Vision loss in type 2 diabetes (T2DM) results from diabetic retinopathy (DR) which can appear at any retinal
location without warning. Diabetes is the leading cause of blindness in working aged Americans but it can be
difficult for clinicians to determine who will start on a path to vision loss and when. There are also millions of
Americans (up to 44% of the population) with prediabetes (PreDM). These patients have impaired fasting
glucose, elevated Hemoglobin A1c (HbA1c) and/or Oral Glucose Tolerance Tests (OGTT). They are at higher
risk for T2DM, and most do not know their diagnosis. There is a major gap in our understanding of how and
when PreDM affects the eye. It is important we close this gap as there are no treatments in the eye outside of
glycemic control for early T2DM and PreDM. Methods for early diagnosis and detection, especially if location-
specific, could aid in delaying DR and over the long term, saving sight. Our long-term goal is to understand
how glucose dysregulation impacts the vascular and neural retina, cornea and tear film. We also seek to
understand if systemic objective phenotypic differences (meaning tests of T2DM health such as fat distribution,
activity levels from accelerometry and OGTT) in these patients are related to or predictive of ocular health. It is
known that current tests of ocular structure and function such as multifocal electroretinograms (mfERG), ocular
coherence tomography angiography (OCTA), adaptive optics scanning laser ophthalmoscopy (AOSLO),
corneal confocal microscopy and tear composition are altered in early T2DM. However, PreDM has not been
included in this work, and local retinal oxygenation changes have never been evaluated with these other ocular
tests. There is also no knowledge as to which objective systemic and lifestyle factors put the patient most at
risk for ocular changes in PreDM. Our central hypothesis is that local retinal oxygenation is altered by
changes in glucose tolerance. This drives the relationship between vessel changes and retinal function, in local
retinal areas. In Aim 1, a cross sectional study, we will compare subjects in the following groups: controls,
PreDM patients with a wide range of impaired glucose tolerance, T2DM with no DR, and T2DM with DR. We
will also use the best objective measures available to fully phenotype subject characteristics with regards to
factors such as body fat and sedentary lifestyle. We will then evaluate differences between groups for
structural and functional eye testing using the tests above, as well as local oximetry and levels of glucose
impairment to see relationships in systemic and eye health. In Aim 2, we will follow these subjects at 1 and 2
years in a prospective cohort study to see how these phenotypes influence ocular change over time. We also
plan to evaluate the timeline of ocular structure and function changes across the eye. We expect that
differences in impaired glucose tolerance/phenotypes will alter ocular testing over time especially in PreDM.
The ability to predict which areas are most affected and which patients are most at risk, could constitute a
significant advance in diagnosis and management of this disease, which has reached epidemic proportions.
