C-peptide in type 1 diabetes

Connecting (C) peptide is a 31 amino acid peptide that bridges the insulin A and B chains in the proinsulin molecule. It is released in a 1:1 ratio with insulin as this is secreted. C-peptide was considered to be biologically inert, but might have a biological role, and has been considered as a possible therapy for diabetic neuropathy and nephropathy. C-peptide has a half-life of about 30 minutes, and is cleared by the kidneys; 5–10% is excreted in the urine, and it can be measured in either serum, plasma or urine. C-peptide is more reliable than insulin as a measure of endogenous insulin secretion, and (not being present in injectable insulin preparations) can also be measured in insulin-treated patients. Fasting or stimulated serum or plasma C-peptide measurement is used to measure endogenous insulin reserve in people with diabetes. A spot urine sample measuring urine C-peptide:creatinine ratio (UCPCR) or a timed collection over 24 hours provide non-invasive integrated measures of insulin secretion. C-peptide testing can be used to differentiate type 1 diabetes from MODY or type 2, and can also be used to monitor endogenous insulin secretion in the course of type 1 intervention trials.

Synthesis and secretion

The K-ATP Channel
The K-ATP Channel
Preproinsulin, the transcriptional product of the insulin gene, is produced in the endoplasmic reticulum of the beta cell. Microsomal enzymes cleave preproinsulin to proinsulin, which contains the insulin alpha and beta chains, linked by a connecting peptide, C-peptide. Proinsulin is then transported to the Golgi complex, where it is packaged within clathrin-coated secretory granules. C-peptide is essential for the correct folding of proinsulin by forming two disulphide bridges between cysteine residues of the alpha and beta chains and one within the alpha chain. Following maturation, the secretory granule loses its clathrin coat and proinsulin undergoes proteolytic cleavage and further processing into insulin and C-peptide, which are co-secreted in equimolar amounts into the portal circulation. Once C-peptide is cleaved, the terminal end of the beta chain can bind to the insulin receptor.[1]

C-peptide metabolism

C-peptide is removed from the peripheral circulation at a constant rate. It is metabolised in the proximal renal tubules, and about 5–10% is excreted unchanged in the urine .

Biological role

Although traditionally considered to be biologically inert, there is some evidence that C-peptide has active properties. It binds to a membrane structure, probably a G-protein coupled membrane receptor, eliciting a rise in intracellular Ca2+ concentration and subsequent activation of at least two enzyme systems, Na+,K+ ATPase and endothelial nitric oxide synthase (eNOS).

C-peptide administration leads to increased blood flow in skeletal muscle and skin, diminished glomerular hyperfiltration, reduced urinary albumin excretion and improved nerve function in patients with type 1 diabetes who lack C-peptide, but not in healthy subjects. It has therefore been proposed that it might have therapeutic potential in preventing some of the late complications of diabetes.[2]

C-peptide in health

C-peptide reflects insulin secretion, and the amount of insulin secreted reflects the metabolic needs of the body, i.e. the degree of insulin sensitivity or insensitivity. The body becomes more resistant to insulin with the onset of puberty, and again later in life when insulin resistance increases because of weight gain or for other reasons. C-peptide secretion by a healthy pancreas thus reflects the insulin requirement of the body .

C-peptide in diabetes: type 1 diabetes, type 2 diabetes and MODY

Hyperglycaemia develops when the pancreatic islets are no longer able to generate sufficient insulin to meet the requirements of the body. An insulin-insensitive individual will thus develop type 2 diabetes despite increased insulin production ('high output failure'), whereas type 1 diabetes is associated with near-normal insulin sensitivity and 'low-output failure'. This difference will be reflected in their levels of C-peptide at diagnosis.

Childhood and adolescent diabetes is heterogeneous. The great majority, in populations of European descent, have type 1 diabetes, but obesity-associated type 2 diabetes is increasingly prevalent in post-pubertal adolescents from other ethnic backgrounds.[3] To complicate matters further, overweight adolescents may well develop autoimmune diabetes in association with other features more suggestive of type 2 diabetes, a condition sometimes referred to as 'double diabetes'.[4] Maturity onset diabetes of the young (MODY), a rare monogenic form of diabetes, may also present in childhood or adulthood, further complicating the differential diagnosis.[5]

Correct diagnosis is crucial for optimal management. In type 1 diabetes, insulin is needed from diagnosis, whereas patients with type 2 diabetes may respond well to diet, lifestyle and oral agents, and MODY patients frequently require only low-dose sulphonylureas (HNF1A-MODY) or no treatment at all (GCK-MODY). A diagnosis of MODY, which is generally suspected on the basis of family history and the absence of islet autoantibodies, requires confirmation by genetic testing, which is expensive, so ubiquitous testing in the clinic is not possible.

Clinical features and islet antibodies can help the clinician discriminate diabetes subtypes but are not perfect tests.[6][7] Clinical features may overlap between MODY, type 1 diabetes and type 2 diabetes (such as in the young obese patient with a parent affected, who may have familial type 1 diabetes, obesity-related type 2 diabetes or MODY). Islet antibodies reflect autoimmune type 1 diabetes, but may not always be present in type 1 diabetes, particularly when single rather than multiple antibodies are tested, when measured away from diagnosis and if based on animal rather than human sera (such as ICA assays).

C-peptide measurement has a key role in the correct diagnosis of the type of diabetes in adults.[8] and in children.[9] In type 1 diabetes, the majority of patients become severely insulin deficient within 5 years of diagnosis (2–3 years in children),[10] whereas in MODY and type 2 diabetes C-peptide persists. C-peptide testing is most useful beyond 2–3 years of diabetes and can not discriminate MODY from type 2 diabetes.

Measuring C-peptide

C-peptide can be measured in plasma or serum, fasting or following stimulation. Blood samples need to be taken on ice and processed immediately to prevent degradation by blood peptidases, which limits testing to a hospital setting with on-site laboratory facilities .

Stimulated C-peptide secretion can be assessed in response to a standard mixed meal tolerance test (MMTT) or following glucagon injection. The MMTT is better tolerated, with less nausea, and is more reproducible.[11] On the other hand, it is cumbersome, requires an overnight fast, and is rarely performed in routine clinical practice. Its main use is in intervention trials.

Fasting C-peptide correlates well with stimulated C-peptide, and is more routinely used in clinical care . A spot urine sample measuring urinary C-peptide creatinine ratio (UCPCR) may provide a useful non-invasive alternative, a particular advantage for children [12].

Natural history of C-peptide secretion in type 1 diabetes

Most patients with type 1 diabetes become severely insulin deficient within 5 years of diagnosis due to T cell mediated autoimmune destruction of pancreatic beta cells. C-peptide levels are lower in children compared with adults, and the speed of C-peptide decline is more rapid (particularly in children aged <5 years).[13] Increasing use of sensitive C-peptide assays have demonstrated that type 1 diabetes patients may continue to secrete C-peptide at low levels, often for decades after diagnosis [14], and these beta cells may continue to be functionally reactive to stimulation with a mixed meal load [15]

Persistence of C-peptide is advantageous for the patient. The Diabetes Control and Complications Trial (DCCT) demonstrated that 90 minute stimulated C-peptide ≥0.2 nmol/l (200 pmol/l) was associated with improved clinical outcomes (less retinopathy, neuropathy and severe hypoglycaemia). Efforts have subsequently focussed on attempts to preserve C-peptide. The honeymoon period (also known as partial remission), the time following diagnosis when some beta cell recovery occurs, can be followed by measuring C-peptide, usually during a MMTT, in type 1 diabetes trials to monitor interventions aimed at preserving beta cell function. C-peptide is rarely measured in routine clinical practice to follow the honeymoon period in part because of the difficulties in C-peptide measurement and uncertainty about its use. Instead, clinical factors are used, such as insulin dose and HbA1c, or combined measures.[16]

Summary

C-peptide is a useful measure of endogenous insulin secretion in insulin-treated diabetes. C-peptide can be measured in blood or urine, during a fasting or stimulated sample. The main roles for C-peptide testing are in the discrimination of diabetes subtypes, which in turn informs correct management and to monitor interventions aimed at preserving beta cell function.

References

  1. ^ Marques, RG, Fontaine, MJ, Rogers J. C-peptide – much more than a byproduct of insulin biosynthesis. Pancreas 2004;29(3): 231–8

  2. ^ Wahren J et al. The clinical potential of C-peptide replacement in type 1 diabetes. Diabetes 2012;61:761–72

  3. ^ Zeitler, P. Update on nonautoimmune diabetes in children. J Clin Endocrinol Metab 2009;94(7):2215–20

  4. ^ Libman IM, Becker DJ. Coexistence of type 1 and type 2 diabetes:"double diabetes"? Pediatr Diabetes 2003;4:110–3

  5. ^ Hattersley A, Bruining J, Shield J, et al. ISPAD Clinical Practice Consensus Guidelines 2006–2007. The diagnosis and management of monogenic diabetes in children. Pediatr Diabetes 2006;7(6):352–60

  6. ^ Shields et al. The development and validation of a clinical prediction model to determine the probability of MODY in patients with young-onset diabetes. Diabetologia 2012;55(5):1265-72

  7. ^ McDonald TJ et al. Islet autoantibodies can discriminate maturity onset diabetes of the young (MODY) from type 1 diabetes. Diabetic Medicine 2011;28(9):1028-33

  8. ^ Besser, RE, Shepherd, MH, McDonald, TJ, et al. Urinary C-peptide creatinine ratio is a practical outpatient tool for identifying hepatocyte nuclear factor 1-{alpha}/hepatocyte nuclear factor 4-{alpha} maturity-onset diabetes of the young from long-duration type 1 diabetes. Diabetes Care 2011;34(2):286–91

  9. ^ Ludvigsson et al. C-peptide in the classification of of diabetes in children and adolescents. Pediatric Diabetes 2012;13(1):45–50

  10. ^ Palmer JP, Fleming GA, Greenbaum CJ, et al. C-peptide is the appropriate outcome measure for type 1 diabetes clinical trials to preserve beta-cell report of an ADA workshop, 21-22 October 2001. Diabetes 2004;53(1):250–64

  11. ^ Greenbaum CJ, Mandrup-Poulsen T, McGee PF, et al. Mixed-meal tolerance test versus glucagon stimulation test for the assessment of beta-cell function in therapeutic trials in type 1 diabetes. Diabetes Care 2008;31(10):1966–71

  12. ^ Besser RE et al. Urine C-peptide creatinine ratio is a noninvasive alternative to the mixed-meal tolerance test in children and adults with type 1 diabetes. Diabetes Care 2011;34:607–9

  13. ^ XXX. Effect of intensive therapy on residual beta-cell function in patients with type 1 diabetes in the diabetes control and complications trial. A randomized, controlled trial. The Diabetes Control and Complications Trial Research Group. Ann Intern Med 1998;128(7):517–23

  14. ^ Wang L et al. Persistence of prolonged C-peptide production in type 1 diabetes as measured with an ultrasensitive C-peptide assay. Diabetes Care 2012;35(3):465–70

  15. ^ Oram RA et al.The majority of patients with long-duration type 1 diabetes are insulin microsecretors and have functioning beta cells.Diabetologia. 2014 Jan;57(1):187-91.

  16. ^ Mortensen HB et al. New definition for the partial remission period in children and adolescents with type 1 diabetes. Diabetes Care 2009;32(8):1384–90

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