China: Research published in Cardiovascular Diabetology has suggested a bidirectional effect of C-peptide on cardiovascular (CV) risk in nondiabetic adults and patients newly diagnosed with type 2 diabetes. The study found that the association of C-peptide with cardiovascular biomarkers and events was different between people without previous T2D and those with previous T2D.
"The bidirectional effect of C-peptide on cardiovascular risk implies that it plays a beneficial role at a low level and may be harmful at a high level in patients with newly diagnosed T2D and nondiabetic adults," Fu-Sheng Fang, Chinese PLA General Hospital, Beijing, China, and colleagues wrote in their study.

Insulin and C-peptide are produced from a similar precursor and secreted in equimolar amounts into circulation. However, C-peptide is subjected to negligible hepatic first-pass metabolism, unlike insulin, has almost five to ten times higher half-life, and has been recognized as a surrogate marker of beta cell function in the pancreas.
C-peptide is reported to be a biologically active peptide and has been shown to reduce hyperglycemia-induced inflammation and provide protection against diabetic complications in diabetes mellitus. Also, C-peptide is seen as a therapeutic strategy for preventing diabetic vasculopathy in type 1 diabetes. Recent research has shown a positive correlation between C-peptide and arterial stiffness and cardiovascular death in nondiabetic patients. Increased C-peptide levels may play a causal role in early pathogenesis in T2D patients. Overall, the beneficial effects of C-peptide seem insignificant and negative in healthy people and T2D patients.
More studies are required to establish the role of C-peptide, particularly in nondiabetic adults and T2D patients, given the limited number of studies investigating the effects of C-peptide and the potential for confounding, like insulin levels. Considering this, the research team examined associations between fasting C-peptide and cardiovascular biomarkers and events in healthy people and T2D patients. Associations were also discussed, stratified by insulin resistance index and glucose metabolism status.
The study included a total of 55636 participants who had a health examination from 2017 to 2021, out of which 6727 patients visited the hospital at least twice. Measuring cardiovascular biomarkers like high-sensitivity cardiac troponin T (hs-cTnT) and high-sensitivity C-reactive protein (hs-CRP) was done, and their relationships with fasting C-peptide were investigated for all patients. During the last visit, cardiovascular events were obtained, and their associations with C-peptide were evaluated for patients who visited the hospital at least twice.
The study demonstrated the following findings:
· 11.1% had a previous type 2 diabetes (T2D).
· In the participants without previous T2D, the relation between fasting C-peptide and hs-CRP and hs-cTnT was negative in cases where the value of fasting C-peptide was < 1.4 ng/mL and positive if the value was ≥ 1.4 ng/mL.
· These relationships remained significant after adjustment for insulin resistance index, hemoglobin A1c, and its interaction with C-peptide.
· Hazard ratios of CV events first decreased and then increased with baseline C-peptide levels, though these associations became insignificant.
· The associations of C-peptide with cardiovascular biomarkers and events were insignificant in the patients with the previous T2DM, unlike the participants without previous T2DM.
"Further research is needed to examine the role of C-peptide, the mechanism behind the role, and the difference in this role in nondiabetic adults and T2D patients," the researchers concluded.
Reference:
Yan, ST., Sun, J., Gu, ZY. et al. The bidirectional association of C-peptide with cardiovascular risk in nondiabetic adults and patients with newly diagnosed type 2 diabetes mellitus: a retrospective cohort study. Cardiovasc Diabetol 21, 201 (2022). https://doi.org/10.1186/s12933-022-01636-z