Case 14

Shavings from the Carpenter’s Bench:

The Biological Role of the Insulin C-peptide

Focus concept

Recent experiments indicate that the insulin C-peptide, which is removed upon conversion of proinsulin to insulin, may have biological activity in its own right.

Prerequisites

  • Amino acid structure.
  • Principles of protein folding.
  • Membrane transport proteins.

Background

The protein hormone insulin is synthesized as a prohormone and is processed by cleavage of two peptide bonds to yield the mature hormone, which consists of two separate polypeptide chains, A, and B, linked by disulfide bonds. The spliced out portion is referred to as the C peptide and, although the excised C peptide is secreted along with the mature insulin, scientists believed that the C peptide was biologically inactive. However, recent evidence indicates that the C peptide may have biological activity in its own right. This discovery has important implications for the treatment of diabetes.

Pharmacological doses of C-peptide administered to diabetic rats increased the level of activity of the Na+K+ATPase pump, improved nerve conduction, vascular permeability and blood flow, but did not decrease hyperglycemia, nor did it prevent the glycosylation of many proteins seen in diabetics. Interestingly, a synthetic C-peptide made up of D-amino acids was able to bring about these same effects. Rat and human C-peptides showed the biological effects just described while C-peptides from pig and cow did not.

The authors proposed that the C-peptides were able to alter biological activity of cells by becoming integrated into the cell membrane, forming an ion channel and altering cell function. However, other researchers think that this hypothesis is unlikely.

Table 14.1:Sequences of human and animal insulins. The amino acid residues that make up the C peptide are underlined.

Questions

1.What are the physiological symptoms of untreated diabetes?

2.What is the structural purpose of the C peptide? In other words, why is insulin synthesized as a prohormone rather than being synthesized as separate A and B chains?

3.Prohormone convertase enzymes convert proinsulin to insulin. What do you note about the substrate specificity of the convertases?

4.In the human disease familial hyperinsulinemia, the arginine at position 89 has been mutated to a histidine. What are the biochemical consequences of this mutation?

5.Why do you think that a synthetic C-peptide consisting of D-amino acids (rather than the naturally occurring L amino acids) is as biologically active as the natural C-peptide which consists of L-amino acids? What can you conclude about the structural requirements for C-peptide biological activity?

6.Why do you think that the rat and human C-peptides had biological activity whereas the porcine and bovine C-peptides did not?

7.Evaluate the hypothesis that the C-peptide functions as a channel-former.

8.How is diabetes currently treated in this country? Based on the information presented here, would you modify the protocol in any way?

References

Ido, Y., Vindigni, A., Chang, K., Stramm, L., Chance, R., Heath, W. F., DiMarchi, R. D., DiCera, E., Williamson, J. R.(1997) Science277, pp. 563-566.

Steiner, D. F., and Rubenstein, A. H. (1997) Science277, pp. 531-532.

Wahren, J., Johansson, B.-L., and Wallberg-Henriksson, H. (1994) Diabetologica [Suppl 2]37, pp. S99-S107.

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