Link between fasting C-peptide and diabetic retinopathy in people with type 2 diabetes mellitus

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A team of Chinese researchers reported that fasting C-peptide (FCP) has a complicated relationship with the development of diabetic retinopathy (DR). Below a specific threshold, FCP exerts a protective effect, but above that threshold the protective effect becomes uncertain, according to Jicai Ma, MD, and colleagues from the Department of Endocrinology, The Second Hospital of Jilin University, Changchun, Jilin, People’s Republic of China.

In their recent study, the group found a nonlinear relationship between the FCP level and the risk of developing DR that initially was negatively correlated but stabilized at a lower level when FCP exceeded 4.11 ng/mL.

Ma and colleagues explained that the “C-peptide concentration in peripheral blood is generally considered to be the most suitable marker of insulin secretion, as it is released in equal amounts with insulin and reflects the overall health of β-cells by assessing their ability to produce insulin.^2,3 However, the changes in the FCP concentration in individuals with DR, particularly in those with type 2 diabetes, can reflect not only reduced β-cell function but also the degree of insulin resistance.^4,5”

In light of this, they wanted to take a close look at the link between the FCP concentration and DR in patients with type 2 diabetes; previous research had not evaluated the dose-response between FCP and DRand had not determined if a linear relationship was present between DR risk and elevated C-peptide.

This observational analysis included 1,661 patients with type 2 diabetes, the primary outcome of which was the DR categorized based on the patients’ FCP levels.

Analysis of FCP levels

“Our study found a non-linear relationship between the FCP level and DR, as well as a threshold effect at an FCP of 4.11 ng/mL. Below the critical value, each 1 ng/mL increase in the FCP levels was associated with a 24% lower risk of DR (odds ratio [OR]: 0.74, 95% confidence interval [CI]: 0.64– 0.86),” they reported. However above the cutoff, they found a non-significant trend toward an increased risk of developing DR (OR: 1.52, 95% CI: 0.87–2.66).

In their discussion, the authors suggested that “the nonlinear relationship between the two might result from the dual influence of C-peptide on DR.⁶ The defensive impact of C-peptide on DR stems from these mechanisms. C-peptide has the potential to avert retinopathy through suppressing intracellular reactive oxygen species accumulation, lowering the formation of stress fibers, preserving the integrity of endothelial cells, and limiting the vascular endothelial growth factor-triggered rise in microvascular permeability.⁷ At the same time, previous studies have shown that in the presence of type 2 diabetes, elevated endogenous C-peptide levels can have harmful effects.^6,8,9

They suggested that excessive C-peptide may lead to antagonism between the protective and harmful impacts of C-peptide concerning the onset and progression of DR, resulting in no significant protective effect on DR when C-peptide exceeds the threshold level.

References

1. Ma J, Han C, Lv Y, Cai H. Non-linear relationship between fasting C-peptide and retinopathy in patients with type 2 diabetes mellitus - a retrospective study. Diabetes Metab Syndr Obes. 2025;18:1035-1045. https://doi.org/10.2147/DMSO.S501361

2. Kim BY, Jung CH, Mok JO, Kang SK, Kim CH. Association between serum C-peptide levels and chronic microvascular complications in Korean type 2 diabetic patients. Acta Diabetol. 2012;49:9–15. doi:10.1007/s00592-010-0249-6

3. Prystupa K, Renklint R, Chninou Y, et al. Comprehensive validation of fasting-based and oral glucose tolerance test-based indices of insulin secretion against gold standard measures. BMJ Open Diabetes Res Care. 2022;10:e002909. doi:10.1136/bmjdrc-2022-002909

4. Young EE, Chinenye S, Unachukwu CN. Beta cell response to a mixed meal in nigerian patients with type 2 diabetes. BMC Endocr Dis. 2012;12:11. doi:10.1186/1472-6823-12-11

5. Souto SB, Campos JR, Fangueiro JF, et al. Multiple cell signalling pathways of human proinsulin C-peptide in vasculopathy protection. Int J Mol Sci. 2020;21:645. doi:10.3390/ijms21020645

6. Dakroub A, Dbouk A, Asfour A, et al. C-peptide in diabetes: a player in a dual hormone disorder? JCell Physiol. 2024;239:e31212. doi:10.1002/jcp.31212

7. Lim YC, Bhatt MP, Kwon MH, et al. Prevention of VEGF-mediated microvascular permeability by C-peptide in diabetic mice. Cardiovasc Res. 2014;101:155–164. doi:10.1093/cvr/cvt238

8. Mavrakanas T, Frachebois C, Soualah A, et al. C-peptide and chronic complications in patients with type-2 diabetes and the metabolic syndrome. Presse Med. 2009;38. doi:10.1016/j.lpm.2009.02.023

9. Liu Y, Zhao X, Yang Z, Wang S, Han C, Zhang H. Correlation between serum C-peptide-releasing effects and the risk of elevated uric acid in type 2 diabetes mellitus. Endocr J. 2022;69:773–784. doi:10.1507/endocrj.EJ21-0492