Diabetes and Auditory-Vestibular Pathology

Abstract

The relationship between diabetes mellitus (DM) and the auditory/vestibular system has been investigated for more than a century. Most population-based investigations of hearing loss in persons with diabetes (PWD) have revealed a slow progressive, bilateral, high-frequency sensorineural hearing loss. Despite the growing research literature on the pathophysiology of DM-related hearing loss using various animal models and other human studies, knowledge of specific mechanism of the degenerative changes of the inner ear and/or auditory nerve is far from full elucidation. Recent investigations of the mechanisms underlying the association between hearing loss and DM suggest complex combined contributions of hyperglycemia, oxidative stress resulting in cochlear microangiopathy, and auditory neuropathy. An even lesser understood complication of DM is the effect on the vestibular system. Here we provide an overview of animal and human evidence of pathophysiological changes created by DM and its effects on auditory-vestibular anatomy and function.

In contrast to the large number of clinical and epidemiological studies of DM, very few studies have directly examined the basic pathological interaction between DM and hearing loss. The limited understanding of the cellular and molecular pathways contributing to hearing loss in persons with diabetes (PWD) is likely related to the absence of an appropriate animal model of DM and lack of access to cochlear tissue in humans in vivo.

Role of Glucose and Insulin in the Cochlea

Glucose is the primary energy source for the cochlea. ¹ This energy is required to maintain the large voltage gradient between the sensory receptors of the inner ear and the cochlear fluids, called the endocochlear potential. Experiments creating hypoglycemia reduce the endocochlear potential and cochlear microphonic, a receptor potential primarily generated by the outer hair cells (OHCs). Zuma e Maia and Lavinsky ² gave sheep a bolus injection of insulin and showed reductions in distortion product otoacoustic emissions (DPOAEs). OAEs represent distortions and reflections of the inner ear related to the system's nonlinearity and amplification; OHC integrity is critical to the presence and amplitude of OAEs. The reduction in DPOAEs observed by Zuma e Maia and Lavinsky was primarily limited to the more metabolically demanding basal portion of the cochlea approximately 60 minutes after induction of hypoglycemia. The timeline for these pathophysiological effects may be related to the findings of Juhn and Youngs ³ who reported that glucose levels in cochlear fluids parallel those in the blood, albeit with a delay of about an hour between the time of maximum concentration of glucose in cochlear fluids and maximum concentration in blood. A further delay has been observed for changes to cochlear microphonic amplitude of approximately 2 to 3 hours.

Insulin is an anabolic polypeptide hormone with numerous roles at plasma membrane, cytoplasmic, mitochondrial, and genomic levels. The regulation of glucose uptake and metabolism is one of the major actions of insulin, but not all tissues are subject to this function. High-affinity insulin receptors exist in the cochlea, but the role of insulin within the inner ear is not believed to regulate glucose uptake, rather primarily functioning in protein synthesis and phospholipid signaling. ⁴

Diabetes and Auditory/Vestibular System: Evidence from Animal Models

Animal Models of Diabetes Mellitus

The most commonly used animal model of DM is the streptozocin (STZ)-treated rat. Most studies of DM and hearing loss in animals have used this model, ^{5 6} including those examining susceptibility to noise-related hearing loss. ^{7 8 9} However, the problem with this model is that STZ itself may interfere with hair cell metabolism and obscure direct effects of DM on auditory function. ¹⁰

A second model, the rat-strain SHR/N-cp, is a rat that develops DM-like symptomology at 12 months of age. This model also has been used in auditory function studies, ¹¹ including noise. ¹² However, cochlear pathology in the model was demonstrated at 5 months of age, which was 7 months prior to the animal being diagnosed with “diabetes.” Therefore, the cause may represent a genetic mutation rather than direct effect of DM itself. Ishikawa et al ¹³ studied another rat model, the WBN/Kob rat, that developed symptoms consistent with pre-DM at 6 to 7 months of age and DM at 12 to 13 months of age. The WBN/Kob rat shows changes in auditory brainstem response (ABR), an auditory-evoked potential that represents the onset neural response of the auditory nerve and brainstem, number of afferent neural fibers, and stria vascularis integrity. The T2DM rat is a strain developed in 2004 that develops diabetes nephropathy. Arteaga et al ¹⁴ showed significant decline in ABR with age compared with age-matched controls. At younger ages, the T2DN rats showed higher suprathreshold ABR wave I amplitude suggesting hyperglycemic increase in aggregate neural response. Another model of type-2 DM, the Goto-Kakizaki rat (GK rat), has not been examined for effects on auditory function.

The non-obese diabetic (NOD) model of mice also has been used to study auditory function, in particular autoimmune effects of DM. ^{15 16 17} Another mouse model, the ob/ob mouse (OM), represents a model of DM (specifically T2DM) and obesity. The ob/ob mouse has demonstrated early onset of hearing loss with age, specifically loss of cochlear and neural cells. Yet, the probable compounding effects of concurring leptin deficiency in this model along with severe obesity and hyperglycemia has not been clearly ruled out when explaining these auditory effects.

Finally, hyperinsulinemia/diabetes has been explored in the rhesus monkey. ¹⁸ This model was justified, as the rhesus monkeys are phylogenetically similar to humans than other research animals and also provide a better model for examining the effects of age and diet restrictions on the auditory system. The study by Fowler et al ¹⁸ included three groups of eight monkeys (matched for age and sex): calorie-restricted monkeys that have a reduced risk of hearing loss, normal control group, and a group of diabetic monkeys with fasting hyperinsulinemia (>90th percentile). The auditory measures that were investigated included DPOAEs ( f ₂ frequencies from 2,211 to 8,837 Hz) and ABRs for clicks and tonebursts (8, 16, and 32 kHz). The findings suggested primary damage to the basal region of the cochlea with reduced DPOAEs for higher frequencies. Although the ABR thresholds for the diabetic group were several decibel higher (worse) than those of the control (normal and caloric restricted) groups, these results were not significant. Another important finding from this study was that the deteriorating effects of the auditory function began at the hyperinsulinemic, prediabetic stage.

Thus, it appears that no particular animal model of DM is perfect and much work is needed in understanding the cellular and molecular influences of DM on susceptibility to hearing loss. The primary pathological findings in these studies examining animals with “diabetes” are OHC loss (with mostly preserved inner hair cells), pathological changes of the stria vascularis, reduced endocochlear potential (the battery that drives cochlea involving K+ recycling with the stria vascularis), and changes in afferent auditory nerve fiber integrity.

Biochemical Hypotheses

DM, or more specifically hyperglycemia, initiates a complex cascade of biochemical consequences. Three main effects are nonenzymatic glycation, activation of the polyol pathway, and generation of reactive oxygen/nitrogen species. Metabolic processes disrupted include energy production, abnormal accumulation of metabolic by-products, nitric oxide and glutathione dysregulation, glycation (advanced glycation end products), lipid balance abnormalities, and protein synthesis dysfunction. Tissue damage associated with DM includes endothelial, neural, extracellular, and collagen compromise. ¹⁹ Upregulation of vascular endothelial growth factor (VEGF) and nitric oxide isoforms has been demonstrated in the cochlea of DM rats. ²⁰

Increased oxidative stress also has been implicated in DM pathogenesis and comorbidities associated with DM including hearing loss. ²¹ Attempts have been made to correlate oxidative stress with glycated hemoglobin (Hb _A1c ). ^{22 23} Autoimmune factors have been associated with both DM and hearing loss. However, the precise interaction of autoimmune disease, DM, and hearing loss has been elusive. In NOD mice models of autoimmune effects, the main implications are believed to be related to strial pathology. In the case of T1DM, primary damage involves inflammatory infiltration and destruction of organs and connective tissue. By contrast, cochlear pathology in these mice does not show inflammation, but instead immunoglobulins that bind to endothelial cells and capillary basement membranes. ¹⁶ The cumulative effects of these biochemical changes contribute to damage of blood vessels and compromised metabolic function. The high-energy demands of the cochlea could be disrupted by these changes, particularly with additional stimulation-related demands (e.g., noise exposure).

Noise and Diabetes Mellitus Interaction

The effects of noise exposure alone on hearing are well documented. Noise-induced damage is related to both mechanical and metabolic compromise. Overexposure to noise can alter cochlear homeostasis resulting in excessive reactive oxygen/nitrogen species, vascular changes (an initial ischemia followed by reperfusion), activation of apoptosis-like pathways (e.g., Bcl-2 family), excitotoxic events (excessive glutamate), and subsequent cellular damage. ²⁴ The pathological effects of noise on the auditory system may be exacerbated by the consequences of genetic, autoimmune, and biochemical interactions associated with DM discussed earlier.

Controlled animal experiments have demonstrated a more significant loss of OHCs in noise-exposed rats with DM (STZ injected) compared with noise-exposed controls but without consideration of molecular mechanisms and relationship with glucose metabolism. ^{7 8} McQueen et al ¹² found significant basement membrane thickening of the cochlea (microangiopathy) in rats (SHR/N-cp) with DM, however only in the combination with obesity and/or exposure to noise. Wu et al ⁹ found that rats (STZ injected) with DM demonstrated impaired recovery from a noise-induced temporary threshold shift (TTS); this recovery was improved to control levels with insulin treatment. Fujita et al ²⁵ showed significant changes to spiral ganglion despite preservation of hair cells following a TTS-inducing noise exposure in DM rats compared with controls.

Age-Related Hearing Loss and Diabetes Mellitus

Lee et al ²⁶ showed early onset of hearing loss with age in the ob/ob mouse compared with wild-type controls with damage to cochlear and neural cells. Vasilyeva et al ¹⁷ examined the interaction of age and DM in two animal models, one representative for T1DM (STZ) and a second representative of T2DM (dietary induced). The results demonstrated reduced auditory function in both models, but the ABR thresholds and wave I amplitudes were significantly altered only in the T2DM model.

Ototoxicity and Diabetes Mellitus

There is limited study on ototoxic drugs and risk for hearing loss in animal models of DM. Garcia-Quiroga et al ²⁷ demonstrated protection against kanamycin-induced ototoxicity in hyperglycemic animals. Kanamycin competes with glucose transport and thus, paradoxically, hyperglycemia may help control this pathway for damage.

Vestibular Impairment and Diabetes Mellitus

Little animal work has explored vestibular deficits of DM. Perez et al ²⁸ found prolonged latency and reduced amplitudes for vestibular evoked potentials, although no histological evidence was provided. Myers et al ²⁹ reported on myelin-sheath abnormalities of the vestibular nerve. Myers and his group had previously described morphological changes in the utricle and saccule as well. ^{30 31}

Summary of Animal Studies

Evidence for increased risk of noise and age-related neuropathology also has been demonstrated in DM animal models ^{9 17 25} and is consistent with the prolonged latency and decreased amplitude of the ABR in humans with DM. ³² Possible mechanisms proposed included microangiopathy, abnormal accumulation of metabolic by-products due to mitochondrial dysfunction (e.g., oxidative stress), glutathione dysregulation, glycation, and protein synthesis dysfunction. ³³ Anjaneyulu et al ³⁴ suggested glutamate excitotoxicity and, in particular, compromised metabotropic glutamate receptor function underlying DM neuropathologies. Glutamate excitotoxicity is also a hypothesized mechanism contributing to noise-induced synaptopathy. ³⁵ Overall, the literature suggests that PWD may have increased susceptibility to acquired auditory neuropathology including that related to noise.

Animal models of diabetes are limited. However, in general they show that the cumulative effects of diabetes contribute to damaged blood vessels and compromised metabolic function; comparable changes have been attributed to vision deficits in PWD. The high-energy demands of the cochlea could be disrupted by these changes, particularly with additional demands created by noise exposure. Human studies of diabetes have generally excluded individuals with a history of noise exposure or ignored the potential interaction between noise and diabetes on hearing status. Furthermore, no animal models have considered tinnitus and DM or central auditory deficits beside changes in ABR responses.

Diabetes and Auditory/Vestibular System: Evidence from Human Pathophysiology

The primary clinical manifestation of DM is that of a metabolism disorder of glucose, lipid, and protein secondary to an impaired production and/or metabolism of insulin. The elevated blood glucose levels result in increased deposits of glycated hemoglobin on the vascular walls, abnormal growth of endothelial cells, and elevated blood lipid levels which all contribute to arthrosclerosis characterized by thickening of the basement membranes of the vessels. The constricting effect of DM on the vessels appears to be more pronounced on body systems that are dependent on microvascular supply. ³⁶ One such system would be the cochlea that depends on an intricate microcirculation to provide energy and substrates, dispose metabolic waste, and maintain internal homeostasis.

Although histopathological investigations of the inner ears of PWD have dated back to the early 1960s, ³⁷ the pathophysiology of the auditory deficits associated with DM still remains hypothetical. ²¹ DM is known to affect the microvasculature and neuronal tissues of the retina, kidneys, and other skeletal muscles leading to retinopathy, nephropathy, and neuropathy. The underlying pathophysiological mechanisms are believed to be hyperglycemia-induced oxidative and nitrosative stress, which in turn results in endothelial dysfunctions and DNA damage at a cellular level. ³⁸ These histological changes are believed to be the underlying cause of the significant complications related to DM such as vascular ischemia in neural tissue resulting in atrophy and demyelination. ³⁹

Human Anatomical and Physiological Effects of Diabetes Mellitus

Human Temporal Bone Studies

Microscopic analyses of cadaver temporal bones of PWD by several researchers ^{40 41 42 43 44} have suggested a spectrum of pathogenic mechanisms in the peripheral auditory system of long-standing diabetes. Significant changes include thickening of the capillaries in the stria vascularis, ^{40 41} demyelination of the vestibulocochlear nerve, narrowing of the internal auditory artery, thickening of the basilar membrane, and degeneration of inner and outer hair cells of the cochlea. ^{11 15 26 45} Investigations ^{11 40 45} indicate that OHCs, particularly at the basal turn of the cochlea, are more susceptible to damage than the inner hair cells of individuals with long standing (> 15 years) T1DM. Diabetes appears to accelerate and exaggerate cochlear presbycusis in these individuals. Wackym and Linthicum ⁴⁶ also revealed a relationship between the degree of microangiopathic changes in the basilar membrane and percentage of histologically normal hair cells within PWD. Diabetes also has been associated with the significant atrophy of fibrocytes in the spiral ligament ⁴⁰ and loss of spiral ganglion neurons ⁴³ ; both anomalies appear to be independent of aging effects.

Histologic investigations of the temporal bones of PWD reveal pathological changes in different cochlear cell types, particularly in densely vascular regions of the stria vascularis, spiral ganglion, and spiral ligament along the basal turn of the cochlea. ³⁸ Not all of the studies revealed the same syndrome of histopathological changes and variability in the degree of abnormality exists, particularly across the different cell types within the cochlea. This variability is hypothesized to be because different cochlear cells have different mechanisms of glucose and insulin transportation that renders them differentially susceptible to toxic effects of hyperglycemia. ⁴⁷

Auditory: Peripheral System Physiology

The most common histopathological findings in the inner ear of PWD are related to microangiopathy characterized by atrophic changes in the vascular membranes of the stria vascularis, basilar membrane, and the endolymphatic sac (for a review, please refer to the study of Akinpelu et al ³⁸ ). The generation of the endocochlear potential, that drives the cochlear transduction process, depends on a continuous metabolism of oxygen and glucose from the stria vascularis. Thus, any disruption or insufficiencies in these vascular networks may underlie some of the peripheral auditory complications (i.e., sensory hearing loss) related to diabetes.

Another pathophysiological mechanism related to diabetic microangiopathy is the compromised macrophagic activity that is responsible for the migration of waste products from areas such as the endolymphatic sac. ⁴⁶ Inadequate removal may result in accumulation of high molecular waste products and debris that will have toxic effects on inner ear hair cells leading to hair cell dysfunction. Thus, the detrimental effects of the accumulation of the toxic waste may be related to the statistically significant relationship ⁴⁶ between hearing loss and microvascular changes in the endolymphatic sac of PWD.

Recent investigations have suggested that oxidative stress (decreased serum levels of nitric oxide and vitamins C and E and increased nitric oxide levels) ²¹ may play an important role in hearing impairment in PWD.

Auditory: Central System Physiology

The vascular abnormalities and sustained high glucose levels secondary to DM also result in affecting the cranial nerves beginning with malnourishment and progressing to dysplasia and necrosis of the nerve cell membrane and demyelization. ⁴⁸ These changes are believed to result in reduced conduction efficiency, which is the hallmark of diabetic peripheral neuropathy. Other degenerative changes in the auditory brainstem pathway include ischemia and sclerosis in the ventral and dorsal cochlear nuclei, inferior colliculus, and medial geniculate body. ⁴⁴

These pathological effects likely underlie the specific impairments of the auditory brainstem function in PWD that are reflected as abnormal ABR responses such as prolonged peak and interpeak latencies and reduced peak amplitudes. ^{32 49 50} The auditory neuropathic complications may also be responsible for the degraded neural temporal coding in the upper brainstem resulting in central auditory processing deficits such as higher interaural phase differences, poorer frequency discrimination limens, and increased gap detection thresholds. ⁵¹

Vestibular Apparatus

Epidemiological studies have revealed that the odds for vestibular dysfunction are 70% higher in adults with DM ⁵² and an increased risk for falls appears to be independent of the presence of peripheral neuropathy and retinopathy. Several investigators have reported on morphological and physiological changes in the peripheral vestibular apparatus in experimental animal models of diabetes. ^{28 30} However, histopathologic changes that may underlie the association between DM and vestibular dysfunction have not been characterized in humans and there is a dearth of literature on this area. A human temporal bone study ⁵³ revealed a significantly increased presence of cupular and free-floating deposits in the lateral and posterior semicircular canals of T1DM. They associated the resulting ectopic otoconia with the increased probability of benign paroxysmal positional vertigo in PWD. ⁵³ Other temporal bone abnormalities in the vestibular anatomy include significantly lower (i.e., 16–17%) density of type I vestibular hair cells among the saccules of diabetic subjects. ⁵⁴

Summary

Animal and human evidence supports DM and DM-related consequences (e.g., hyperglycemia) as pathological to the auditory-vestibular system. Animal models of DM are limited by how reflective the model is to the human condition. Human research of DM pathophysiology is limited by accessibility to cochlear tissues. In general, animal and human research supports that the cumulative effects of diabetes contribute to damaged blood vessels and compromised metabolic function; comparable changes have been attributed to vision deficits in PWD. The high-energy demands of the cochlea could be disrupted by these changes, particularly with additional demands created by noise exposure.