Background: Corneal nerve fibers express diffusible, trophic neuropeptides such as substance P and calcitonin gene-related peptide (CGRP) into tears in response to neurogenic inflammation. Impaired corneal nerve fibers have been proposed as early indicators of diabetic peripheral neuropathy (DPN). However, the changes that occur in the concentration of these neuropeptides and their relationship with peripheral neuropathy in the diabetic cohort has not been explored.Aim: To demonstrate the changes the concentrations of substance P and CGRP in tears as a result of corneal denervation in diabetes and their association with severity of DPN. Methods: The concentrations of substance P and CGRP in flush tears were measured by enzyme-linked immunosorbent assay. Corneal nerve fibers were assessed using corneal confocal microscopy. Motor nerve axonal excitability tests were conducted to assess axonal function.Results: Age was identified as a confounding factor and controlled in all subsequent studies. Corneal nerve fiber loss was associated with early markers of axonal dysfunction and severity of neuropathy in type 1 diabetes, suggesting that corneal nerve loss is a generalized neuropathic process. There was a significant reduction in the concentration of substance P in tears in people with type 1 diabetic neuropathy. The concentration of substance P in tears was associated with corneal nerve loss and with the severity of peripheral neuropathy in type 1 diabetes. In type 2 diabetes, there was no difference in neuropeptides between groups, regardless of neuropathic status. In both type 1 and type 2 diabetes, corneal nerve parameters were significantly decreased in DPN. Corneal confocal microscopy had a better diagnostic performance than the nerve excitability measures for detecting DPN in a cohort of participants with type 1 and type 2 diabetes. Tear film substance P concentration had a relatively good diagnostic efficiency in the assessment of DPN and may be used as a potential proxy marker for peripheral neuropathy in type 1 diabetes, but not in type 2 diabetes. The co-existence of renal dysfunction with diabetes does have an added detrimental effect on corneal small nerve fibers.Conclusion: The ocular surface can indeed be a useful means to detect peripheral neuropathic status in diabetes. The measurement of tear film substance P offers significant promise in the detection of DPN. Advisors/Committee Members: Markoulli, Maria, Optometry & Vision Science, Faculty of Science, UNSW, Willcox, Mark, Optometry & Vision Science, Faculty of Science, UNSW, Poynten, Ann, Department of Endocrinology, Prince of Wales Hospital, Sydney.