Mechanisms of action and therapeutic potential of proinsulin C-peptide

Abstract

C-peptide generated by proinsulin proteolysis is not only a chaperone for insulin in β-cells, but also a signaling molecule that regulates many physiological and biochemical processes via specific C-peptide receptors. Regulatory effects of C-peptide are tissue-specific and largely depend on the physiological state of an organism, C-peptide concentration, and its ability to form complexes. In type 1 diabetes mellitus, which is characterized by a C-peptide deficiency, C-peptide replacement therapy prevents the development of inflammation in vascular endothelial cells, whereas C-peptide excess, in contrast, reveals its pro-inflammatory properties. By affecting a number of effector proteins and transcription factors in the retinal pigment epithelium, C-peptide prevents both blood–retinal barrier damage and retinal neovascularization, which makes it one of the most promising drugs to treat and prevent diabetic retinopathy. C-peptide has been established to be involved in the regulation of synthesis and secretion of adipokines, which is indicative of its role in controlling energy homeostasis. Considering the efficiency of C-peptide in the treatment of diabetic nephropathy, neuropathy and retinopathy, C-peptide medicinal forms are now being developed. Among these forms, of greatest interest are C-peptide analogs modified by polyethylene glycol, C-peptide complexes with zinc cations and albumin, and C-terminal fragments of C-peptide comparable by their biological activity to a full-length molecule.