Physiological effects and therapeutic potential of proinsulin C-peptide

Abstract

Connecting Peptide, or C-peptide, is a product of the insulin prohormone, and is released with and in amounts equimolar to those of insulin. While it was once thought that C-peptide was biologically inert and had little biological significance beyond its role in the proper folding of insulin, it is now known that C-peptide binds specifically to the cell membranes of a variety of tissues and initiates specific intracellular signaling cascades that are pertussis toxin sensitive. Although it is now clear that C-peptide is a biologically active molecule, controversy still remains as to the physiological significance of the peptide. Interestingly, C-peptide appears to reverse the deleterious effects of high glucose in some tissues, including the kidney, the peripheral nerves, and the vasculature. C-peptide is thus a potential therapeutic agent for the treatment of diabetes-associated long-term complications. This review addresses the possible physiologically relevant roles of C-peptide in both normal and disease states and discusses the effects of the peptide on sensory nerve, renal, and vascular function. Furthermore, we highlight the intracellular effects of the peptide and present novel strategies for the determination of the C-peptide receptor(s). Finally, a hypothesis is offered concerning the relationship between C-peptide and the development of microvascular complications of diabetes.

The Physiology of Proinsulin C-Peptide: Unanswered Questions and a Proposed Model

“…C-peptide also has been shown to initiate multiple intracellular signaling cascades, including protein kinase A (PKA), protein kinase C (PKC), and activation of MAK kinase, all of which are consistent with the interaction of C-peptide with a G-protein-coupled receptor (GPCR). In agreement with this assertion, the actions of C-peptide in several cell systems are pertussis toxin sensitive (26,48,52), indicating that C-peptide may signal via a GPCR coupled to G␣ i/o . Using a unique deductive ligand-receptor matching strategy (53), our group identified the orphan GPCR GPR146 as an essential part of the C-peptide signalosome and a potential receptor for C-peptide (51).…”

“…Despite this fact, C-peptide does not appear to directly alter glucose metabolism (12,25,47,52). However, it does appear that C-peptide-and insulin-initiated signaling cascades interact (FIGURE 2) and that this interaction is important for the normal functioning of both peptides, particularly in erythrocytes (39 -41).…”

“…In plasma, insulin and C-peptide exhibit remarkably different kinetics, since insulin has a serum half-life of ϳ2-3 min, and C-peptide, which escapes first-pass metabolism by the liver, has a halflife of ϳ30 min (10,46,52). For many years, C-peptide was thought to be a biological by-product of insulin processing, but because of its stability in plasma, it was and still is used clinically as a marker of ␤-cell function.…”

“…It is now known that C-peptide is a biologically active peptide, although its physiological significance in normal physiology has not been fully elucidated. Although the role of C-peptide in mitigating diabetes-related complications (20,33,36), its potential clinical relevance in diabetes (20,33,47,52), and proposed signaling mechanisms underlying these effects (18,19) have been reviewed elsewhere, multiple questions remain. First, are the effects of C-peptide receptor mediated, and, if so, what is the C-peptide receptor(s)?…”

Long-Acting C-Peptide and Neuropathy in Type 1 Diabetes: A 12-Month Clinical Trial

“…Much new information on C-peptide physiology has appeared during the past 20 years; for an overview, see Wahren et al (1). C-peptide has been shown to bind specifically to cell membranes (2) and elicit intracellular signaling via G-protein-and Ca 2+ -dependent pathways (3,4), resulting in activation and increased expression of endothelial nitric oxide (5), Na + , K + -ATPase (6), and several transcription factors of importance for antioxidative, anti-inflammatory, and cell-protective reactions (7,8) Studies in animal models of diabetes and early clinical trials in patients with type 1 diabetes (T1DM) demonstrate that C-peptide in physiological replacement doses elicits beneficial effects on early stages of diabetes-induced functional and structural abnormalities of the peripheral nerves, the autonomic nervous system, and the kidneys (9). Even though much is still to be learned about C-peptide and its mechanism of action, the available evidence presents the picture of a bioactive peptide with therapeutic potential.…”