Proinsulin C-peptide elicits disaggregation of insulin resulting in enhanced physiological insulin effects

Abstract

Abstract. Using surface plasmon resonance (SPR) and electrospray mass spectro metry (ESI-MS), proinsulin C-peptide was found to influence insulin-insulin interactions. In SPR with chip-bound insulin, C-peptide mixed with analyte insulin increased the binding, while alone C-peptide did not. A control peptide with the same residues in random sequence had little effect. In ESI-MS, C-peptide lowered the presence of insulin hexamer. The data suggest that C-peptide pro motes insulin disaggregation. Insulin/insulin oligomer μM dissociation constants were determined. Compatible with these findings, type 1 diabetic patients receiving insulin and C-peptide developed 66% more stimula tion of glucose metabolism than when given insulin alone. A role of C-peptide in promoting insulin disaggregation may be important physiologically during exo cytosis of pancreatic β-cell secretory granulae and pharmacologically at insulin injection sites. It is compatible with the normal co-release of C-peptide and insulin and may contribute to the bene ficial effect of C-peptide and insulin replacement in type 1 diabetics.Keywords. Surface plasmon resonance, electrospray ionization mass spectrometry, insulin effect, diabetes type 1, proinsulin C-peptide, insulin disaggregation, insulin hexamer decrease.

Proinsulin C-peptide activates α-enolase: implications for C-peptide–cell membrane interaction

“…However, the molecular bases of these interactions remain obscure, with the exception of C-peptide-insulin interaction as described above [38][39][40], and none of these is likely to engage with C-peptide-membrane interactions, although these proteins might be involved in the C-peptide signals and functions such as cell proliferation [46]. In contrast, it was previously shown that α-enolase is expressed on the cell surface of hematopoetic, epithelial and endothelial cells and serves as a plasminogen receptor [30][31][32][33], as well as on A31 cells in this study.…”

“…The N-terminal region of C-peptide is shown to be essential for disaggregation of insulin oligomers and intramolecular chaperone-like activity for proinsulin folding [38][39][40]. The central region of C-peptide (i.e.…”

“…Other than α-enolase, C-peptide has been reported to interact with following proteins: insulin [38][39][40], -chain of spectrin, myosin light chain kinase, cytoskeletal keratin type II, calcium/calmodulin-dependent serine protein kinase [44], protein tyrosine phosphatase 1B [45] and histone H4 [46]. However, the molecular bases of these interactions remain obscure, with the exception of C-peptide-insulin interaction as described above [38][39][40], and none of these is likely to engage with C-peptide-membrane interactions, although these proteins might be involved in the C-peptide signals and functions such as cell proliferation [46].…”

C‐peptide evolution: Generation from few structural restrictions of bioactivities not necessarily functional

“…Some C-peptide effects extend to the organismal level, with C-peptide measurably affecting glomerular filtration rates, circulation and nerve conductivity [13][14][15]. C-peptide has also been suggested to prevent late complications such as diabetic neuropathy [16], perhaps by chaperoning effects on insulin [17,18], and diabetes mellitus to be a double-deficiency disease [19].…”

Peptides in the Brain: Mass Spectrometry–Based Measurement Approaches and Challenges

“…In this (nonsignaling) role, the atrial natriuretic peptide's acidic domain affects the size and shape of Catabolism: extracellular processing and degradation of signaling peptides as a mechanism for peptide deactivation the resulting DCVs (39). Also, specific peptides in a prohormone may be required for correct folding and disulfide bond formation, as in the case of the insulin C-peptide, which links the A-and B-chains to promote their effective folding and assembly into insulin and may aid in the solubilization of insulin after vesicular release (40,41). Thus, the functions of the peptides derived from a single prohormone are diverse, and only a subset of these functions pertain to cell-cell signaling.…”