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

Abstract

Background: Diabetes is a chronic disorder that affects more than 500 million individuals worldwide. It is a life-long disease with complications that attack nearly all other systems within the body. Although there is a slight increase in the prevalence of diabetes in males, ocular surface complications are equally present in males and females. Aim:This review provides a discussion on preclinical studies related to the dysregulation of a biological pathway that appears to be causally related to diabetic ocular surface complications including dry eye, delayed corneal epithelial healing, and decreased corneal sensitivity. Most basic science and clinical studies focus on male sex in animal models in order to avoid confounders related to hormonal cycling. However, with approximately 10.2% of all women in the US aged 18-44 being diagnosed with diabetes and nearly 4% additional women having undiagnosed disease, it is prudent to examine the onset of these dysregulations also in females and to note any sex-related differences in the timing of onset or severity of ocular surface complications. Summary: Data from several well-controlled investigations have documented that female rats with type 1 diabetes develop ocular surface complications before male rats. In part, this finding may be due to the increase in the inhibitory peptide Opioid Growth Factor (OGF) that occurs within 2 weeks of the induction of hyperglycemia in female animals in comparison to the changes in OGF levels in male rats which occur at 4 weeks. It was noted that estrogen levels drop within weeks of induction of hyperglycemia and could serve as another marker for the onset of disease activity and/or its complications. Finally, insulin does not appear to protect against early changes in OGF levels or estrogen secretion in diabetic female rats, setting the stage for a distinction in the disease profile of diabetes between males and females. These data encourage further studies on both sexes in order to establish a complete understanding of the underlying pathologies associated with complications associated with diabetes.