C-peptide evolution: generation from few structural restrictions of bioactivities not necessarily functional

The proinsulin C-peptide has molecular, cellular and organismal activities but lacks disease-associated mutations or short-term loss-of-function effects. This dilemma between activity and function may be explained from its evolutionary setting with insulin as an ancestral partner. The charge, approximate length and flexibility of C-peptide are all that is required for the insulin interactions, while remaining aspects are free to evolve, where new bioactivities can emerge. They can initially be transient, weak, and non-functional, but may gradually be consolidated. In this manner, C-peptide may have acquired multiple bioactivities, explaining why some yet have limited functions but could represent early-stage hormonal-like activities.