Diabetes mellitus, hearing loss, and therapeutic interventions: A systematic review of insights from preclinical animal models

Abstract

Objectives: The aim of this systematic review article is to evaluate the relationship between diabetes mellitus (DM) and sensorineural hearing loss (SNHL) utilizing preclinical animal models. The review focused on studies assessing SNHL in diabetic animal models, elucidating the mechanisms of DM-associated SNHL, and exploring the response of diabetic animal models to noise overexposure. We also discussed studies investigating the efficacy of potential therapeutic strategies for amelioration of DM-associated SNHL in the animal models.

Methods: A protocol of this systematic review was designed a priori and was registered in the PROSPERO database (registration number: CRD42023439961). We conducted a comprehensive search on PubMed, Science Direct, Web of Science, Scopus, and EMBASE databases. A minimum of three reviewers independently screened, selected, and extracted data. The risk of bias assessment of eligible studies was conducted using the Systematic Review Center for Laboratory Animal Experimentation (SYRCLE) tool.

Results: Following the screening of 238 studies, twelve original articles were included in this systematic review. The studies revealed that hyperglycemia significantly affects auditory function, with various pathological mechanisms contributing to DM-induced hearing impairment, including cochlear synaptopathy, microangiopathy, neuropathy, oxidative stress, mitochondrial abnormalities, and apoptosis-mediated cell death. Emerging interventions, such as Asiaticoside, Trigonelline, Chlorogenic acid, and Huotanquyu granules, demonstrated efficacy in providing otoprotection for preserving cochlear hair cells and hearing function.

Conclusions: Our systematic review delves into the intricate relationship between DM and hearing impairment in animal models. Future research should focus on targeted therapies to enhance cochlear mitochondrial function, alleviate oxidative stress, and regulate apoptosis. The association between SNHL and social isolation as well as cognitive decline underscores the necessity for innovative therapeutic modalities addressing yet undiscovered mechanisms. Translating findings from animal models to human studies will validate these findings, offering a synergistic approach to effectively manage DM-associated co-morbidities such as hearing impairment.

Fig 1. Preferred reporting items for systematic reviews and meta-analyses (PRISMA) flowchart showing the article selection process.

Fig 2. A schematic representation of potential molecular mechanisms underlying diabetes-induced hearing loss.

The hyperglycemia prevalent during diabetes initiates a cascade of pathological events, leading to microangiopathy, oxidative stress, and neuropathy. These molecular events can cause damage to the sensory structures such as stria vascularis, spiral ganglion neurons and hair cells leading to hearing impairment. This damage is measurable through two key auditory tests: distortion product otoacoustic emissions (DPOAE) and auditory brainstem responses (ABRs). DPOAE assesses the function of outer hair cells in the cochlea. A probe with two speakers is inserted into the external ear canal to deliver two different frequency tones (f1 and f2). These tones travel through the ear, reaching the cochlear receptor and generating mechanical distortions at various basilar membrane positions, including the prominent 2f1-f2 location. The interaction of these tones depends on the normal function of outer hair cells, which amplify sound through electromotility. The resulting distortions travel back to the external ear and are recorded by a sensitive microphone, measured as DPOAEs in terms of frequency and amplitude in dB SPL. On the other hand, ABRs is an electrophysiological test that evaluates the integrity of the central auditory pathway from the cochlea to the brainstem. Electrodes placed on the scalp capture electrical activity generated by the auditory nerve and brainstem in response to sound stimuli, usually clicks or tone bursts, delivered through earphones. The recorded neural responses form a characteristic waveform, with several peaks corresponding to different points in the central auditory pathway. The central auditory pathway image was taken from Wikimedia Commons uploaded by Jonathan E. Peelle from https://osf.io/u2gxc/ under the Creative Commons Attribution 4.0 International license. Created with BioRender.com.

Fig 3. Assessment of risk of bias using the Systematic Review Center for Laboratory Animal Experimentation (SYRCLE) tool.