Exploring the Association of Hearing Loss with Diabetes Mellitus: A Critical Review

Transcription

1 Exploring the Association of Hearing Loss with Diabetes Mellitus: A Critical Review Amanda K. Wolfe, Au.D., 1 Julie A. Honaker, Ph.D., 1 and T. Newell Decker, Ph.D. 1 ABSTRACT The prevalence of diabetes mellitus is quickly growing in the U.S. population, and among these individuals, many suffer from auditory impairment of increased severity compared with healthy individuals without diabetes. Clinical implications of diabetes mellitus and its affect on the auditory system have been widely recognized in the literature. This article reviews current evidence detailing the association between hearing loss and diabetes mellitus. Traditional and novel methods used in research of this association will be discussed, and descriptions for general audiological precautions for diabetic patients will be outlined. Although controversy exists in the literature, knowledge of the possible audiological aspects of the diabetic individual is paramount and exceedingly relevant to audiological practice as this population continues to increase. Continued research will provide further insight for which specific audiological management of these patients may be established. KEYWORDS: Diabetes, type 1 diabetes, type 2 diabetes, hearing loss Learning Outcomes: As a result of this activity, the participant will be able to: (1) list three audiological tests that may present with abnormal findings and (2) describe the findings often associated with the above tests. Diabetes mellitus is quickly becoming an epidemic, affecting 25.8 million people in and a projected 30 million people by Diabetes mellitus is a metabolic disease characterized by autoimmune-related insulin deficiency (type 1) and the improper use of insulin by body cells (type 2). Type 1 is often referred to as insulin-dependent diabetes (IDDM) and affects 5 to 10% of the diabetic population. 3 Type 2 is referred to as non-insulin-dependent University of Nebraska Lincoln, Lincoln, Nebraska. Address for correspondence and reprint requests: Amanda K. Wolfe, Au.D., 1414 Laurel Ave., #L312, Minneapolis, MN ( Amanda.wolfe@huskers. unl.edu). Hearing Loss as a Result of Common and Rare Medical Conditions: Clinical Findings, Management Options, and Prevention Strategies; Guest Editor, Julie A. Honaker, Ph.D. Semin Hear 2011;32: Copyright # 2011 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA. Tel: +1(212) DOI: ISSN

2 THE ASSOCIATION OF HEARING LOSS WITH DIABETES MELLITUS/WOLFE ET AL 333 diabetes (NIDDM) and affects 90 to 95% of the diabetic population. 3 As hearing loss is associated with this disease, it is important to consider its presence during the evaluation and differential diagnosis of these individuals. BACKGROUND Jordao initially documented diabetes-related hearing loss (as cited in Pessin et al 4 ), and interest in this association has grown among the research community since that time. Controversial data exist on the incidence of hearing loss among the diabetic population. Estimates of 0 to 80% have been reported by Lisowska et al. 5 This variability is most likely due to the currently unknown pathogenesis of hearing loss as well as the heterogeneity among study methodologies. Although prevalence reports are variable, Bainbridge et al 6 conducted a large, national cross-sectional analysis to determine if hearing impairment was indeed more prevalent within the diabetic population. Data between the years of 1999 to 2004 were obtained from the National Health and Nutrition Examination Survey by the National Center for Health Statistics. The sample size consisted of 5140 U.S. adults aged 20 to 69 years who underwent audiometric testing and a diabetes questionnaire. Results of the survey demonstrated a statistically significant increase in prevalence of hearing impairment in participants who reported a diabetes diagnosis compared with those who did not report a diagnosis, with estimates of 21% and 9%, respectively. 6 The increase in prevalence was significant for the age groups of 20 to 49 years and 50 to 59 years of age. Diabetes and the hyperglycemic states that are associated with the disease may lead to significant health-related conditions that can be related to poor metabolic control and duration of diabetes. As it relates to the auditory system, glucose is important for the proper functioning of the cochlea, and alterations in normal glucose levels, such as with chronic hyperglycemia, may cause disruptions in cochlear structures resulting in hearing loss. 7 A relationship exists between these glucose alterations, microangiopathy, neuropathy, and excessive free radicals within the diabetic individual 7 9 and are theorized as correlating with hearing loss. 7 Other published theories include hyperlipidemia, as Pulec et al reported the biochemistry behind hyperlipidemia, or increased low-density lipoprotein cholesterol, may lead to alterations in inner ear function (as cited in Ren et al 10 ). Hypertension may also play a role; however, these two conditions have not been investigated to the same extent as those previously mentioned. 10 Microangiopathy, otherwise termed disease of small blood vessels, is caused by a build-up of sugar-based substances on vessel walls, 11 causing them to thicken. Consequently, the blood vessels weaken, and blood flow throughout the body is decreased. 11 Retina and kidney damage as a consequence of microangiopathy are the most common conditions seen in diabetics and are termed retinopathy and nephropathy, respectively. 12 Neuropathy, also a common complication of diabetes, is a term used for nerve damage that may be caused by microangiopathy. 12,13 Cochlear microangiopathy is demonstrated by thickened vessels of the cochlea (stria vascularis and basilar membrane) that may disrupt the normal blood flow in the cochlea, reduce the transportation of nutrients, and cause secondary degenerations in the eighth cranial nerve. 13,14 Fukushima et al 15 conducted a cross-sectional study on 26 temporal bones of type 1 diabetics and 30 temporal bones of agematched individuals serving as controls. The average age of the individuals at death was 37.5 years; however, the ages ranged from 18 to 68 and 12 to 67 for the diabetic and control group, respectively. Analysis of the cochlea s outer hair cells, lateral walls, vessels, and spiral ganglion cells via light microscopy revealed that diabetic cochleas demonstrated significantly thickened vessel walls of the basilar membrane as well as vessels of the stria vascularis throughout the entire cochlea. Interestingly, older subjects had thicker vessel walls of the basilar membrane compared with younger subjects, and this process seemed to occur faster in older diabetic cochleas compared with controls. 15 Aging and thickness of the vessel walls of the stria vascularis was not significant. A correlation was found between the thickening of

3 334 SEMINARS IN HEARING/VOLUME 32, NUMBER basilar membrane vessel walls and outer hair cell loss in the diabetic subject group only in the lower basal turn. 15 Further examination of the cochlea also revealed atrophy of the stria vascularis throughout the entire cochlea. Total absence of the stria vascularis in parts of the cochlea and occlusion of the vessels of the stria vascularis was found in some diabetic patients. Outer hair cells and the cells of the spiral ligament were found to be significantly scarce or absent in the cochlea s lower and upper turns, respectively. 15 An increase in the loss of outer hair cells in the lower turn of the cochlea and atrophy of the stria vascularis was noted to correspond with the thickening of vessel walls in diabetic cochleas. 15 The observed cochlear damage in the vessel walls of the basilar membrane, outer hair cell loss, and atrophy of the stria vascularis in diabetics seemed to occur at a faster rate with age, compared with controls. Duration of diabetes was found to be correlated with outer hair cell damage. 15 Examination of the spiral ligament revealed a significant decrease of fibrocytes in diabetic cochleas compared with controls in the lower middle, upper middle, and apical turns 15 ; however, the total number of spiral ganglion cells as well as inner hair cells was not significantly different between the diabetic and control groups. The authors concluded that cochlear microangiopathy may be a result of type 1 diabetes, causing degeneration of the outer hair cells and the lateral walls of the cochlea. Fukushima et al 16 performed a cross-sectional temporal bone study using light microscopy on 18 cochleas from type 2 diabetic individuals, with duration of illness of greater than 7 years. Eleven subjects, aged 44 to 65 years, had taken insulin injections, and the remaining seven subjects, aged 45 to 64 years, had taken oral hypoglycemic agents. Data from the diabetic patients were compared with 26 age-matched controls. The results of the study demonstrated thickened vessel walls of the basilar membrane as well as in the vessel walls of the stria vascularis throughout the entire cochlea, in the individuals who had managed diabetes with insulin injections. Thickening of the stria vascularis was found in individuals taking oral hypoglycemic agents however, only in the basal turn. Atrophy of the stria vascularis in those who had taken insulin injections was observed in the lower basal, lower middle, upper middle, and apical turns, whereas this was only observed in the lower middle turn 16 of those who had taken oral hypoglycemic agents. When comparing the two diabetic groups, those who had managed their diabetes with insulin injections demonstrated increased atrophy of the stria vascularis in the apical turn region of the cochlea. 16 Interestingly, no correlation between atrophy and thickness of the stria vascularis was found. The upper and lower basal turns of the cochlea also revealed significantly less outer hairs cells in all diabetic patients, as compared with the control group. Similar to the previous study on type 1 diabetics, spiral ganglion cells and inner hair cells did not seem to be significantly affected. There was no correlation between the number of spiral ganglion cells and the number of either inner or outer hair cells. The authors report this finding may be explained by the anatomic configuration of the two types of spiral ganglion cells, given that the majority of type 1 cells innervate inner hair cells. 16 The data seem to demonstrate increased damage to the cochlea in diabetic individuals compared with healthy controls, as well as increased damage in those diabetics who had taken insulin injections, compared with those managed through oral hypoglycemic agents. The authors reported the observed atrophy of the stria vascularis, as well as outer hair cell damage, may be due to a combined effect of apoptosis, hypertension, noise exposure, and oxidative stress. 16 In addition, Wackym and Linthicum reported that microangiopathy may be one of the primary causes of hearing loss among the diabetic population (as cited in Fukushima et al 16 ). The stria vascularis, a microvascular-dependent organ, may be more prone to damage and hair cell transduction, and signal transmission may be compromised due to weak vessels caused by microangiopathy, leading to changes in auditory electrolyte homeostasis. 7 The data from this study support diabetic hearing loss as demonstrated by damage to the stria vascularis and outer hair cells, as well as the presence of microangiopathy in the cochlea. 16

4 THE ASSOCIATION OF HEARING LOSS WITH DIABETES MELLITUS/WOLFE ET AL 335 Similar findings have been reported in previous histopathologic studies; however, Fukushima et al 15 reported that a distinction between type 1 or type 2 diabetic temporal bones, and the effects of presbycusis have not been addressed in the majority of reported findings. Nonetheless, other studies have been conducted on diabetic animal models as well as human temporal bones. These studies have revealed an abnormal number of ganglion cells, thickening of the vaso nervorum vessel walls, thickening of the modiolus capillaries and stria vascularis, atrophy of the spiral ganglion, nerve fiber loss in the spiral lamina, and VIIIth nerve and central auditory pathway demyelination and degeneration, respectively. 4,13 Diabetic encephalopathy was first introduced by Reske-Nielsen, Lundbaek, and Rafaelsen (1965) as a term to describe degenerative changes within the central nervous system (as cited in Lisowska et al 5 ). Kovar found both endolymphatic and perilymphatic hemorrhages when examining diabetic temporal bones (as cited in Lisowska et al 5 ). The investigation of diabetic temporal bones in animals must be reviewed with caution, as there are many pathological differences that exist between diabetes in animals and in humans. Diabetes in laboratory animals is most always induced, and genetic differences between animals and humans may alter the way diabetes affects the body. 15 AUDITORY FUNCTION AND DIABETES Unfortunately, there is not a single diagnostic test specific for the evaluation of auditory function and diabetes. However, abnormalities have been noted during pure-tone audiometry, auditory brain stem response (ABR) and otoacoustic emission (OAE) testings (see Table 1). In a 2000 study of ABR in diabetic individuals with and without complications, Bayazit et al 17 detected abnormal wave latency, amplitude, and morphology in 59 middle-aged diabetic (type 1 or 2) individuals with either retinopathy or nephropathy as compared with 20 diabetic individuals without complications. A significant increase was noted for waves I, III, and V. In addition, the researchers reported longer interpeak latencies of waves I to III, III to V, and I to V in the study group; however, statistical significance was only found for the interpeak latencies of I to III and I to V. Significantly diminished amplitude was only noted for wave V in the study group as compared with controls. Abnormal morphology was noted in 55.2% and 27.6% of the patients in the study and control groups, respectively. 14 Pure-tone averages revealed mild sensorineural hearing loss in all subjects. Based on the ABR data, it is apparent that diabetics with complications, specifically retinopathy and/or nephropathy, demonstrate higher degrees of abnormalities compared with those without such conditions. Thus, the use of ABR testing in the early detection and intervention of retinopathy and/or nephropathy may be of clinical utility once further research has been conducted in this area. The authors concluded the presence of brainstem neuropathy 14 can be evaluated through ABR testing and that microangiopathy and neuropathy are the main reasons behind diabetic complications. Díaz de León-Morales et al 18 assessed the influence of multiple variables on the auditory system. Included in the analysis were current age, age at diagnosis, hemoglobin A1c (HbA1c) levels, duration of diabetes, and presence of retinopathy and neuropathy. Pure-tone audiometry, speech discrimination, and ABR testing was conducted on 94 middle-aged, type 2 diabetic subjects and 94 age- and sex-matched controls. All study participants had no history of excess noise exposure, ototoxic medications, otologic disease, or any disease affecting the cardiovascular or central nervous system. 18 Pure-tone audiometry revealed that diabetic patients had a significant increase in the highfrequency pure-tone average (2, 4, and 8 khz), and solely at 8 khz. The latter was significantly correlated with patient age and duration of diabetes. ABR abnormalities revealed longer absolute latencies of wave V and interpeak latencies of waves I to V and III to V. A higher rate of wave V asymmetry between ears as compared with controls was also observed. Statistical analyses revealed these brainstem responses were independent from the evidence of retinopathy, peripheral neuropathy and nephropathy. 18 Based on the data, the

5 336 SEMINARS IN HEARING/VOLUME 32, NUMBER Table 1 Audiological Abnormalities in Diabetic Patients Abnormal Audiometric Results Author n Type of DM Pure-Tone Audiometry Significant ABR Latency Prolongations OAE Aladag et al 9 * 63 total; 28 SNHL Type II 28 DMSNHL; 18 CSNHL Austin et al 23y 165 Types I and II Increased Thresholds Bayazit et al 17z 59 Types I and II Mild SNHL I, III, V; I III, I V Díaz de León-Morales et al Type II Increased thresholds V, I V; III V Durmus et al 20k 43 total; 17 (type I), 26 (type II) Types I and II WNL I,III,V, I V, I III, III V (DM versus controls); III, V (type 1 versus type 2) Frisina et al 7ô 30 Type II Increased thresholds Reduced amplitudes (DPOAE) Lisowska et al 5 42 Type I WNL I, III, V; I V Reduced amplitudes (DPOAE) Loader et al 22# 18 Type II Increased thresholds Ottaviani et al 21** 60 Type I WNL I, III, V Reduced amplitudes (DPOAE and TEOAE) Vaughan et al 19yy 261 Unspecified Increased thresholds III and V; I V, I III, III V DM, diabetes mellitus; SNHL; sensorineural hearing loss; HL; hearing level; WNL, within normal limits; DMSNHL, diabetes mellitus with sensorineural hearing loss; CSNHL, control with sensorineural hearing loss; ABR, auditory brain stem response; OAE, otoacoustic emissions; DPOAE, distortion product otoacoustic emissions; TEOAE, transient evoked otoacoustic emissions;, no data were available in the cited publications. *Bilateral pure-tone average worse than 30-dB HL. y Increased thresholds differed with age tertile and type of diabetes. z Pure-tone average of the study group was 39-dB HL and 33-dB HL for the control group. Significant increase in the high-frequency pure-tone average (2, 4, 8 khz), and at 8 khz. k ABR prolongation increased in type 2. ô Increased thresholds for pure-tone averages (0.5, 1, 2 khz), (1, 2, 4 khz), (4, 8, 9 khz), (10, 11, 12, 14 khz). # Increased thresholds from 125 Hz to 8 khz. **Only wave V and III V correlated with neuropathy. yy Data from six patients with unreported diabetic status were excluded due to the inability to obtain the necessary data from their files; increased thresholds at pure-tone average 1, 2, 3, 4 khz; prolonged ABR latencies with respect to earspecific and polarity-specific data. authors concluded that diabetic individuals experience subclinical hearing loss and increased high-frequency pure-tone thresholds that are related to age and duration of diabetes. No other examined factors were correlated. In addition, the authors state that although presbycusis is observed in the high frequencies, the observed correlation between duration of diabetes along with the use of age- and sexmatched controls suggests that diabetes mellitus

6 THE ASSOCIATION OF HEARING LOSS WITH DIABETES MELLITUS/WOLFE ET AL 337 is associated with hearing loss and could aggravate the hearing loss related to age. 18 Lisowska et al 5 further examined the relationship between hearing loss and diabetes, in particular, the presence of microangiopathy (i.e., nephropathy and retinopathy) as a possible mechanism for hearing loss. OAE and ABR testing on 42 individuals with type 1 diabetes and normal pure-tone thresholds were examined. ABR testing revealed significantly prolonged latencies for absolute waves I, III, and V and a prolonged interpeak I to V latency for all diabetic subjects, as compared with controls. Reduced distortion product OAE amplitudes were also found in all diabetic subjects compared with controls. Within the diabetic cohort, two subgroups were formed based on the presence or absence of microangiopathy. For both subgroups, no correlation was found between the presence or absence of microangiopathy and test abnormalities. The fact that no correlation was found between impaired ABRs and microangiopathy may be explained by the late onset of microangiopathy and the early observation of ABR abnormalities. In addition, early metabolic changes may have compromised OAEs. 5 Vaughan et al 19 also evaluated the effects of diabetes on ABRs. The 5-year (1999 to 2004) prospective study analyzed reliable ABR in 581 patients, 261 with diabetes and 326 nondiabetic controls. Data from six patients with unreported diabetic status were excluded due to the inability to obtain the necessary data from their files. ABRs were obtained using both rarefaction and condensation stimuli, resulting in summed responses. When the right ear was stimulated with condensation clicks, diabetic patients demonstrated prolonged latencies for absolute waves III and V in the right ear only. The factors of subject age and hearing loss were found to be significant for all of the prolonged absolute wave latencies of the right ear. The diabetic group also demonstrated prolongation of the interpeak latency I to V in both ears with both stimuli. The I to III interpeak latency also was prolonged in both ears, however, only with condensation. Rarefaction stimulation resulted in a prolongation of the III to V interpeak latency in the left ear of the diabetic subject group. A moderate correlation was found between age and hearing loss, and both contributed independently to the absolute latency differences between the two subject groups. 19 The authors report that use of condensation stimuli may be useful in detecting latency prolongations in diabetic patients as compared with healthy, nondiabetic patients. Diabetesrelated conditions were not correlated with latency prolongations after subject age and hearing loss were accounted for. In addition, the authors found that factors related to diabetes, such as insulin use, glucose level, duration of diabetes, HbA1c level, retinopathy, and kidney malfunction, were not able to predict latency prolongations or differences in the diabetic subject group. Addressing the concern of whether ABR latency differences between diabetics and nondiabetics are clinically relevant, the authors reported that although the differences found in this study were statistically significant, they were small (less than 0.13 milliseconds). However, as reported by Díaz de León-Morales et al 18 and Lisowska et al, 5 the use of ABR testing and OAEs may be useful in detecting subclinical hearing loss. Durmus et al 20 further explored a possible correlation between subclinical hearing loss with duration of diabetes, metabolic control, and neuropathy. ABR testing was implemented on a group of 43 diabetic individuals with normal pure-tone thresholds that were divided into subgroups of type 1 and type 2 diabetes. When compared with controls, both diabetic groups demonstrated prolonged absolute latencies for the waveforms I, III, and V and for the interpeak latencies of I to III, III to V, and I to V. When comparing the two diabetic groups to each other, the only significant increase in latencies was found for the absolute latencies of waves III and V, which were longer in the type 2 diabetic subgroup. Interestingly, regardless of statistical significance, the latencies of the type 2 diabetic subgroup were longer when compared with the type 1 subgroup. With significant delays noted in waveforms V, I to V, and III to V, along with less severe latency shifts of wave I compared with other waveforms, the researchers reported abnormalities of a more central rather than peripheral origin. Given this information, the

7 338 SEMINARS IN HEARING/VOLUME 32, NUMBER researchers reported that the effects of diabetes on the brain may initiate premature aging, therefore explaining why even young individuals may show increased latency shifts. Although latency delays were more robust in individuals with neuropathy, and was noted in 50% of the type 2 subgroup, the authors found no correlation between it, metabolic control, age, blood glucose level, or duration of diabetes. Individual evaluation, along with the use of ABR testing, was supported by the researchers who also concluded that ABR testing is a valuable tool in detecting subclinical loss in diabetic individuals. Ottaviani et al 21 also supported the notion of subclinical hearing loss in some diabetic patients. This study was a replication of Arlinger s (1982) research (as cited in Ottaviani et al 21 ) and included subjects with normal pure-tone hearing thresholds. Ottaviani et al 21 used transient and distortion product OAE and ABR tests to examine the cochlear function of 60 type 1 diabetic subjects (average age years) with an average duration of diabetes of years and 58 control subjects. Retinopathy was present in 26 subjects, nine with microalbuminuria, and 17 with peripheral neuropathy. The authors established that no significant differences were noted in pure-tone hearing thresholds between control and diabetic subjects for the frequencies of 250 to 8000 Hz. However, increased ABR latencies of waves I, III, and V were observed in diabetic subjects when compared with controls. Interestingly, the examined interpeak waves demonstrated no significant differences between subject groups, suggesting normal neural transmission. Correlations were found between peripheral neuropathy and ABR latencies of wave V and the interpeak latency of waves III to V, which suggests a subclinical neuropathy of the VIII nerve. No correlations were found between the ABR latencies and interpeak intervals with age, disease duration, daily insulin dose, HbA1c, presence of microalbuminuria, or retinopathy. 21 Transient-evoked OAE intensity and reproducibility were reduced significantly in diabetics compared with controls. Absence of emissions was found in at least one ear in 17 of 60 patients. Of those 17, the absence of emissions in both ears was noted in five diabetic subjects, and 12 had significantly reduced emission levels in the contralateral ear when compared with the average emissions of the rest of the diabetic subject group. The 43 remaining subjects demonstrated present emissions in both ears, with a significant reduction of average emission levels noted at the average frequencies of 1 to 4 khz when compared with controls. Distortion product OAE levels were reduced at all examined frequencies except for 4306 and 5121 Hz. The middle frequencies demonstrated the most significant reduction in emission level. No correlations between the above, including neuropathy, were found with OAEs. In addition to pure-tone audiometry, ABR and OAE recordings, Ren et al 10 investigated changes in the right ear advantage for middleaged type 2 diabetic patients. Specifically, the authors were interested in correlations with the declining right ear advantage as a result of the damage to vascular endothelial walls that occurs in type 2 diabetes. 10 As shown by decreased amplitude of transient-evoked OAEs in the right ear for diabetic patients, the right ear advantage appears to suffer an early decline and subclinical hearing loss is present in middle aged type 2 diabetics. Frisina et al 7 were interested in the interaction between presbycusis and type 2 diabetes mellitus and also found a decline of the right ear advantage in older diabetic subjects. Specifically, the use of pure-tone audiometry, speech reception threshold (SRT), the Hearing in Noise Test, gap detection, wideband noise thresholds, distortion product and transient-evoked OAE tests were performed on a total of 60 older volunteers (30 type 2 diabetics and 30 healthy age- and sex-matched controls). Decline of the right ear advantage was noted in pure-tone testing, wideband noise thresholds, distortion product OAEs, and SRT. A possible explanation for this decline is the fact that as one develops presbycusis, the right ear advantage is lost. 7 As supported with that proposed by Ren et al, 10 diabetes is very likely the cause for the accelerated decline. An interesting route in the examination of diabetes and hearing loss was reported by Loader et al. 22 They compared hearing thresholds as well as blood samples in 18 diabetic

8 THE ASSOCIATION OF HEARING LOSS WITH DIABETES MELLITUS/WOLFE ET AL 339 subjects (ages 34 to 75 years) and 18 nondiabetic age-matched controls to assess whether levels of a biomarker for microangiopathy, stromal cell-derived factor 1a (SDF-1a), was correlated to pure-tone hearing thresholds. No significant neuropathic complications, nephropathy, or retinopathy was noted in the diabetic subjects. Higher plasma concentrations of SDF-1a as well as higher pure-tone thresholds were found in diabetic subjects. This trend increased as pure-tone hearing thresholds worsened. Correlations also were found between SDF-1a concentration, duration of diabetes, and body mass index, with higher concentrations in those with a longer duration of illness and higher body mass index. From this, the authors state, in combination with the known heightened risk of vascular pathologies in long-time type 2 diabetic patients and the phenomenon of presbyacusis, the question can be raised whether long-time exposure to elevated plasma SDF-1a in a diabetic patient with raised BMI can be observed as an audiologic risk factor. 22 The data from this study support the role of microangiopathy in diabetic hearing loss, as well as provide interesting information on the possible benefit that blood testing may have in discovering the link between diabetes and hearing loss in future studies. Oxidative stress effects on the auditory status of diabetics were recently investigated. Aladag et al 9 obtained audiometric data and fasting blood samples from 63 type 2 diabetics with no evidence of microangiopathy or neuropathy and 37 nondiabetic controls. Further separation of subjects in each group was based on presence or absence of sensorineural hearing loss as determined by a pure-tone average greater than or equal to 30-dB hearing level. The results indicated that diabetic subjects had significantly higher serum levels of protein oxidation products, nitric oxide, enzymatic antioxidant activity (i.e., glutathione peroxidase and superoxide dismutase), compared to the control group. 9 When comparing levels based on the presence or absence of hearing loss, it was found that diabetic subjects with normal hearing had significantly higher levels of nitric oxide compared with diabetic subjects with hearing loss and healthy controls with normal hearing. In both hearing-impaired groups, there was significantly higher levels of glutathione peroxidase activity... superoxide dismutase activity and protein oxidation products, compared with subjects with normal hearing. 9 Based on these data, it appears the role of oxidative stress in hearing loss in diabetes is significant and that nitric oxide may provide a defense against hearing impairment. IDDM is thought to be a more severe type of diabetes than NIDDM. 23 Due to this, Austin et al 23 hypothesized that 77 veteran participants with IDDM would have higher puretone thresholds than 88 participants who did not take insulin. Diabetic study participants and healthy controls were divided into three age categories: less than 50 years old, 50 to 56 years old, and greater than 57 years old, with a maximum age set at 70 years old. A significant correlation was found between blood glucose level and hearing thresholds at 250 and 500 Hz for all age groups. A significant correlation was also found between HbA1c levels and pure-tone thresholds at 500 Hz, which was stronger in the youngest age group. When the hearing thresholds for each age group were compared with each other, they were found to increase in general for the diabetic patients in all age groups as frequency increased. 23 The differences were more significant for the younger participants with diabetes and were not as significant for the older diabetic participants. Older participants with IDDM have significantly higher thresholds than those without diabetes. The authors state that diabetes mellitus severity appears to have an important effect on hearing even after adjusting for the age of the patient, but the magnitude of that effect depends on the age of the patient and the test stimulus frequency. 23 The data from this study show that individuals with diabetes have higher pure-tone thresholds than those without diabetes, and this difference is more noticeable in younger subjects in the high frequencies. In older subjects with IDDM, the differences were more noticeable in the lower frequencies. Additionally, young participants with NIDDM demonstrated higher thresholds than those with IDDM, disagreeing with the original hypothesis. The authors support the use of high-frequency audiometry in young subjects to examine the progression of

9 340 SEMINARS IN HEARING/VOLUME 32, NUMBER high-frequency hearing loss, because they showed the greatest differences in that frequency region. The authors state that patient age and insulin usage are related to the differences found in hearing thresholds. Because this study focused on veterans, noise exposure was an issue. The authors examined the differences in hearing threshold with self-reports of noise exposure for all age groups. They found the differences in hearing thresholds were not accounted for by history of noise exposure. The results support that young diabetics with less than a moderate sensorineural hearing loss are at an increased risk for hearing loss, compared with nondiabetic individuals. In addition, the authors reported that chronic hyperglycemia may lead to cochlear damage, and thus duration of diabetes could be a significant factor in hearing loss for diabetic individuals. 23 TIPS FOR AUDIOLOGISTS As evidenced by the previously discussed literature and supported by the careful medical management of diabetic individuals in other health care professions, audiologists must make a thorough analyses of auditory function and adjust clinical protocols accordingly. 13 Proposals have been set forth in the research providing valuable and clinically relevant information for developing best practice in diabetic hearing health care. Hearing screening to determine the need for further diagnostic testing may easily be performed at community events targeted toward diabetic individuals or at the office of the primary care physician. 24 Diagnostic testing with the use of high-frequency audiometry on all diabetic patients will provide the clinician with information that may lead to further testing, such as ABR and OAEs, because subclinical auditory impairment can be observed through these tests on some patients. 23 Abnormalities in ABR can be present in patients without hearing or vision deficiencies. 4,5,10,17 21,25 However, performing these tests in the clinic without subjective auditory complaints and/or evidence of hearing loss by means of behavioral testing may not be justified. On the other hand, there may be a possibility of a subclinical complication when abnormal ABR findings are present, as reported by Bayazit et al. 17 The combined use of ABR and standard laboratory testing from the physician may serve as a predictor for diabetic complications; however, further research is still needed in this area. The detection of diabetic complications through ABR testing may be feasible in the future, once standards are established for such purposes. 17 Combining audiological and laboratory tests also was supported by Loader et al, 22 who suggested using serological studies in conjunction with clinical tests to aid in screening for prognostic and pathophysiologic factors in otologic microangiopathy, 22 thus expanding knowledge in the area of diabetic hearing loss. From a clinical standpoint, the authors reported that increased body mass index and longer duration of illness may serve as risk indicators for hearing loss. Furthermore, relationships between hearing loss, diabetes duration, metabolic control, and diabetic complications have received much attention in the literature. Durmus et al 20 suggested careful monitoring of metabolic status when an abnormality in auditory-evoked potential testing is observed, to prevent further VIIIth nerve damage. Interestingly, Virtaniemi et al 26 found that prolonged ABR latencies observed in baseline testing did not decrease when metabolic status improved in subjects with type 1 diabetes, suggesting that poor metabolic control is not a direct factor in diabetic hearing loss. If future research indicates a consistent relationship between duration of diabetes, poor metabolic control, diabetic complications, and auditory impairment among diabetic individuals, clinical standards can be created to assess patients with these possible risk factors. Synergistic effects of risk factors also may be of concern. Noise exposure may put diabetics at a higher risk for hearing impairment than nondiabetics as the two risk factors may combine and elevate hearing thresholds further than expected. Microvascular disease seen in diabetes may increase the risk of noise-induced hearing loss, due to compromised antioxidant molecule delivery, possibly reducing the chance of recovery from a temporary threshold shift from noise. 24 As a result, counseling about noise exposure and hearing protection is of

10 THE ASSOCIATION OF HEARING LOSS WITH DIABETES MELLITUS/WOLFE ET AL 341 the upmost importance when emphasizing the preservation of residual hearing. 24 Early intervention and prevention of hearing loss is one of the main objectives for audiologists; therefore, the proposed clinical management of diabetic patients may eventually lead to the formal development of a specific clinical protocol for this at-risk population. Assessment of the clinical efficacy of intervention strategies for diabetic patients in formal longitudinal studies as well as in evidencebased practice is necessary and will aid in determining the most appropriate audiological care. 21 CONCLUSION Harmful effects of diabetes mellitus may extend to the auditory system in some individuals. Consequently, it is essential the audiologist and primary care physician are aware of this risk and the associated test findings to assist in the differential diagnosis of these patients. As many aspects of diabetes may act synergistically upon the auditory system, future research using large subject groups in longitudinal studies, and implementing a combination of current and novel test methods will provide increased insight into the complexities of this relationship. ACKNOWLEDGMENT The authors wish to thank Alyson M. Gruhlke, B.A., for her assistance in preparing this manuscript. REFERENCES 1. Centers for Disease Control and Prevention (CDC). National diabetes fact sheet, National estimates and general information on diabetes and prediabetes in the United States. Available at: pdf/ndfs_2011.pdf. Accessed September 24, World Health Organization (WHO). WHO Region of the Americas Available at: en/index3.html. Accessed July 20, Centers for Disease Control and Prevention (CDC). National diabetes fact sheet, General information and national estimates on diabetes in the United States. Available at: Accessed July 20, Pessin AB, Martins RH, Pimenta WdeP, Simões AC, Marsiglia A, Amaral AV. Auditory evaluation in patients with type 1 diabetes. Ann Otol Rhinol Laryngol 2008;117: Lisowska G, Namysłowski G, Morawski K, Strojek K. Early identification of hearing impairment in patients with type 1 diabetes mellitus. Otol Neurotol 2001;22: 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 Ann Intern Med 2008;149: Frisina ST, Mapes F, Kim S, Frisina DR, Frisina RD. Characterization of hearing loss in aged type II diabetics. Hear Res 2006;211: Lisowska G, Namysłowski G, Morawski K, Strojek K. Cochlear dysfunction and diabetic microangiopathy. Scand Audiol Suppl 2001;(52): Aladag I, Eyibilen A, Güven M, Ati O, Erkokmaz U. Role of oxidative stress in hearing impairment in patients with type two diabetes mellitus. J Laryngol Otol 2009;123: Ren J, Zhao P, Chen L, Xu A, Brown SN, Xiao X. Hearing loss in middle-aged subjects with type 2 diabetes mellitus. Arch Med Res 2009;40: Kishore P. Diabetes mellitus Available at: and_metabolic_disorders/diabetes_mellitus_dm/ diabetes_mellitus.html?qt¼kishore&alt¼sh. Accessed July 2, Saudek C, Rubin R, Shump C. The Johns Hopkins Guide to Diabetes for Today and Tomorrow. Baltimore, MD & London, UK: The Johns Hopkins University Press; Diniz TH, Guida HL. Hearing loss in patients with diabetes mellitus. Braz J Otorhinolaryngol 2009;75: Taylor IG, Irwin J. Some audiological aspects of diabetes mellitus. J Laryngol Otol 1978;92: Fukushima H, Cureoglu S, Schachern PA, et al. Cochlear changes in patients with type 1 diabetes mellitus. Otolaryngol Head Neck Surg 2005;133: 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: Bayazit Y, Yilmaz M, Kepekçi Y, Mumbuç S, Kanlikama M. Use of the auditory brainstem response testing in the clinical evaluation of the patients with diabetes mellitus. J Neurol Sci 2000; 181:29 32

11 342 SEMINARS IN HEARING/VOLUME 32, NUMBER Díaz de León-Morales LV, Jáuregui-Renaud K, Garay-Sevilla ME, Hernández-Prado J, Malacara- Hernández JM. Auditory impairment in patients with type 2 diabetes mellitus. Arch Med Res 2005;36: Vaughan N, James K, McDermott D, Griest S, Fausti S. Auditory brainstem response differences in diabetic and non-diabetic veterans. J Am Acad Audiol 2007;18: Durmus C, Yetiser S, Durmus O. Auditory brainstem evoked responses in insulin-dependent (ID) and non-insulin-dependent (NID) diabetic subjects with normal hearing. Int J Audiol 2004; 43: 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: Loader B, Stokic D, Riedl M, et al. Combined analysis of audiologic performance and the plasma biomarker stromal cell-derived factor 1a in type 2 diabetic patients. Otol Neurotol 2008;29: Austin DF, Konrad-Martin D, Griest S, McMillan GP, McDermott D, Fausti S. Diabetes-related changes in hearing. Laryngoscope 2009;119: AgrawalY,PlatzEA,NiparkoJK.Riskfactors for hearing loss in US adults: data from the National Health and Nutrition Examination Survey, 1999 to Otol Neurotol 2009;30: Padam A, Puri R, Sharma ML. Brainstem auditory evoked potential in diabetes mellitus. Indian J Physiol Pharmacol 2002;46: 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: