C‐peptide Modulates VEGF Release: Implications for Diabetic Retinopathy

Diabetic retinopathy (DR) is one of the leading causes of non‐traumatic blindness in the developed world and is characterized by the neovascularization of the retina with weak blood vessels that may eventually break, potentially leading to blindness. The underlying etiology of DR is not fully understood; however, the hypersecretion of VEGF in the retina appears to play a major role. VEGF normally is released from the retinal pigment epithelium (RPE) and maintains the fenestrated choriocapillaris. However, in the setting of high glucose, the RPE secretes pathologically high levels of VEGF, which can stimulate aberrant retinal neovascularization. Current therapeutic strategies targeting VEGF hypersecretion are extremely invasive, and while effective, are not curative and at best stall the progression of DR. Alternative, non‐invasive strategies to prevent the development of DR are of high interest, such as the development of proinsulin C‐peptide‐based therapeutics, since C‐peptide has been shown to ameliorate blood flow abnormalities associated with DR in both experimental animals and in humans. We have found that GPR146, the putative receptor of C‐peptide, is expressed in the human RPE and in the human RPE cell line, ARPE‐19. Given C‐peptide's known protective actions in the eye, we hypothesized that C‐peptide would reduce VEGF release from ARPE‐19 cells. We found that C‐peptide inhibited both basal and glucose‐stimulated VEGF secretion, and furthermore, that C‐peptide partially reversed insulin‐induced VEGF release from ARPE‐19 cells. While future experiments will determine the mechanisms underlying this effect, these results suggest that C‐peptide may serve as a therapeutic target for the reduction of VEGF hypersecretion and the progression of DR.