Proinsulin C‐peptide prevents hyperglycemia‐induced vascular leakage and metastasis of melanoma cells in the lungs of diabetic mice

C‐peptide has a beneficial effect against diabetic complications, but its role in hyperglycemia‐induced metastasis is unknown. We investigated hyperglycemia‐mediated pulmonary vascular leakage and metastasis and C‐peptide inhibition of these molecular events using human pulmonary microvascular endothelial cells (HPMVECs) and streptozotocin‐induced diabetic mice. VEGF, which is elevated in the lungs of diabetic mice, activated transglutaminase 2 (TGase2) in HPMVECs by sequential elevation of intracellular Ca 2+ and reactive oxygen species (ROS) levels. VEGF also induced vascular endothelial (VE)‐cadherin disruption and increased the permeability of endothelial cells, both of which were prevented by the TGase inhibitors monodansylcadaverine and cystamine or TGM2 ‐specific small interfering RNA. C‐peptide prevented VEGF‐induced VE‐cadherin disruption and endothelial cell permeability through inhibiting ROS‐mediated activation of TGase2. C‐peptide supplementation inhibited hyperglycemia‐induced ROS generation and TGase2 activation and prevented vascular leakage and metastasis in the lungs of diabetic mice. The role of TGase2 in hyperglycemia‐induced pulmonary vascular leakage and metastasis was further demonstrated in diabetic Tgm2 −/− mice. These findings demonstrate that hyperglycemia induces metastasis, and C‐peptide prevents the hyperglycemia‐induced metastasis in the lungs of diabetic mice by inhibiting VEGF‐induced TGase2 activation and subsequent vascular leakage.—Jeon, H.‐Y., Lee, Y.‐J., Kim, Y.‐S., Kim, S.‐Y., Han, E.‐T., Park, W. S., Hong, S.‐H., Kim, Y.‐M., Ha, K.‐S. Proinsulin C‐peptide prevents hyperglycemia‐induced vascular leakage and metastasis of melanoma cells in the lungs of diabetic mice. FASEB J. 33, 750–762 (2019). www.fasebj.org