Author ORCID Identifier

Date Available


Year of Publication


Degree Name

Doctor of Philosophy (PhD)

Document Type

Doctoral Dissertation


Arts and Sciences



First Advisor

Dr. Ann C. Morris


Hundreds of millions of people are affected by diabetes worldwide. Whether they are diagnosed with prediabetes or Type I or II diabetes, there are a variety of mechanisms in the pathogenesis of diabetes. Diabetes is a disease which consists of recurring states of hyperglycemia that can be difficult to manage due to either lack of insulin production or improper utilization of insulin. While these mechanisms of action differ, complications induced by diabetes occur in both poorly regulated Type I and II. Common complications of diabetes include nerve damage, kidney damage, and eye damage. Eye damage specifically is called diabetic retinopathy and occurs in 80% of individuals with dysregulated diabetes for 20 or more years.

Diabetic retinopathy is the principal cause of adult-onset blindness in the US. The mechanism by which diabetic retinopathy works is not fully understood. Various mechanisms have been explored in the understanding of diabetic retinopathy pathogenesis, but recent work has looked closely at the role of photoreceptors in this process. Photoreceptors are light sensing cells in the outermost portion of the retina that capture light signals which are converted into an electrical signal sent through the inner retinal layers then to the brain via the optic nerve. Each retinal neuron plays a critical role in this process of relaying electric signals. In the context of hyperglycemia and diabetes though, photoreceptors cells are unique in that they are disproportionately metabolically demanding compared to the other retinal neurons. Recent studies have found photoreceptors degenerate in animal models that experience recurring hyperglycemia similar to what happens in dysregulated diabetes in adults. Interestingly, this degeneration affected visual function and preceded vasculature damage. Together, it is known that recurring hyperglycemia in adults leads to photoreceptor degeneration, vasculature damage, and progressive blindness. However, few studies are conducted in the context of a pregnant individual that is experiencing recurring hyperglycemia and how that impacts the developing embryo. Given that glucose passes through the blood placental barrier, this is an imperative gap in the literature to fill.

Embryonic development, specifically of the retina, is susceptible to a variety of complications, from genetic mutations to exposure to teratogenic molecules passed through the blood placental barrier. Therefore, this dissertation was dedicated to understanding how hyperglycemia during embryonic development affects retinogenesis, using different methods including genetic knockout, transgenesis, and high glucose exposure. Following hyperglycemia induction, the number and morphology of retinal cell types were analyzed as well as cell death and proliferation. Taken together, this provides substantial insight to the impact of hyperglycemia on retinal development.

Chapter 1 of this dissertation provides a comprehensive review of how hyperglycemia affects development in human and animal models in terms of the whole body and what is known in the eye specifically. In Chapter 2, two animal models of hyperglycemia (genetically and nutritionally induced) are compared with respect to retinal development. All retinal cells, cell proliferation, and cell death are assessed in the two models throughout development and a few weeks post embryonic development to understand short term effects of hyperglycemia. Chapter 3 utilized a third model for hyperglycemia induction via a transgenic line called insulin CFP nitroreductase. This line allows for the temporal ablation of insulin-producing cells in the pancreas, which in turn induces hyperglycemia, at any point of the fish’s lifetime. With this line, we studied the long-term effects of hyperglycemia on the retina by inducing hyperglycemia during embryonic development, raising fish in normoglycemic conditions, and then inducing hyperglycemia again during young adulthood. This methodology provides an avenue for understanding how embryonic metabolic programming affects susceptibility to retinal damage later in life. Chapter 4 is a comprehensive conclusion of findings from Chapters 2 and 3, how these data impact our understanding of hyperglycemia and the retina, as well as future directions this work guided by the findings. Finally, the Appendix chapter of this dissertation is a collaboration project with Dr. Jakub Famulski and Dr. Warlen Pereira Piedade, focused on the role of Siah1, an E3 ubiquitin ligase in retinal development.

Digital Object Identifier (DOI)

Funding Information

National Institutes of Health National Eye Institute (R01EY021769, to A.C.M.), 2018-2021

The National Science Foundation Bridge to the Doctorate Fellowship (NSF HRD 2004710, to K.F.T-T.), 2020-2021

University of Kentucky Lyman T. Johnson graduate fellowship (to K.F.T-T.), 2017-2019

University of Kentucky Biology Merit Fellowship (to K.F.T-T.), 2019

Gertrude F. Ribble Mini Grant (to K.F.T-T.), 2018 and 2020