Ocular surface complications result from dysregulation of the OGF‑OGFr signaling pathway in female diabetic rats

Abstract

Approximately 4.5 million women in the United States exhibit diabetes-associated ocular complications. The time course and magnitude of these complications, and their association with the dysregulation of the opioid growth factor (OGF)-OGF receptor (OGFr) signaling pathway are unknown. The present study investigated the onset and magnitude of ocular surface complications and the association with a dysregulated OGF-OGFr signaling pathway in diabetic female rats. Adult female Sprague-Dawley rats were injected with streptozotocin in order to establish a model of type 1 diabetes (T1D), and a subset received insulin (T1D-INS). Blood glucose, body weight, tear production and corneal sensitivity, as well as serum and tissue expression levels of OGF and OGFr, were assessed. Corneal epithelial wound healing was also evaluated. In a second study, female T1D rats were treated with topical naltrexone (NTX) to determine whether blockade of the OGF-OGFr signaling pathway by NTX altered development of corneal surface complications. Female T1D rats had elevated glucose levels and reduced body weight compared with control and T1D-INS rats. In both diabetic groups, tear production was decreased within 2 weeks and corneal sensitivity was decreased 2.5-fold within 5 weeks, while corneal epithelial wound healing was delayed only in T1D rats. Serum and tissue levels of OGF and OGFr were elevated in diabetes. Twice daily NTX treatment reversed most ocular surface complications in the diabetic female rats. The present data demonstrated a seminal discovery in female T1D rats, in which the onset and magnitude of diabetes-associated ocular surface complications were associated with dysregulation of the OGF-OGFr regulatory pathway. Blockade of the OGF-OGFr pathway with the opioid receptor antagonist NTX prevented the onset and/or decreased the magnitude of these deficits. The current data support the need for translational research on this therapeutic approach for diabetic human subjects.

Opioids and Ocular Surface Pathology: A Literature Review of New Treatments Horizons

“…The onset and magnitude of diabetes complications are associated with the elevations of OGF tissue and serum levels in diabetic rats [ 36 , 38 , 39 , 40 ]. These complications appear with more frequency and severity in female animal models, similarly associated with descended estradiol levels and elevated OGF levels [ 40 ].…”

Sex Differences in Diabetic Ocular Surface Complications and Dysregulation of the OGF-OGFr Pathway

“…Our research has shifted to focus on the timing of the onset of corneal complications in T1D rats, with follow up studies exploring whether prophylactic administration of NTX beginning at the appearance of hyperglycemia can prevent or delay the onset of dry eye, deceased corneal sensitivity, and delayed corneal epithelial wound healing [ 14 , 15 ]. Given the relative prevalence of disease in both genders, studies on female rats were indicated [ 16 ]. The time course and magnitude of ocular surface complications and their association with the dysregulation of the OGF - OGFr signaling pathway were determined in a cohort of male and female T1D rats some of which received insulin implants in order to maintain blood glucose levels.…”

“…The highest T1D male OGF level was approximately 60 pg/ml. Increases in enkephalin levels in diabetes have been documented in humans [ 22 ] and mice [ 23 ], but the sex differences related to the timing of the rapid increase within a few weeks of hyperglycemia is novel [ 14 , 16 ]. These differences may explain in part the early on set of complications in female rats.…”

“…Therefore, the addition of OGF or a receptor antagonist can increase or decrease the inhibitory effects, respectively. Recently, it was determined that this regulatory pathway becomes dysregulated shortly after the onset of diabetes leading to an increased level of the inhibitory growth factor OGF in both blood and ocular tissues [ 14 - 16 ]. These changes in the balance of cell proliferation contribute to the onset and magnitude of ocular surface abnormalities observed in T1D.…”

“…These changes in the balance of cell proliferation contribute to the onset and magnitude of ocular surface abnormalities observed in T1D. Despite the nearly equal proportion of males and females with diabetes, most preclinical studies, including our own, utilize male rodents as a model for study [e.g., 14 , 15 ], with an independent focus on female adult rats [ 16 ]. The OGF-OGFr regulatory pathway functions in normal rodents and humans, but in the diabetic model, healing of corneal epithelial defects and other ocular surface abnormalities are significantly delayed providing a reproducible model for studying the mechanism underlying delayed epithelial wound healing in diabetes.…”