Obstructive sleep apnea (OSA) and Type 2 diabetes mellitus (T2DM) are epidemic, comorbid conditions which affect millions of patients worldwide. While the complex relationship between OSA and T2DM is still poorly understood, the pathophysiological changes that underlie OSA and T2DM-related complications indicate overlapping, synergistic mechanisms. Importantly, severe ocular complications have been reported with both conditions. T2DM has been identified as a leading cause of adult blindness, including chronic, often painful, corneal complications resulting from diabetic corneal neuropathy. Research investigating the effects of hyperglycemia in T2DM on corneal nerves is limited, as current studies have failed to address the interactive effects of co-existent condition such as OSA. Recently, a potential link between OSA, T2DM and diabetic peripheral neuropathy has been identified. The goal of this R21 project is to identify and characterize novel relationships between OSA, T2DM and pathological corneal nerve changes that may help us to mitigate the potentially additive effects of OSA on corneal and ocular surface disease. In this proposal, we will test two novel hypotheses: (1) that corneal nerve morphology is altered in patients with OSA resulting in pathological corneal and ocular surface changes;and (2) that the interaction between OSA and T2DM exacerbates the deleterious effects of hyperglycemia on the corneal subbasal nerve plexus (SBNP), leading to increased ocular surface damage in patients with comorbid disease. We will test these hypotheses in Aim 1 using in vivo confocal microscopy to investigate potential corneal nerve and epithelial cell changes in patients with OSA, T2DM and comorbid disease compared to healthy controls.
In Aim 2, we will examine potential systemic variables that are associated with alterations in the SBNP and assess the subsequent effects of changes in the SBNP on the ocular surface. This exploratory proposal utilizes a comprehensive multidisciplinary team approach to investigate a novel contributory role for OSA in diabetic corneal neuropathy. Unlike Type 1 disease, available evidence suggests that glycemic control alone is not sufficient to halt the neuropathic complications of T2DM. This study will establish, for the first time, whether corneal nerve morphology is altered in OSA and provide insight into the potential inflammatory and immunological mechanisms associated with OSA that contribute to the pathophysiology of corneal nerve damage in diabetic disease. The inclusion of co-morbid disease associated with T2DM represents an innovative clinical approach towards understanding the biology of diabetic-induced nerve loss.

Public Health Relevance

Ocular complications associated with obstructive sleep apnea and/or Type 2 diabetes mellitus represent a significant public health issue affecting millions of patients in the U.S. and have the potential to increase dramatically due to the growing obesity epidemic. The overall goals of this proposal are to establish a relationship between obstructive sleep apnea and corneal nerve structure and function;and, to determine the interactive effects of obstructive sleep apnea and Type 2 diabetes on the cornea and ocular surface. The potential identification of obstructive sleep apnea as a risk factor for corneal nerve damage in diabetes may help us to mitigate the potentially additive effects of obstructive sleep apnea on corneal and ocular surface disease.

National Institute of Health (NIH)
National Eye Institute (NEI)
Exploratory/Developmental Grants (R21)
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Special Emphasis Panel (DPVS)
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Mckie, George Ann
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University of Texas Sw Medical Center Dallas
Schools of Medicine
United States
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Titone, Rossella; Zhu, Meifang; Robertson, Danielle M (2018) Insulin mediates de novo nuclear accumulation of the IGF-1/insulin Hybrid Receptor in corneal epithelial cells. Sci Rep 8:4378
Zhou, Scott; Robertson, Danielle M (2018) Wide-Field In Vivo Confocal Microscopy of Meibomian Gland Acini and Rete Ridges in the Eyelid Margin. Invest Ophthalmol Vis Sci 59:4249-4257
Patel, Roshni; Zhu, Meifang; Robertson, Danielle M (2018) Shifting the IGF-axis: An age-related decline in human tear IGF-1 correlates with clinical signs of dry eye. Growth Horm IGF Res 40:69-73
Stuard, Whitney L; Titone, Rossella; Robertson, Danielle M (2017) Tear Levels of Insulin-Like Growth Factor Binding Protein 3 Correlate With Subbasal Nerve Plexus Changes in Patients With Type 2 Diabetes Mellitus. Invest Ophthalmol Vis Sci 58:6105-6112
Stuard, Whitney L; Gallerson, Bryan K; Robertson, Danielle M (2017) Alterations in corneal nerves following crack cocaine use mimic diabetes-induced nerve damage. Endocrinol Diabetes Metab Case Rep 2017:
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Petroll, W Matthew; Robertson, Danielle M (2015) In Vivo Confocal Microscopy of the Cornea: New Developments in Image Acquisition, Reconstruction, and Analysis Using the HRT-Rostock Corneal Module. Ocul Surf 13:187-203
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Wei, Cynthia; Zhu, Meifang; Petroll, W Matthew et al. (2014) Pseudomonas aeruginosa infectious keratitis in a high oxygen transmissible rigid contact lens rabbit model. Invest Ophthalmol Vis Sci 55:5890-9
Posch, Leila C; Zhu, Meifang; Robertson, Danielle M (2014) Multipurpose care solution-induced corneal surface disruption and Pseudomonas aeruginosa internalization in the rabbit corneal epithelium. Invest Ophthalmol Vis Sci 55:4229-37