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C-Peptide Levels in Diabetes Management

Can C-peptide help attain adequate glycemic control in diabetes patients?

C-peptide has served as a biomarker for understanding glycemic control in diabetes patients. Its role in normal physiology and diabetes serves mainly as an endogenous antioxidant that responds to rise in blood glucose despite normal uptake of glucose by peripheral tissues. Under normal physiologic conditions, C-peptide is synthesized from the cleavage of proinsulin, which yields insulin and C-peptide. Once stored in pancreatic beta cells, both of these byproducts are released in equimolar amounts in response to rises in glucose. However, this effect is not seen in type 1 diabetes patients due to lack of insulin, which can be a predisposition for patients to develop microvascular and macrovascular complications. The postulated mechanism by which this vascular injury occurs is thought to be attributed to the toxic effects of hyperglycemia, which can precipitate the formation of reactive oxygen species, leading to oxidative stress and apoptosis. Thus, C-peptide can counteract these oxidative effects and reduce inflammation in the vascular endothelium, hence improving blood flow in certain tissues and organs. Based on the hypothesized mechanism by which C-peptide works, researchers have focused on expanding the role of C-peptide in diabetes patients. In a double-blind randomized control trial, patients with type 1 diabetes and incipient nephropathy received C-peptide for 4 weeks. At the 2-week and 4-week mark, glomerular filtration and kidney blood flow were improved. Similar effects have been found after administering C-peptide for 3 months and improvement in albuminuria were noted. The role of C-peptide in retinopathy has shown promising results through VGEF regulation; however, clinical studies involving human subjects have not been done.

The DCCT research study showed that lower A1c levels can be obtained with maintenance of measurable C-peptide secretion. This finding showed that the residual beta cell function and C-peptide levels in type 1 diabetes patients can possibly be maintained by a more intensive insulin therapy. Based on this discovery, Buckingham and colleagues conducted a randomized controlled trial in which patients with type 1 diabetes were followed for two years after the initial diagnosis. Researchers sought to determine the association between continuous glucose monitoring and A1c and C-peptide response. A total of 67 patients (7-45 years of age) were enrolled six days following the diagnosis of type 1 diabetes mellitus. Afterwards these patients were randomized in a 2:1 ratio to an intensive group or usual-care group. C-peptide levels were monitored at 2 and 6 weeks, then every 3 months until the 2-year study completion.

The results in this study indicate a gradual decline in C-peptide levels. Peak C-peptide level (> 0.2 pmol/ml) decreased from 98% at 3 months to 59% at 24 months. However, an association was observed with the glucose values obtained and the peak C-peptide levels. Those blood glucose values between 3.9 and 7.8 mmol/L were associated with C-peptide peak level of greater than 0.2 pmol/ml (p=0.001). However, the positive predictive value for a C-peptide level to predict glucose levels and vice versa was weak. Interestingly, peak C-peptide levels did not predict hypoglycemic episode. However, glucose variability was influenced by C-peptide levels. It was also observed that higher C-peptide levels were associated with lower glucose variability (p=0.02). Lastly, an association was found between C-peptide levels and A1c. Across time, A1c levels less than 6% were associated with peak C-peptide levels of greater than 0.2 pmol/ml. But again, the positive predictive value for this association was weak (p<0.001 and p=0.01 for within-subject and between subject effects, respectively).

In summary, the role of C-peptide in diabetes management has been expanding for the past years. The physiological mechanism by which this peptide elicits anti-oxidative and anti-inflammatory effects has helped in the management of diabetes. Nonetheless, challenges arise when dealing with such biomarkers. For instance, ordering, interpreting, and covering the expenses for these laboratory tests is a difficult barrier to overcome. Other studies should consider long-term benefits (> 2 years) of C-peptide. The disease-modifying strategies of the C-peptide rely on utilizing these biomarker findings to predict pancreatic beta cell secretory function and help obtain adequate glycemic control in diabetes patients. More studies with stronger evidence need to be established for the use of C-peptide in order to highlight its potential benefits.

Practice Pearls:

  • C-peptide can provide hemodynamic benefits to the vascular endothelium, which can help prevent major microvascular and macrovascular complications.
  • Utilizing more intensive insulin regimens once patient is diagnosed can help delay decrease in C-peptide levels by preserving pancreatic beta cells and their secretory functions.
  • A1c levels and glucose levels can be predicted by obtaining C-peptide levels; however, the positive predictive value for these warrants close attention and further research.


Buckingham, Bruce, Peiyao Cheng, Roy W. Beck, Craig Kollman, Katrina J. Ruedy, Stuart A. Weinzimer, Robert Slover, Andrew A. Bremer, John Fuqua, and William Tamborlane. “CGM-measured Glucose Values Have a Strong Correlation with C-peptide, HbA1c and IDAAC, but Do Poorly in Predicting C-peptide Levels in the Two Years following Onset of Diabetes.” Diabetologia 58.6 (2015): 1167-174. Web.

Hao, Wei, Steven Gitelman, Linda A. Dimeglio, David Boulware, and Carla J. Greenbaum. “Fall in C-Peptide During First 4 Years From Diagnosis of Type 1 Diabetes: Variable Relation to Age, HbA1c, and Insulin Dose.” Diabetes Care Dia Care (2016): Dc160360. Web.

Wahren, John, and Charlotte Larsson. “C-peptide: New Findings and Therapeutic Possibilities.” Diabetes Research and Clinical Practice 107.3 (2015): 309-19. Web.
Researched and prepared by Pablo A. Marrero-Núñez – USF College of Pharmacy Student Delegate – Doctor of Pharmacy Candidate 2017, reviewed by Dave Joffe, BSPharm, CDE