Exploring the impact of diabetes mellitus on dry eye disease and ocular health: a narrative review

Introduction

Background

Diabetes mellitus (DM) is a chronic metabolic disorder defined by persistent hyperglycemia resulting from insufficient insulin production, impaired insulin action, or both. According to the World Health Organization, DM has reached alarming global proportions, affecting approximately 14% of adults aged 18 years and older in 2022—doubling its prevalence since 1990 (1). Notably, more than half of adults over 30 years living with diabetes were not receiving appropriate pharmacological treatment, with the burden of disease being disproportionately higher in low- and middle-income countries. As a result, diabetes remains a leading cause of morbidity and mortality worldwide, directly accounting for 1.6 million deaths in 2021 and contributing significantly to cardiovascular and renal disease mortality through sustained hyperglycemia (1).

This condition affects multiple organ systems, causing complications such as nephropathy, neuropathy, retinopathy, and macrovascular issues like peripheral vascular disease and ischemic heart disease. Among the many systemic complications of DM, ocular involvement is particularly significant, with diabetic retinopathy (DR) representing the most prevalent and extensively studied manifestation (2). DR is a progressive microangiopathy that primarily affects the retinal microvasculature, characterized by increased vascular permeability, intraretinal hemorrhages, lipid exudates, and capillary closure, ultimately leading to the formation of pathological neovascularization on the retina and the posterior hyaloid surface (2)

The incidence and severity of diabetic retinopathy are closely associated with the duration of diabetes, glycemic control, and the presence of comorbid conditions such as hypertension and hyperlipidemia (3).

In addition to retinopathy, DM has been increasingly recognized as a contributing factor to various other ocular pathologies. Notably, it plays a significant role in the development of glaucoma (4). While diabetic patients are particularly susceptible to neovascular glaucoma—a severe secondary glaucoma resulting from fibrovascular membrane proliferation on the anterior iris surface and within the iridocorneal angle, leading to synechiae formation, angle closure, and elevated intraocular pressure (5). There is also evidence supporting a link between diabetes and primary open-angle glaucoma (POAG). In this context, diabetes is considered a potential risk factor for POAG, alongside age, family history of glaucoma, and ocular hypertension. Proposed mechanisms include microvascular compromise and oxidative damage to the optic nerve head, contributing to the pathogenesis of glaucomatous neurodegeneration (6).

Furthermore, diabetic patients exhibit an increased risk for cataract development, particularly age-related (senile) cataracts. This heightened susceptibility is attributed to an enhanced oxidative load in the lens environment, where hyperglycemia-induced free radical production exacerbates oxidative stress and lens protein damage, accelerating lens opacification (7).

Among these complications, diabetic retinopathy has been the most extensively studied, affecting up to one-third of all patients with DM and serving as a reliable marker of systemic disease severity (8).

In addition to these well-documented complications, diabetes has significant effects on the anterior segment of the eye, including changes to the lens, cornea, conjunctiva, lacrimal glands, and other ocular surface structures. These alterations result in abnormal ocular functions, leading to an increased prevalence of conditions such as dry eye disease (DED), recurrent corneal erosions, and delayed corneal wound healing. Collectively, these corneal changes are often referred to as diabetic keratopathy, a lesser-known but equally impactful consequence of diabetes (9,10).

Rationale and knowledge gap

Beyond posterior segment complications, diabetes has a profound yet underrecognized impact on the anterior segment of the eye, particularly the ocular surface. Diabetic keratopathy, encompassing a range of corneal and ocular surface abnormalities, remains underdiagnosed and undertreated despite its clinical significance. While several reviews have addressed the relationship between DM and DED, they often provide a general overview without a detailed analysis of the specific pathophysiological mechanisms by which diabetes affects the ocular surface. Additionally, these reviews frequently overlook recent advances in diagnostic techniques, the impact of metabolic dysregulation, and the clinical implications of systemic diabetic treatments on ocular surface health.

Objective

This narrative review aims to comprehensively explore the complex relationship between DM and ocular surface disease, with a particular focus on DED and diabetic keratopathy. By synthesizing current evidence, the review seeks to clarify the metabolic, inflammatory, and neural pathways involved, discuss diagnostic and screening strategies specific to diabetic patients, and highlight areas for future research. This work intends to fill existing gaps by providing a detailed, integrative perspective that extends beyond what previous reviews have addressed. We present this article in accordance with the Narrative Review reporting checklist (available at https://aes.amegroups.com/article/view/10.21037/aes-25-3/rc).

Methods

This literature review was primarily conducted using the PubMed database, selected for its extensive, well-maintained, and regularly updated repository of biomedical publications, as well as its efficiency in retrieving high-quality and relevant scientific literature.

The search was limited to articles published in English to ensure clarity and accessibility. Titles and abstracts were manually screened for relevance in alignment with the study objectives. Full-text articles were then reviewed to extract detailed information regarding glandular dysfunction, immune mechanisms, neural alterations, and microbiota imbalances involved in the pathophysiology of DED in diabetic patients. Additionally, ocular surgical procedures and their impact on the ocular surface in this population were assessed.

To supplement the electronic search, manual reference tracking of key articles was performed to ensure comprehensive coverage of the topic. This search strategy aimed to provide an integrated overview of the various diabetes-associated alterations that contribute to ocular surface dysfunction and the development of DED. The search strategy is summarized in Table 1.

Key content and findings

Pathophysiology of DED

The ocular surface is a complex system comprising the corneal epithelium, conjunctiva, primary and accessory lacrimal glands, meibomian glands, and the tear drainage system. These components interact dynamically through intricate networks of innervation, vascularization, and immune responses to maintain a healthy and stable ocular environment. Disruption of any of these components can disturb the delicate balance of the ocular surface, potentially leading to DED (11).

DED is a prevalent condition affecting millions of individuals worldwide, making it one of the most common reasons for consultations in ophthalmology clinics. This condition is characterized by a self-perpetuating cycle of tear film instability, hyperosmolarity, ocular surface inflammation, and neurosensory abnormalities. Clinically, DED manifests as symptoms of ocular discomfort, pain, and reduced visual acuity. These symptoms can significantly impair daily activities, social interactions, and professional performance, ultimately affecting the overall quality of life and socioeconomic well-being (11).

DED can be broadly classified into two main types: evaporative and aqueous-deficient. In aqueous-deficient dry eye, reduced tear production leads to hyperosmolarity, while evaporative dry eye results from excessive tear evaporation due to meibomian gland dysfunction and inadequate lipid layer production. However, it is increasingly recognized that many cases exhibit overlapping features, making it difficult to clinically distinguish between the two types. Consequently, this binary classification is gradually being replaced by a more integrated understanding of DED as a multifactorial disease (12).

According to the Tear Film and Ocular Surface Society Dry Eye Workshop (TFOS DEWS) II guidelines, diagnosing DED requires a combination of objective clinical signs and subjective symptoms. Objective assessments include fluorescein staining, reduced tear break-up time (TBUT), increased tear osmolarity, and tests like the Schirmer test. Subjective symptoms are typically evaluated using validated questionnaires such as the Dry Eye Questionnaire-5 (DEQ-5) and the Ocular Surface Disease Index (OSDI). A positive score on these questionnaires, combined with at least one objective sign, confirms the diagnosis of DED (12).

Diabetes and DED

DM is a well-established risk factor for DED. Studies have consistently shown that the prevalence of DED is significantly higher in diabetic populations than in non-diabetic counterparts. For instance, research by Mangoli et al. highlighted that the duration of diabetes played a critical role in the prevalence of dry eye, with individuals who had been diagnosed with diabetes for over a decade and those with poor glycemic control exhibiting markedly higher rates of DED (13).

Naik et al. supported these findings, revealing a strong association between diabetes, glandular dysfunction, reduced TBUT, and diminished Schirmer test values. Their research also underscored that these associations were more pronounced in patients with poor glycemic control, as indicated by elevated hemoglobin A1C (HbA1c) levels, and in those with longer disease durations (14).

A comprehensive meta-analysis conducted by Kuo et al. further corroborated these observations, demonstrating significant tear dysfunction in diabetic individuals, as evidenced by reduced Schirmer test and TBUT scores. However, it was noted that patients with well-controlled diabetes (HbA1c ≤6.5%) or gestational diabetes did not exhibit statistically significant differences compared to healthy individuals. This suggests a direct correlation between tear film dysfunction, glycemic control, and the duration of diabetes (15).

Mansuri et al. expanded on this by establishing a link between the severity of diabetes and DED prevalence. Their findings indicated that individuals with diabetic retinopathy were more likely to suffer from DED, emphasizing the importance of routine screening for DED in diabetic retinopathy clinics to ensure timely diagnosis and management (16).

The protective effects of certain antidiabetic therapies on DED have also been investigated. Pan et al. identified that patients treated with dipeptidyl peptidase 4 (DPP-4) inhibitors, GLP-1 agonists, SGLT-2 inhibitors, or insulin monotherapy had a lower incidence of DED compared to those on metformin monotherapy. Among these, SGLT-2 inhibitors demonstrated the most significant protective effect, likely due to their ability to reduce oxidative stress and inflammation. GLP-1 agonists and DPP-4 inhibitors may also offer neuroprotective benefits that contribute to this effect. Additionally, known risk factors for DED, such as female gender, advanced age, high HbA1c levels, and diabetic retinopathy, were reaffirmed (17).

Ocular surface changes in diabetic dry eye

Diabetes-induced glandular dysfunction

The lacrimal functional unit (LFU) is a sophisticated system responsible for regulating the components of the tear film to ensure ocular surface homeostasis. This unit comprises the meibomian glands, Zeiss glands, Moll glands, eyelids, conjunctiva, cornea, and neural networks interconnecting these components (18).

The superficial location of the meibomian glands enables their detailed anatomical evaluation through advanced imaging techniques like meibography and confocal microscopy. In healthy individuals, these glands appear as regularly spaced structures along the lid margin, displaying a concentric ring-like architecture under the microscope. However, aging and advanced gland dysfunction disrupt this arrangement, leading to clinical signs of meibomian gland dysfunction (MGD), such as irregular lid margins, vascular engorgement, and glandular orifice obstruction (18).

In diabetes, hyperglycemia activates the polyol pathway, in which aldose reductase reduces glucose to sorbitol. The intracellular accumulation of sorbitol causes osmotic stress, leading to cellular edema and glandular dysfunction. This results in impaired tear secretion and instability of the tear film. Moreover, hyperglycemia damages goblet cells in the conjunctiva and cornea, further compromising mucin production and tear film stability. Autonomic dysfunction, a common feature of diabetic neuropathy, exacerbates glandular secretion abnormalities, aggravating DED (19).

MGD, the leading cause of evaporative DED, is particularly prevalent among diabetic patients. Abu et al. reported a 55.3% incidence of MGD in individuals with type 2 diabetes compared to 25.5% in healthy controls (20). Similar findings have been documented globally, with diabetic individuals showing a two-fold increased risk of DED and a three-fold increased risk of epithelial damage as evidenced by staining (21,22).

Wu et al. conducted a detailed analysis of glandular dysfunction in diabetic patients, demonstrating significant impairments compared to controls. Their study established a direct relationship between worse glycemic control, longer disease duration, and more severe glandular dysfunction (23).

Neural impairment in diabetic dry eye

The cornea is the most densely innervated tissue in the human body, with approximately 7,000 nociceptors per square millimeter at its center. These nerves, derived from the nasociliary branch of the ophthalmic trigeminal nerve, enter the anterior stroma, branch into the sub-basal nerve plexus, and terminate in the epithelium (17). Corneal nerves play a crucial role in regulating tear secretion, wound healing, and maintaining the integrity of the ocular surface (24).

In diabetic patients, these nerves undergo significant structural and functional changes. Studies utilizing in vivo confocal microscopy have shown reduced corneal nerve fiber length and density, accompanied by increased edema in the sub-basal nerve plexus (10). These alterations correlate strongly with diminished corneal sensitivity, a hallmark of diabetic neuropathy. Corneal sensitivity can be measured using various tools, such as contact esthesiometers like the Cochet-Bonnet or non-contact methods like the non-contact corneal aesthesiometer (NCCA) (10).

More than half of diabetic individuals exhibit reduced corneal sensitivity, with higher prevalence rates observed in those with long-standing type 1 or type 2 diabetes. Confocal microscopy has also revealed increased dendritic cell density in the corneas of diabetics, suggesting immune system interactions in the development of corneal neuropathy. Additionally, longitudinal studies have reported an annual corneal nerve cell loss rate of approximately 6% in 17% of diabetic patients (25-27).

Effect of surgical procedures on DED in diabetic patients

Intraocular surgeries, particularly cataract surgery involving clear corneal incisions, have been identified as exacerbating factors for DED. These procedures disrupt the peripheral stromal nerve plexuses, reducing corneal sensitivity and impairing reflex tear production. Additionally, surgical incisions compromise the uniformity of the ocular surface, altering tear film distribution and contributing to postoperative symptoms such as discomfort and foreign body sensation (28).

In diabetic patients, the impact of cataract surgery on DED is even more pronounced. Research by Momin et al. revealed a significantly higher incidence of DED in diabetics following cataract surgery compared to non-diabetic patients. Diabetic patients also demonstrated worse Ocular Surface Disease Index scores and corneal staining, with reduced tear production persisting for a longer duration post-surgery (29).

In a study conducted by Yang et al., the incidence of DED was evaluated in patients with type 2 DM undergoing phacoemulsification surgery using clear corneal incisions of different sizes (2.2 vs. 3.0 mm). The findings demonstrated that smaller incisions (2.2 mm) were more effective in preventing the development or exacerbation of dry eye symptoms compared to larger incisions (3.0 mm) (30). This was reflected in significantly lower dry eye symptom scores and OSDI scores, as well as longer TBUT in the group with smaller incisions (30). These results suggest that in diabetic patients, phacoemulsification should be performed using the least invasive approach possible in order to minimize disruption of the ocular surface and reduce the risk of postoperative DED.

Immune-mediated mechanisms in DM-related ocular surface damage

In individuals with DM, the corneal epithelium is particularly susceptible to damage due to the pro-inflammatory and oxidative stress effects of chronic hyperglycemia. This vulnerability arises in part from the insulin-independent uptake of glucose by corneal cells. Under hyperglycemic conditions, excessive intracellular glucose accumulation initiates multiple pathogenic pathways, including activation of the polyol pathway and the accumulation of advanced glycation end products (AGEs). These metabolic disturbances contribute significantly to oxidative stress and cellular dysfunction (31,32). Oxidative stress leads to the activation of nuclear factor-kappa B (NF-κB), a key transcription factor that initiates and sustains an inflammatory cascade, ultimately impairing epithelial regeneration. Concurrently, AGEs stimulate nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity, enhancing the production of reactive oxygen species (ROS). These ROS, in turn, promote cellular apoptosis, particularly affecting corneal endothelial cells (33).

Moreover, hyperglycemia elevates intracellular levels of diacylglycerol (DAG), resulting in the activation of protein kinase C (PKC). PKC activation further amplifies ROS generation and disrupts essential protective signaling pathways such as the epidermal growth factor receptor-phosphoinositide 3-kinase/protein kinase B (EGFR-PI3K/Akt) axis, which is critical for cell survival and epithelial wound healing (34). Additionally, transforming growth factor-beta (TGF-β), activated in response to oxidative stress and ROS, contributes to fibrogenesis and delays re-epithelialization, further complicating corneal repair (35,36).

Another relevant pathological mechanism is pyroptosis, a form of programmed cell death triggered by metabolic stress via activation of the NLRP3 inflammasome in corneal cells (37). Activation of this inflammasome complex leads to caspase-1 activation and the subsequent release of pro-inflammatory cytokines such as interleukin-1 beta (IL-1β) and interleukin-18 (IL-18), which exacerbate inflammation and tissue damage in the cornea (38,39).

In addition to these molecular mechanisms, diabetic corneas exhibit increased infiltration of immune cells, including mast cells, natural killer (NK) cells, and CD4⁺ T lymphocytes. These immune cells respond to cellular stress and injury, perpetuating the pro-inflammatory microenvironment and contributing to the chronic inflammation observed on the diabetic ocular surface (40).

Ocular surface microbiota alterations

The ocular surface microbiota comprises commensal organisms that suppress pathogenic microbes, maintaining ocular health. In healthy individuals, this microbiota exhibits low diversity and stability (41).

DED is associated with altered microbiota, favoring coagulase-negative Staphylococcus, Staphylococcus aureus, and Corynebacterium. Increased glucose and glycated products on the ocular surface in diabetes alter normal colonization, enhance ocular inflammation, and impair pathogen clearance. Reduced blinking reflex and glandular dysfunction further exacerbate these effects (42).

Zhang et al. found greater microbial diversity in diabetics with and without DED and non-diabetics with DED compared to healthy controls. Clostridiale and Lactobacillus were relatively abundant in diabetic DED patients. Chen et al. reported similar findings in diabetic children, identifying Lactococcus, Bacteroides, Acinetobacter, and others linked to DED pathogenesis (43,44).

Symptom burden in diabetic dry eye

Despite increased DED prevalence in diabetics, subjective symptom scores such as OSDI do not always correlate. Locatelli et al. found lower OSDI scores in diabetics with organ damage (neuropathy, nephropathy, or retinopathy) despite higher ocular surface abnormalities, suggesting asymptomatic DED is common in these patients (45).

Almohammed et al. corroborated these findings, noting greater DED symptoms in diabetics with HbA1c levels of 6.5–9% compared to those exceeding 9%. Poorly controlled diabetics may experience reduced symptoms, underscoring the need for rigorous DED screening in this population to avoid underdiagnosis (46).

Screening and treatment

Effective diagnosis and management of DED in patients with DM requires systematic integration of ocular surface assessment into routine ophthalmic evaluations and, therefore, should be incorporated into the standard annual diabetic retinopathy screening (12,47). However, more frequent evaluation may be warranted in high-risk subgroups, including patients with long-standing or poorly controlled diabetes, a history of diabetic retinopathy, postmenopausal diabetic women (particularly those on hormone replacement therapy), and individuals with systemic comorbidities such as hypertension, Parkinson’s disease, or depression (48).

The diagnostic approach should combine both subjective and objective measures. Subjectively, symptom-based screening questionnaires (e.g., OSDI or DEQ-5) are recommended as initial tools to identify patients who may require further evaluation (12). Objective assessments typically involve slit-lamp biomicroscopy and fluorescein staining to detect signs of ocular surface damage or tear film instability. The choice of additional diagnostic tests—such as tear osmolarity, Schirmer’s test, or meibography—should be based on availability and clinical relevance, particularly when early or subtype-specific treatment is considered (12).

Management aims to restore ocular surface homeostasis and interrupt the cycle of inflammation, tear film instability, and epithelial damage. This often requires addressing not only tear film insufficiency but also contributing systemic or local factors (49).

The therapeutic principles in diabetic patients are generally aligned with those in the non-diabetic population, and therefore should be implemented based on TFOS DEWS II treatment guidelines (12). Therapy is structured in a stepwise fashion:

• Step 1: focuses on patient education regarding disease nature and prognosis, environmental and dietary modifications (including supplementation with essential fatty acids), review and possible discontinuation of topical or systemic medications that may exacerbate DED, and initiation of ocular lubricants—particularly lipid-based drops in the presence of meibomian gland dysfunction. Eyelid hygiene with warm compresses, massage, and cleansing of the eyelid margin using pH-neutral shampoos or commercial wipes is also emphasized, having shown improvement in symptoms and eyelid margin status (12).
• Step 2: includes escalation to preservative-free lubricants, treatment of Demodex infestation with tea tree oil-based products, tear preservation through punctal occlusion or moisture chamber goggles, and nighttime therapy with ocular gels. In-office procedures such as thermal expression of meibomian glands or intense pulsed light (IPL) therapy may be beneficial. Pharmacologic options at this stage involve topical antibiotics or corticosteroid-antibiotic combinations (for blepharitis), short-term corticosteroids, topical secretagogues, non-glucocorticoid immunomodulators, Lymphocyte function-associated antigen-1 (LFA-1) antagonists, and oral macrolides or tetracyclines (12).
• Step 3: entails the use of oral secretagogues, autologous serum eye drops, or therapeutic soft or scleral contact lenses for persistent or severe DED (12).
• Step 4: involves advanced therapies such as long-term topical corticosteroids, amniotic membrane grafts, surgical punctal occlusion, and surgical interventions like tarsorrhaphy or minor salivary gland transplantation in refractory cases (12).

Overall, the management of DED in diabetic patients should be comprehensive and individualized, integrating screening into routine diabetes care and escalating therapy according to disease severity and subtype. Early detection and intervention are essential to improve quality of life and prevent further ocular surface damage.

Strengths and limitations

This review was conducted through a search of the existing literature concerning the impact of DM on the ocular surface, with a particular emphasis on its association with DED). By synthesizing findings from multiple peer-reviewed publications over the past five years, the review presents up-to-date and clinically relevant information, reflecting the current understanding and trends in this field.

One of the strengths of this work lies in its broad perspective, offering a high-level overview that contextualizes the relationship between diabetes and ocular surface disease. This approach provides clinicians and researchers with an accessible yet integrated view of the burden of DED in diabetic patients and highlights the nuanced aspects of diagnosis and management that are specific to this population.

However, some limitations must be acknowledged. The literature search was restricted to the PubMed database, which, despite being a robust and widely used biomedical repository, may not encompass all relevant studies indexed in other bibliographic platforms or gray literature sources. Consequently, certain valuable findings published outside of PubMed-indexed journals may have been overlooked.

Moreover, although the review touches upon key pathogenic mechanisms linking diabetes and DED, it was not designed to provide an in-depth exploration of the molecular, biochemical, and cellular pathways involved. These complex mechanisms, which may contribute significantly to disease development and progression, were beyond the scope of this general review. Future focused investigations addressing these molecular underpinnings could further advance understanding and potentially lead to the identification of novel therapeutic targets.

Conclusions

DM significantly impacts ocular surface health, with DED emerging as a prevalent and underrecognized complication. Diabetic keratopathy—driven by glandular dysfunction, neural impairment, and microbiota changes—disrupts tear film stability and contributes to ocular surface damage, particularly in patients with poor glycemic control and long-standing disease. Effective management requires early screening, integrated care, and targeted treatments, including artificial tears and anti-inflammatory therapies. Patient education and optimized systemic control are essential, and further research is needed to explore novel therapies and the role of ocular microbiota in DED pathogenesis.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the Narrative Review reporting checklist. Available at https://aes.amegroups.com/article/view/10.21037/aes-25-3/rc

Peer Review File: Available at https://aes.amegroups.com/article/view/10.21037/aes-25-3/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://aes.amegroups.com/article/view/10.21037/aes-25-3/coif). H.P.F. serves as an unpaid editorial board member of Annals of Eye Science from October 2024 to December 2026. The other authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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