Ocular surface complications in diabetes: The interrelationship between insulin and enkephalin

Diabetes is a multi-faceted disorder with increasing prevalence and rising healthcare costs. The burden of diabetes is increased because of associated complications affecting nearly all organs including the eye. The underlying pathophysiology for the onset of these ocular surface disorders is not well known. Enkephalins are endogenous opioids that originate in the brain and have numerous actions in the human body. Opioid growth factor (OGF), chemically termed [Met⁵]-enkephalin, binds to a novel, nuclear-associated receptor and mediates cellular homeostasis. Serum OGF levels are elevated in diabetic individuals and rodent models of diabetes. Sustained blockade of the OGF receptor (OGFr) with opioid receptor antagonists, such as naltrexone (NTX), reverses many complications of diabetes in the animal model, including delayed cutaneous wound healing, dry eye, altered corneal surface sensitivity, and keratopathy. The increased enkephalin levels observed in diabetes suggest a relationship between endogenous opioid peptides and the pathophysiology of diabetes. It is common for diabetic patients to undergo insulin therapy to restore normal blood glucose levels. However, this restoration does not alter OGF serum levels nor ameliorate ocular surface complications in the animal model of diabetes. Moreover, sex differences in the prevalence of diabetes, response to insulin therapy, and abnormalities in the OGF-OGFr axis have been reported. This review highlights current knowledge on the dysregulation of the OGF-OGFr pathway and possible relationships of insulin and enkephalins to the development of ocular surface defects in diabetes. It proposes that this dysregulation is a fundamental mechanism for the pathobiology of diabetic complications.