Auditory function is pivotal in shaping our social interactions, serving as a fundamental component for both the reception and expression of language, thereby underpinning effective communication. Unfortunately, hearing loss has emerged as a highly prevalent sensory impairment globally. The global prevalence of Sensorineural hearing loss (SNHL) was initially documented by the World Health Organization (WHO) in 1985 (1). According to the latest assessment by the WHO, approximately 466 million individuals, constituting 6.1% of the global population, were affected by disabling hearing loss in 2018. Projections indicate that this figure is anticipated to escalate to 630 million by 2030 and surpass 900 million by 2050 (2). SNHL, characterized by impaired perception of sound and compromised nerve impulse conduction due to lesions in the hair cells of the spiral apparatus, the auditory nerve, or various hearing centers, represents a significant challenge (3, 4). Notably, adults afflicted with SNHL often contend with mental disorders, depression, and heightened occupational stress compared to their unaffected counterparts (1). This predicament not only poses a substantial and intricate economic burden on society and public health but also profoundly influences the overall well-being and mental health of those affected. Effectively addressing and mitigating the impact of SNHL remains an ongoing challenge. In recent years, the correlation between hearing impairments and both type 1 (5) and type 2 (6) diabetes is widely acknowledged. A meta-analysis incorporating cohorts of both type 1 and type 2 diabetes patients revealed a consistent association between diabetes and hearing impairment across both diabetes types. Notably, it is essential to recognize that prediabetes constitutes a risk factor for developing type 2 diabetes and often coexists with the same comorbidities associated with type 2 diabetes (7). Insulin resistance (IR) is a pivotal factor in the progression toward type 2 diabetes (T2D) and is prevalent in the majority of prediabetic (preDM) individuals (8).

IR manifests as a diminished sensitivity and responsiveness to insulin’s actions, often preceding the onset of diabetes mellitus by several years (9). Recent studies increasingly highlight the close association between IR and the aging process. Both IR and SNHL are conditions intertwined with aging, featuring complex and multifactorial pathogeneses. However, despite the acknowledged overlap, there exists a dearth of conclusive information regarding the impact of IR on SNHL. The Triglyceride-Glucose (TyG) index, a composite metric derived from fasting triglyceride and blood glucose levels, serves as an evaluative measure for IR (10). In contrast to conventional methods for assessing insulin resistance (IR) like the hyperinsulinemic-euglycemic clamp technique and the homeostasis model assessment for IR, the TyG index distinguishes itself through its notable cost-effectiveness and straightforward acquisition process (11). Hence, our study aims to elucidate the relationship between the TyG index and SNHL among participants in the National Health and Nutrition Examination Survey (NHANES).

To appraise the influence of the TyG index on the prevalence of SNHL, our initial step involved conducting an observational study utilizing data sourced from the United States population as recorded in the NHANES database (12). Moreover, we applied a Mendelian randomization (MR) approach to thoroughly examine the causal association between circulating lipid and glucose levels and the risk of SNHL. This method facilitates the deduction of causal relationships using genetic instrumental variables (IVs). Leveraging the attributes of random assortment and consistency within germline genotypes, MR holds the potential to mitigate biases stemming from confounding and reverse causation, challenges commonly encountered in observational epidemiology (13).

We utilized genome-wide association studies (GWAS) data from publicly available trials and United States population data extracted from the NHANES database. All the datasets employed in this study have received approval from the ethics committee, obviating the need for separate ethical clearance.

In our cross-sectional study involving 1,851 participants, we present, to our knowledge, the first retrospective investigation with a notably substantial sample size examining the association between the TyG index and SNHL patients. Our study identified an L-shaped relationship between the TyG index and SNHL patients in this cohort, revealing a distinctive turning point at 9.07. This indicates a significant association between elevated TyG index levels and an increased risk of SNHL within a specified range. Notably, our examination of the relationship between fasting glucose and SNHL also revealed an L-shaped pattern, with an inflection point at a fasting glucose level of 94 mg/dL. This implies that maintaining glucose levels within a certain range may impart a protective effect on hearing—a nuanced observation seldom discussed in existing literature. By uncovering these intricate relationships, our study offers valuable insights that could inform strategies for reducing the risk of SNHL and, consequently, contribute to shaping clinical and dietary guidelines. Our findings underscore the importance of individuals with insulin resistance taking proactive measures to prevent hearing loss. This includes maintaining blood glucose within a specific range and adopting a balanced diet. Notably, the broader observation that adherence to a healthy diet correlates with a reduced risk of hearing loss has recently been confirmed in the Nurses’ Health Study II. Participants who adhered to a Mediterranean-style diet or a diet low in processed foods and rich in dietary fiber were less likely to experience hearing loss during a 20-year follow-up period (21). Additionally, individuals with diabetes should be cognizant of the potential association between a higher TyG index and SNHL.

The role of lipids in the pathogenesis of SNHL is extensively discussed in the literature. The cochlea, being an end organ, relies on a continuous supply of nutrients and oxygen to maintain its physiological functions. It exhibits heightened sensitivity to fluctuations in blood circulation (22). Elevated blood viscosity may diminish blood supply to the inner ear, potentially causing inner ear damage (23). Disorders of lipid metabolism can lead to lipid deposition in cochlear hair cells and harm to cochlear nerve cells, impeding nerve conduction (24), Hyperlipidemia is frequently observed in individuals with SNHL (24, 25). and studies have shown that dietary control and lipid-lowering therapy can ameliorate hearing loss associated with cholesterolemia (26). Conversely, the relationship between blood glucose and hearing loss has been approached differently in previous research. While some argue that the auditory system requires glucose for its intricate signal processing and high-energy utilization, others propose that hyperglycemia may adversely affect the cochlea. Increased glucose exposure, even for brief periods, can trigger a metabolic cascade disrupting the cochlea anatomically and physiologically (27). Studies in animal models suggest that combining hyperglycemia with hyperlipidemia and atherosclerosis could exacerbate age-related hearing loss in apolipoprotein E (ApoE)-deficient male mice (28). However, there are conflicting findings, with other research demonstrating that glucose supplementation can protect cochlear hair cells against oxidative stress and noise-induced hearing loss (29), aligning with our Mendelian randomization study that indicates serum glucose has a protective effect against neurological hearing loss. In our NHANES cohort study, we identified an L-shaped relationship between fasting blood glucose and SNHL, with the inflection point at 94 mg/dL. This sheds light on potential explanations for divergent conclusions in prior studies: blood glucose levels exceeding 94 mg/dL increase the risk of sensorineural deafness, emphasizing the importance of maintaining blood sugar levels within a specific concentration range for hearing protection. This phenomenon may be due to the fact that the auditory system is dependent on glucose and high energy for complex signal processing. However, when hyperglycaemia persists, it adversely affects auditory system function through mechanisms such as microvascular lesions, advanced glycosylation end-products and excessive reactive oxygen species (ROS) production, ultimately impairing cochlear function. For instance, the vasodilatory effects of nitrous oxide are compromised in the presence of hyperglycemia and its associated advanced glycosylation end-products, triggering protein kinase C activation and diminishing nitric oxide synthase production (30). Maintaining a critical balance of nitric oxide is crucial for the optimal long-term health of cochlear sensory and support cells. Nitric oxide is strategically situated in key cochlear blood vessels, including the spiral modiolar, basilar membrane, and spiral osseous lamina vessels. Additionally, it is present in vessels proximate to the spiral ganglion, inner and outer hair cells (31, 32). Nitric oxide plays a pivotal role in regulating the cochlear vascular endothelium by responding to ATP-induced increases in cochlear blood flow. Furthermore, it contributes to antithrombotic activity, as well as the regulation of vascular tone and cellular growth (33).

Emerging evidence from animal models underscores the pivotal role of mitochondrial dysfunction and oxidative stress in SNHL pathogenesis (34–36). Mitochondria, as cellular organelles, play crucial roles in cellular activities including metabolism, energy production, apoptosis, and redox signaling (37). Thus, mitochondria become important regulators of cell survival and death. Mitochondria produce ROS by oxidative phosphorylation. The ROS molecules, superoxide anion and hydroxyl radicals that make up ROS, as well as hydrogen peroxide, play crucial roles as cell signaling molecules in cell proliferation, gene expression, and survival (37). Under physiological conditions, ROS levels in cells are regulated by various endogenous antioxidant enzymes. This regulation is essential for the maintenance of cellular homeostasis. However, an imbalance between ROS production and the cellular antioxidant defense system leads to oxidative stress. Oxidative stress in turn causes irreversible damage to cellular components such as proteins, DNA, lipids and other macromolecules. This damage impairs physiological functions and may ultimately lead to cell death. Given the cochlea’s high metabolic demands, particularly in hair cells, vascular striae, and spiral ganglion neurons, these structures are susceptible to the detrimental effects of mitochondria ROS (37). ROS have been identified in cochlear tissue immediately following noise exposure (38). These ROS persist for 7–10 days afterward, spreading from the basal end of the organ of Corti to the apical turn. Additionally, the reactive nitrogen species product peroxynitrite, formed by the combination of nitric oxide and superoxide, has been observed in this context (39). The prolonged presence of oxidative stress resulting from these species can lead to delayed and sustained cochlear injury. Free radicals, comprising ROS and reactive nitrogen species, elicit damage by interacting with various cellular components such as DNA, proteins, cytosolic molecules, cell surface receptors, and membrane lipids. Mitochondria-generated ROS induce lipid peroxidation in the cochlea, giving rise to byproducts like malondialdehyde and 4-hydroxynonenal (40). This process overwhelms the cochlear antioxidant enzyme system, including superoxide dismutase, catalase, glutathione peroxidase, and glutathione reductase, ultimately depleting glutathione—the endogenous antioxidant. The consistent delivery of glucose from the bloodstream ensures that the demanding energy requirements of neurons in the brain are met, supporting physiologic brain function through ATP production (41). Impaired glucose metabolism in the brain is implicated in various neurological disorders, including neurological hypoglycemia, epilepsy, Alzheimer’s disease, and Parkinson’s disease (42–45). Short-term glucose supplementation has also been demonstrated as crucial for tolerating acute oxidative stress (46).

The risk of SNHL escalates when blood glucose surpasses the identified inflection point. Elevated blood glucose levels can induce various adverse physiological changes, including mitochondrial disruption and the inhibition of ATP production linked to aberrant oxidative phosphorylation (47). While the association between type 2 diabetes and hearing impairment has been acknowledged for some time, recent research underscores the broader impact of IR on diverse conditions, such as diabetic complications, occurring prior to the onset of diabetes (48–50). Although the mechanisms underpinning insulin resistance are not entirely elucidated, there is emerging evidence implicating oxidative stress and impaired mitochondrial function (51). Building upon this understanding, our hypothesis posits that insulin resistance impedes ATP production by elevating blood glucose levels, concurrently influencing the body’s glucose utilization. This, in turn, results in decreased production of NADPH—a pivotal cofactor in cellular detoxification and the antioxidant system. Consequently, cellular dysfunction ensues, compromising cell viability and culminating in functional decline (52). The diminished protective capacity against oxidative stress due to insulin resistance could heighten the risk of hearing damage, with oxidative stress reciprocally exacerbating insulin resistance. Recent findings supporting the protective role of G6PD overexpression against oxidative stress and age-related hearing loss further lend credence to our speculations (52). In our current study, we sought to explore the relationship between insulin resistance and SNHL, employing the TyG index as a surrogate measure. The TyG index, derived from fasting triglycerides and fasting blood glucose, serves as an evaluative metric for insulin resistance. Over the past decade, interest in the TyG index has surged, with demonstrated superiority over the HOMA-IR model in assessing insulin resistance in both diabetic and non-diabetic populations (53). Our findings in the present study reveal an L-shaped relationship between the TyG index and SNHL within the U.S. population. Notably, a TyG index exceeding 9.07 was significantly and positively associated with SNHL risk, elucidating an unfavorable correlation between insulin resistance and hearing loss.

Our study is subject to certain limitations that warrant consideration. Firstly, its cross-sectional nature precludes the establishment of temporal relationships, introducing a constraint in discerning causality. Despite our efforts to adjust for various pertinent confounding factors, the potential influence of additional confounders remains a challenge, necessitating cautious interpretation of our findings. Furthermore, the diagnosis of SNHL in our study predominantly relied on pure-tone audiometry, complemented by normal otoscopic examination and tympanograms with peaks >0.3 ml. This methodology may introduce bias towards the conductive component in hearing loss. However, amidst these limitations, our study boasts notable strengths. Leveraging a nationally representative sample, our findings are reflective of a diverse and gender-inclusive adult population in the United States. Furthermore, our study employed a substantial sample size, enabling subgroup analyses and enhancing the validity and generalizability of the findings. This large sample size contributed to the depth and granularity of the investigation. Finally, we incorporated Mendelian randomization to validate the reliability of observational studies by inferring causality from a genetic perspective.

The original contributions presented in the study are included in the article/ Supplementary Material . Further inquiries can be directed to the corresponding authors.

All procedures conducted by NHANES and GWAS studies involving human participants adhered to the ethical standards of the relevant institutional and/or national research committee. The studies were in accordance with the principles outlined in the 1964 Helsinki Declaration and its subsequent amendments or comparable ethical standards.

YW: Data curation, Investigation, Methodology, Software, Writing – original draft, Writing – review & editing. HL: Writing – review & editing. XN: Writing – original draft, Writing – review & editing. NL: Investigation, Writing – review & editing. SY: Investigation, Writing – review & editing. XW: Writing – review & editing. YZ: Writing – review & editing.