original cohort accepted to be recalled for this study, the resulting sample size may have been insufficient to perform regression analyses to examine associations with other clinical variables in greater detail. In conclusion, subclinical auditory alterations can be detected in young adult people with type 1 diabetes and suggest a role for both neurological and vascular pathogenic mechanisms. Similarly to the eye, where observation of microangiopathy in retinal capillaries can be complemented by evaluation of small fiber neuropathy by quantifying nerve fiber degeneration and regeneration in the cornea (35), these findings point at the ear as a potential additional window to assess neurologic and vascular function in diabetes.
Acknowledgements
MMZ was responsible for conception and design of the study, clinical examination, analysed data and wrote the manuscript. AL, AR, EC, GG, MT collected and analysed data. PG and ML performed auditory examination and measurements. LC, FC performed statistical analyses. MP and RA oversaw research, revised the manuscript and contributed to the discussion. All the authors gave the final approval to the submission of the manuscript. MMZ and RA are the guarantors of this work and, as such, had full access to all the data and take responsibility for the integrity of the data and the accuracy of the data analysis.
The authors have nothing to disclose.
1 4
References
1. Fedele D, Martini A, Cardone C, Comacchio F, Bellavere F, Molinari G, Negrin P, Crepaldi G. Impaired auditory brainstem-evoked responses in insulin-dependent diabetic subjects. Diabetes 1984; 33:1085–1089
1. Ottaviani F, Dozio N, Neglia CB, Riccio S, Scavini M. Absence of otoacoustic emissions in insulin-dependent diabetic patients: is there evidence for diabetic cochleopathy? J Diabetes Complications 2002; 16:338–343
2. Kakarlapudi V, Sawyer R, Staecker H. The effect of diabetes on sensorineural hearing loss. Otol Neurotol 2003; 24:382–386
3. Pessin ABB, Martins RHG, Pimenta W de P, Simões ACP, Marsiglia A, Amaral AV. Auditory evaluation in patients with type 1 diabetes. Ann Otol Rhinol Laryngol 2008; 117:366–370
4. Konrad-Martin D, Austin DF, Griest S, McMillan GP, McDermott D, Fausti S. Diabetes-related changes in auditory brainstem responses. The Laryngoscope 2010; 120:150–158 5. Dąbrowski M, Mielnik-Niedzielska G, Nowakowski A. Involvement of the auditory organ
in type 1 diabetes mellitus. Endokrynol Pol 2011; 62:138–144
6. Bainbridge KE, Hoffman HJ, Cowie CC. Diabetes and hearing impairment in the United States: audiometric evidence from the National Health and Nutrition Examination Survey, 1999 to 2004. Ann Intern Med 2008; 149:1–10
7. Horikawa C, Kodama S, Tanaka S, Fujihara K, Hirasawa R, Yachi Y, Shimano H, Yamada N, Saito K, Sone H. Diabetes and risk of hearing impairment in adults: a meta-analysis. J Clin Endocrinol Metab 2013; 98:51–58
8. Akinpelu OV, Mujica-Mota M, Daniel SJ. Is type 2 diabetes mellitus associated with alterations in hearing? A systematic review and meta-analysis. The Laryngoscope 2014; 124:767–776
9. Di Nardo W, Ghirlanda G, Paludetti G, Cercone S, Saponara C, Del Ninno M, Di Girolamo S, Magnani P, Di Leo MA. Distortion-product otoacoustic emissions and selective sensorineural loss in IDDM. Diabetes Care 1998; 21:1317–1321
10. Botelho CT, Carvalho SA da S, Silva IN. Increased prevalence of early cochlear damage in young patients with type 1 diabetes detected by distortion product otoacoustic emissions. Int J Audiol 2014; 53:402–408
11. Virtaniemi J, Laakso M, Kärjä J, Nuutinen J, Karjalainen S. Auditory brainstem latencies in type I (insulin-dependent) diabetic patients. Am J Otolaryngol 1993; 14:413–418
12. Virtaniemi J, Kuusisto J, Karjalainen L, Karjalainen S, Laakso M. Improvement of metabolic control does not normalize auditory brainstem latencies in subjects with insulin-dependent diabetes mellitus. Am J Otolaryngol 1995; 16:172–176
13. Pudar G, Vlaski L, Filipović D, Tanackov I. Correlation of hearing function findings in patients suffering from diabetes mellitus type 1 in regard to age and gender. Med Pregl 2009; 62:395–401
14. Seidl R, Birnbacher R, Hauser E, Bernert G, Freilinger M, Schober E. Brainstem auditory evoked potentials and visually evoked potentials in young patients with IDDM. Diabetes Care 1996; 19:1220–1224
15. Akinpelu OV, Ibrahim F, Waissbluth S, Daniel SJ. Histopathologic changes in the cochlea associated with diabetes mellitus--a review. Otol Neurotol Off Publ Am Otol Soc Am Neurotol Soc Eur Acad Otol Neurotol 2014; 35:764–774
16. Fukushima H, Cureoglu S, Schachern PA, Kusunoki T, Oktay MF, Fukushima N, Paparella MM, Harada T. Cochlear changes in patients with type 1 diabetes mellitus. Otolaryngol Head Neck Surg 2005; 133:100–106
17. Zanone MM, Raviolo A, Coppo E, Trento M, Trevisan M, Cavallo F, Favaro E, Passera P, Porta M, Camussi G. Association of autoimmunity to autonomic nervous structures with nerve function in patients with type 1 diabetes: a 16-year prospective study. Diabetes Care 2014; 37:1108–1115
18. Dyck PJ. Detection, characterization, and staging of polyneuropathy: assessed in diabetics. Muscle Nerve 1988; 11:21–32
19. Early Treatment Diabetic Retinopathy Study Research Group. Grading diabetic retinopathy from stereoscopic color fundus photographs--an extension of the modified Airlie House classification. ETDRS report number 10. Ophthalmology 1991; 98:786-806
20. ALDajani N, ALkurdi A, ALMutair A, ALdraiwesh A, ALMazrou KA. Is type 1 diabetes mellitus a cause for subtle hearing loss in pediatric patients? Eur Arch Otorhinolaryngol 2015; 272:1867-71
21. Botelho CT, Carvalho SA, Silva IN. Increased prevalence of early cochlear damage in young patients with type 1 diabetes detected by distortion product otoacoustic emissions. Int J Audiol 2014; 53:402-408
22. Raphael Y, Altschuler RA. Structure and innervation of the cochlea. Brain Res Bull 2003; 60:397–422
23. Patuzzi R. Ion flow in stria vascularis and the production and regulation of cochlear endolymph and the endolymphatic potential. Hear Res 2011; 277:4-19
24. Rance G, Chisari D, O'Hare F, Roberts L, Shaw J, Jandeleit-Dahm K, Szmulewicz D. Auditory neuropathy in individuals with Type 1 diabetes. J Neurol 2014; 261:1531-1536. 25. Várkonyi TT, Börcsök E, Tóth F, Fülöp Z, Takács R, Rovó L, Lengyel C, Kiss JG, Janáky
M, Hermányi Z, Kempler P, Lonovics J. Severity of autonomic and sensory neuropathy and the impairment of visual- and auditory-evoked potentials in type 1 diabetes: is there a relationship? Diabetes Care 2006; 29:2325–2326
1 6
26. Watkins PJ, Edmonds ME. Sympathetic nerve failure in diabetes. Diabetologia 1983; 25:73– 77
27. Duck SW, Prazma J, Bennett PS, Pillsbury HC. Interaction between hypertension and diabetes mellitus in the pathogenesis of sensorineural hearing loss. The Laryngoscope 1997; 107:1596–1605
28. Fukushima H, Cureoglu S, Schachern PA, Paparella MM, Harada T, Oktay MF. Effects of type 2 diabetes mellitus on cochlear structure in humans. Arch Otolaryngol Head Neck Surg 2006; 132:934–938
29. Loader B, Stokic D, Riedl M, Hickmann S, Katzinger M, Willinger U, Luger A, Thurner S, Wick N. Combined analysis of audiologic performance and the plasma biomarker stromal cell-derived factor 1a in type 2 diabetic patients. Otol Neurotol 2008; 29:739–744
30. Cameron NE, Eaton SE, Cotter MA, Tesfaye S. Vascular factors and metabolic interactions in the pathogenesis of diabetic neuropathy. Diabetologia 2001; 44:1973–1988
31. Witte DR, Tesfaye S, Chaturvedi N, Eaton SEM, Kempler P, Fuller JH: EURODIAB Prospective Complications Study Group. Risk factors for cardiac autonomic neuropathy in type 1 diabetes mellitus. Diabetologia 2005; 48:164–171
32. Sieger A, White NH, Skinner MW, Spector GJ. Auditory function in children with diabetes mellitus. Ann Otol Rhinol Laryngol. 1983 May-Jun;92(3 Pt 1):237-41.
33. Bonora E. Postprandial peaks as a risk factor for cardiovascular disease: epidemiological perspectives. Int J Clin Pract Suppl. 2002 Jul;(129):5-11.
34. Malik RA, Kallinikos P, Abbott CA, van Schie CHM, Morgan P, Efron N, Boulton J. Corneal confocal microscopy: a non-invasive surrogate of nerve fibre damage and repair in diabetic patients. Diabetologia 2003; 46:683–688
Figure legends
Figure 1. Pure Tone Audiometry and DPOAE assessment. Mean ± SD hearing threshold (dB), expressed as mean of all frequencies, in people with diabetes (black) and control participants (white) at the right (R) and the left (L) ear (A).
Mean ± SD Distorsion Product Otoacustic Emissions (dB) in response to different frequencies (kHz) in people with diabetes (black) and control participants (white) (B).
*p < 0.05 compared with values in control participants
Figure 2. Auditory Brainstem Responses. Representative example of a normal auditory brainstem response morphology, without (left) or with (right) evidence of a wave IV pattern (A).
Correlation between systolic blood pressure values and wave V latency at ABR (r = 0.42, p < 0.05) (left) and between systolic blood pressure values and interpeak I-V interval values (r = 0.36, p < 0.05; r = 0.35 p = 0.07 with three outliers removed) (right) (B).
1 8
Table 1. Clinical characteristics of participants
Data are expressed as mean ± SD or median (interquartile range) or frequency
HbA1c levels refer to values of the previous year (mean of three values), the previous 5 years (mean of available data) and the previous 10 years (mean of available data).
Presence of microalbuminuria is defined as urinary albumin-to-creatinine ratio > 30 mg/g People with type 1 diabetes
n = 31
Sex (M:F) 17:14
Age (years) 33.2 ± 2.3
Disease duration (years) 25.7 ± 4.2
BMI (kg/m2) 26.4 ± 3.7
HbA1c mmol/mol (%) 10 years 5 years 1 year
62 ± 11 (7.8 ± 1.0) 62 ± 12 (7.8 ± 1.1) 62 ± 7 (7.8 ± 0.6) Cholesterol (mmol/L) Total
HDL LDL 4.89 ± 0.70 1.55 ± 0.39 2.84 ± 0.65 Triglycerides (mmol/L) 0.86 (0.60-1.25)
Systolic blood pressure (mmHg) 130 (125-130)
Diastolic blood pressure (mmHg) 75 (70-85)
Hypertension 7/31 (23%) Retinopathy Background Laser-treated 26/31 (84%) 24/31 (77%) 2/31 (6%) Microalbuminuria 4/31 (13%)
Table 2. Auditory function and presence of diabetic retinopathy (DR) People with DR n = 26 People without DR n = 5 p value DPOAEs (dB) 1 kHz 6.7 (0.1 - 11.1) 10.2 (8.4 - 18.3) 0.12 2 kHz 4.85 (0.6 - 9.5) 5 (4.8 - 9.2) 0.54 2.8 kHz 0.1 (-2 - 4.3) 1.6 (1.4 - 2.1) 0.3 4 kHz 2.1 (-2.8 - 5.4) 6.9 (6.5 - 8.4) 0.08 6 kHz -0.1 (-6.1 - 5.4) 7.2 (1.1 - 13.4) 0.1 ABR (msec) I 1.72 (1.68 - 1.84) 1.68 (1.6 - 1.76) 0.67 III 3.94 (3.8 - 4.08) 3.88 (3.84 - 4.04) 0.98 V 5.9 (5.8 - 6) 6 (5.96 - 6.04) 0.28 I - V 4.36 (4.16 - 4.36) 4.28 (4.08 - 4.32) 0.45
Data are expressed as median (interquartile range)
2 0
