C-peptide

The connecting peptide, or C-peptide, is a short 31-amino-acid polypeptide that connects insulin's A-chain to its B-chain in the proinsulin molecule. In the context of diabetes or hypoglycemia, a measurement of C-peptide blood serum levels can be used to distinguish between different conditions with similar clinical features.

Not to be confused with C-reactive protein or Protein C.
C-peptide[1]
Identifiers
CAS Number
3D model (JSmol)
ChemSpider
MeSH C-Peptide
PubChem CID
Properties
Chemical formula
 C129H211N35O48
Molar mass 3020.29 g/mol
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
N verify (what is YN ?)
Infobox references

In the insulin synthesis pathway, first preproinsulin is translocated into the endoplasmic reticulum of beta cells of the pancreas with an A-chain, a C-peptide, a B-chain, and a signal sequence. The signal sequence is cleaved from the N-terminus of the peptide by a signal peptidase, leaving proinsulin. After proinsulin is packaged into vesicles in the Golgi apparatus (beta-granules), the C-peptide is removed, leaving the A-chain and B-chain bound together by disulfide bonds, that constitute the insulin molecule.

History

Proinsulin C-peptide was first described in 1967 in connection with the discovery of the insulin biosynthesis pathway.[2] It serves as a linker between the A- and the B- chains of insulin and facilitates the efficient assembly, folding, and processing of insulin in the endoplasmic reticulum. Equimolar amounts of C-peptide and insulin are then stored in secretory granules of the pancreatic beta cells and both are eventually released to the portal circulation. Initially, the sole interest in C-peptide was as a marker of insulin secretion and has, as such, been of great value in furthering the understanding of the pathophysiology of type 1 and type 2 diabetes. The first documented use of the C-peptide test was in 1972. During the past decade, however, C-peptide has been found to be a bioactive peptide in its own right, with effects on microvascular blood flow and tissue health.

Function

Cellular effects of C-peptide

C-peptide has been shown to bind to the surface of a number of cell types such as neuronal, endothelial, fibroblast and renal tubular, at nanomolar concentrations to a receptor that is likely G-protein-coupled. The signal activates Ca2+-dependent intracellular signaling pathways such as MAPK, PLCγ, and PKC, leading to upregulation of a range of transcription factors as well as eNOS and Na+K+ATPase activities.[3] The latter two enzymes are known to have reduced activities in patients with type I diabetes and have been implicated in the development of long-term complications of type I diabetes such as peripheral and autonomic neuropathy.

In vivo studies in animal models of type 1 diabetes have established that C-peptide administration results in significant improvements in nerve and kidney function. Thus, in animals with early signs of diabetes-induced neuropathy, C peptide treatment in replacement dosage results in improved peripheral nerve function, as evidenced by increased nerve conduction velocity, increased nerve Na+,K+ ATPase activity, and significant amelioration of nerve structural changes.[4] Likewise, C-peptide administration in animals that had C-peptide deficiency (type 1 model) with nephropathy improves renal function and structure; it decreases urinary albumin excretion and prevents or decreases diabetes-induced glomerular changes secondary to mesangial matrix expansion.[5][6][7][8] C-peptide also has been reported to have anti-inflammatory effects as well as aid repair of smooth muscle cells.[9][10] ii

Clinical uses of C-peptide testing
  • Patients with diabetes may have their C-peptide levels measured as a means of distinguishing type 1 diabetes from type 2 diabetes or Maturity onset diabetes of the young (MODY).[11] Measuring C-peptide can help to determine how much of their own natural insulin a person is producing as C-peptide is secreted in equimolar amounts to insulin. C-peptide levels are measured instead of insulin levels because C-peptide can assess a person's own insulin secretion even if they receive insulin injections, and because the liver metabolizes a large and variable amount of insulin secreted into the portal vein but does not metabolise C-peptide, meaning blood C-peptide may be a better measure of portal insulin secretion than insulin itself.[12][13] A very low C-peptide confirms Type 1 diabetes and insulin dependence and is associated with high glucose variability, hyperglycaemia and increased complications. The test may be less helpful close to diagnosis, particularly where a patient is overweight and insulin resistant, as levels close to diagnosis in Type 1 diabetes may be high and overlap with those seen in type 2 diabetes.[14]
  • Differential diagnosis of hypoglycemia. The test may be used to help determine the cause of hypoglycaemia (low glucose), values will be low if a person has taken an overdose of insulin but not suppressed if hypoglycaemia is due to an insulinoma or sulphonylureas.
  • Factitious (or factitial) hypoglycemia may occur secondary to the surreptitious use of insulin. Measuring C-peptide levels will help differentiate a healthy patient from a diabetic one.
  • C-peptide may be used for determining the possibility of gastrinomas associated with Multiple Endocrine Neoplasm syndromes (MEN 1). Since a significant number of gastrinomas are associated with MEN involving other hormone producing organs (pancreas, parathyroids, and pituitary), higher levels of C-peptide together with the presence of a gastrinoma suggest that organs besides the stomach may harbor neoplasms.
  • C-peptide levels may be checked in women with Polycystic Ovarian Syndrome (PCOS) to help determine degree of insulin resistance.

Therapeutics

Therapeutic use of C-peptide has been explored in small clinical trials in diabetic kidney disease.[15][16] Creative Peptides,[17] Eli Lilly,[18] and Cebix[19] all had drug development programs for a C-peptide product. Cebix had the only ongoing program until it completed a Phase IIb trial in December 2014 that showed no difference between C-peptide and placebo, and it terminated its program and went out of business.[20][21]

References
  1. C-Peptide - Compound Summary, PubChem.
  2. Steiner D.F.; Cunningham D.; Spigelman L.; Aten B. (1967). "Insulin Biosynthesis: Evidence for a Precursor". Science. 157 (3789): 697–700. doi:10.1126/science.157.3789.697. PMID 4291105.
  3. Hills CE, Brunskill NJ (2008). "Intracellular signalling by C-peptide". Exp Diabetes Res. 2008: 1–8. doi:10.1155/2008/635158. PMC 2276616. PMID 18382618.
  4. Sima AA, Zhang W, Sugimoto K, et al. (July 2001). "C-peptide prevents and improves chronic Type I diabetic polyneuropathy in the BB/Wor rat". Diabetologia. 44 (7): 889–97. doi:10.1007/s001250100570. PMID 11508275.
  5. Samnegård B, Jacobson SH, Jaremko G, Johansson BL, Sjöquist M (October 2001). "Effects of C-peptide on glomerular and renal size and renal function in diabetic rats". Kidney Int. 60 (4): 1258–65. doi:10.1046/j.1523-1755.2001.00964.x. PMID 11576340.
  6. Samnegård B, Jacobson SH, Jaremko G, et al. (March 2005). "C-peptide prevents glomerular hypertrophy and mesangial matrix expansion in diabetic rats". Nephrol. Dial. Transplant. 20 (3): 532–8. doi:10.1093/ndt/gfh683. PMID 15665028.
  7. Nordquist L, Brown R, Fasching A, Persson P, Palm F (November 2009). "Proinsulin C-peptide reduces diabetes-induced glomerular hyperfiltration via efferent arteriole dilation and inhibition of tubular sodium reabsorption". Am. J. Physiol. Renal Physiol. 297 (5): F1265–72. doi:10.1152/ajprenal.00228.2009. PMC 2781335. PMID 19741019.
  8. Nordquist L, Wahren J (2009). "C-Peptide: the missing link in diabetic nephropathy?". Rev Diabet Stud. 6 (3): 203–10. doi:10.1900/RDS.2009.6.203. PMC 2827272. PMID 20039009.
  9. Luppi P, Cifarelli V, Tse H, Piganelli J, Trucco M (August 2008). "Human C-peptide antagonises high glucose-induced endothelial dysfunction through the nuclear factor-kappaB pathway". Diabetologia. 51 (8): 1534–43. doi:10.1007/s00125-008-1032-x. PMID 18493738.
  10. Mughal RS, Scragg JL, Lister P, et al. (August 2010). "Cellular mechanisms by which proinsulin C-peptide prevents insulin-induced neointima formation in human saphenous vein". Diabetologia. 53 (8): 1761–71. doi:10.1007/s00125-010-1736-6. PMC 2892072. PMID 20461358.
  11. Jones AG, Hattersley AT (Jul 2013). "The clinical utility of C-peptide measurement in the care of patients with diabetes". Diabetic Medicine. 30 (7): 803–17. doi:10.1111/dme.12159. PMC 3748788. PMID 23413806.
  12. Clark PM (1999). "Assays for insulin, proinsulin and C-peptide". Ann Clin Biochem. 36: 541–564.
  13. Shapiro ET, Tillil H, Rubenstein AH, Polonsky KS (Nov 1988). "Peripheral insulin parallels changes in insulin secretion more closely than C-peptide after bolus intravenous glucose administration". J Clin Endocrinol Metab. 67 (5): 1094–9. doi:10.1210/jcem-67-5-1094. PMID 3053748.
  14. R, Chandini; Udayabhaskaran V; Binoy J Paul; K.P Ramamoorthy (July 2013). "A study of non-obese diabetes mellitus in adults in a tertiary care hospital in Kerala, India". International Journal of Diabetes in Developing Countries. 33 (2): 83–85. doi:10.1007/s13410-013-0113-7.
  15. Brunskill, NJ (19 September 2016). "C-peptide and diabetic kidney disease". Journal of Internal Medicine. 281 (1): 41–51. doi:10.1111/joim.12548. PMID 27640884.
  16. Shaw, JA; Shetty, P; Burns, KD; Fergusson, D; Knoll, GA (2015). "C-peptide as a Therapy for Kidney Disease: A Systematic Review and Meta-Analysis". PLOS ONE. 10 (5): e0127439. doi:10.1371/journal.pone.0127439. PMC 4439165. PMID 25993479.
  17. "C-peptide - Creative Peptides -". AdisInsight. Retrieved 22 October 2016.
  18. "C-peptide - Eli Lilly". AdisInsight. Retrieved 22 October 2016.
  19. "C-peptide long-acting - Cebix". adisinsight.springer.com. AdisInsight. Retrieved 22 October 2016.
  20. Bigelow, Bruce V. (23 February 2015). "Cebix Shuts Down Following Mid-Stage Trial of C-Peptide Drug". Xconomy.
  21. Garde, Damian (February 24, 2015). "Cebix hangs it up after raising $50M for diabetes drug". FierceBiotech.
  • Media related to C-peptide at Wikimedia Commons
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