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Do C-Peptides Help to Preserve Beta-cells?

Higher C-peptide levels are also associated with better long-term microvascular health including retinopathy…. 

C-peptide is a protein that is secreted in equimolar concentrations with insulin during insulin biosynthesis. Due to the fact that C-peptide experiences negligible first pass metabolism and that C-peptide levels are not affected by exogenous insulin administration, C-peptide has been considered a clinically important biomarker for assessing the pancreas’ ability to produce insulin. C-peptide was once thought to have no biological role following insulin biosynthesis but current evidence suggests it could potentially be a biologically active hormone.

The Eisenbarth model of type 1 diabetes postulated rapid, immune-mediated, linear loss of pancreatic beta cells, eventually leading to an absolute insulin deficiency. Researchers have assumed that the majority of type 1 diabetics would ultimately show no residual C-peptide secretion as pancreatic beta cells rapidly die-off. While the core assumptions of this model remain true, new evidence may indicate that pancreatic beta cell function before, during and after diagnosis of type 1 diabetes, may be more complicated than originally thought.

In the Diabetes Control and Complications Trial (DCCT) researchers demonstrated that tight control of diabetes resulted in less microvascular and macrovascular complications – however, at the expense of increased risk of hypoglycemic events. Researchers also found that patients having a C-peptide level of 0.2 pmol/mL initially or sustained over the course of a year following diagnosis, had significantly less diabetes-related complications. This prompted the further investigation of the role of C-peptide.

Other studies from this data showed C-peptide levels associated with less hyperglycemia, independent of the aggressiveness of blood glucose control. A more recent analysis of this data attained from the DCC trial found that a C-peptide level as low as 0.03 pmol/mL may have some clinical significance with regards to delaying retinopathy progression. Furthermore, a longitudinal analysis on intensively treated DCCT participants showed for every 1pmol/mL increase in baseline stimulated C-peptide was associated with a 1% reduction in HbA1c.

Studies done on patients who underwent islet transplants have shown that small amounts of residual pancreatic beta-cell function may be clinically important. Patients who underwent islet-cell transplants with higher C-peptide levels maintained fasting blood glucose levels at goal, HbA1c values <6.5% and insulin independency post-transplantation, than those with lower C-peptide levels.

Interestingly, in a study done by Nakanishi et al., no difference in the eventual incidence of retinopathy in those with and without C-peptide was seen 5 years after diagnosis. This changed, however, while looking at the prevalence of C-peptide 15 years after diagnosis when researchers found a relationship between those with C-peptide. This may suggest that C-peptide is needed for clinically significant microvascular benefits.

Information from both the Diabetes Prevention Trial – type 1 (DPT01) and Type 1 Diabetes TrialNet provide insight into the pathological events prior to diabetes diagnosis. To identify those at risk for type 1 diabetes, these trials assessed the relatives of type 1 diabetes patients for the presence of autoantibodies. If autoantibodies were present, participants were enrolled in either prevention trials or carefully monitored for type 1 diabetes.

A major observation in antibody positive relatives of type 1 diabetes patients was that the pancreatic beta cell response to glucose tolerance tests remained stable for many years. This intact response appeared to change around the time of diagnosis when there was a change in the sensitivity of the pancreatic beta cell to glucose. This may be indicative that the decline in beta-cell function is in response to hyperglycemia or immune flaring, representing transient beta-dysfunction as opposed to acute beta-cell death.

At the time of type 1 diabetes diagnosis, C-peptide values may vary greatly. One factor is the setting of diagnosis. In patients diagnosed in the community, C-peptide levels may be within normal range of a non-diabetic patient, according to the SEARCH for Diabetes in Youth Study. This is likely the result of the time diabetes is diagnosed. For example, a patient in the community setting is more often diagnosed when a stage insulin resistance is high, resulting in high levels of insulin and corresponding C-peptide levels; whereas a patient diagnosed in a study which screened for type 1 diabetes, the diagnosis is made earlier, before high amounts of insulin are made.

Two other major factors are age and degree of insulin resistance. At the time of diagnosis, children had less measurable C-peptide levels than adults. This may be explained by less pancreatic beta-cell mass as the rate of C-peptide decline is similar among both young adults and children. Patients with a higher body mass index at the time of diagnosis also displayed higher levels of C-peptide – likely a consequence of elevated insulin levels in response to decreased insulin sensitivity.

Studies have also shown approximately 40% residual function in those with type 1 diabetes for more than 4 years. In the Joslin 50-yr Medalist Study – a postmortem analysis study – individuals with a history – over 67 percent of those with type 1 diabetes had at least a minimal of 0.03pmol/mL random C-peptide levels. Further, individuals with undetectable C-peptide levels had insulin-positive beta-cells with evidence of apoptosis. This leads to the possibility that the beta-cells of type 1 diabetics are in a steady-state of apoptosis and proliferation – entertaining the possibility of entirely new therapeutic targets for preserving or preventing beta-cell destruction.

Practice Pearls:
  • Residual beta-cell function is associated with better health outcomes in diabetic patients
  • Association studies suggest that C-peptide may be biologically active and have an active role in preventing type 1-diabetes-related complications – however, direct testing needs to be done to confirm a causal relationship in the event that one exists

Vanbuecken DE, Greenbaum CJ. Residual C-peptide in type 1 diabetes: what do we really know?. Pediatr Diabetes. 2014;15(2):84-90. http://onlinelibrary.wiley.com/doi/10.1111/pedi.12135/full