In china, the incidence of diabetes mellitus has rapidly risen from 0.67% in 1980 to 11.2% in 2020, and its prevalence is increasing every year (1). Diabetic kidney disease (DKD) occurs in 20% to 40% of patients with diabetes, it has become one of the most common complications of diabetes and the leading cause of end-stage renal disease in most of the world (2, 3). DKD has posed a rapidly growing global health care burden (4, 5). Therefore, in order to explore the better preventive and therapeutic methods, and lifestyle of patients with DKD, many researchers have focused on studying the clinical risk factors for occurrence and progression of DKD in patients with diabetes, such as age, gender, blood pressure, glycemic control, diabetes duration, body mass index (BMI), and dyslipidemia, among others (6–8).

C-peptide consists of 31amino acids, and is formed by the cleavage of pro-insulin (9). Compared with insulin, C-peptide is secreted in equimolar amounts and has a longer half-life, hence, it is recognized as a reliable indicator of the function of pancreatic β-cell (10). Recently, C-peptide is no longer considered an inert molecule, it may have multiple functions, including signaling pathways activation, physiological effects, and protection against complications of diabetes (11). Animal studies have demonstrated that C-peptide can improve functional abnormalities in the glomeruli, reduce the risk of albuminuria and hyper-filtration, and prevent the chronic complications of diabetes (9, 12). However, several small-scale clinical trials and/or animal studies showed the divergent findings in the role of C-peptide administration in the outcomes of patients with DKD (9). Therefore, the association of serum C-peptide with the risk of DKD is complicated, and it needs to be further clarified in patients with diabetes mellitus.

More recently, some studies have identified serum uric acid (UA) as an independent clinical risk factor for chronic kidney disease in patients with diabetes mellitus (13, 14), however, others do not (15, 16). The association between kidney impairment risk and the different stratification of serum UA level in patients with type 2 diabetes mellitus (T2DM) remains unclear. Given the above, we hypothesized that there were non-linear relationships between C-peptide, UA and renal dysfunction odds. Therefore, we conducted a real-world observational study to further explore the relationships of different stratification of C-peptide and UA levels with renal dysfunction in patients with T2DM.

In the present study, we found that although fasting C-peptide, C0/C2 ratio and UA were independently associated with the odds of renal dysfunction in patients with T2DM, the probability of renal dysfunction did not linearly rise with the increase of serum fasting C-peptide and UA levels. Based on the RCS analysis, the renal impairment risk was non-linearly associated with the fasting C-peptide and UA levels after adjustment for the potential confounders, including age, gender, SBP, DBP, BMI, HbA1c level, diabetic duration, and hypertension (yes or no). Specifically, when 0.28 ≤ fasting C-peptide ≤ 0.56 nmol/L and/or when 276 ≤ UA ≤ 409 μmol/L, patients with T2DM might have the relatively lower renal dysfunction odds.

Chronic kidney disease is a very common complication of T2DM in clinical practice, its early diagnosis, intervention and treatment may have a critical impact on the delay of its progression to end-stage renal disease and the improvement of the patients prognosis (22). In recent years, the physiological function of C-peptide has been gradually discovered (11), C-peptide may block the activity of renal Na⁺-K⁺-ATPase, thus decreasing the Na⁺ reabsorption by the proximal convoluted tubule and the glomerular filtration pressure (9); the decrease of C-peptide may also promote the occurrence of microvascular complications in patients with diabetes mellitus (23). Therefore, some researchers had focused on exploring the effects of exogenous human C-peptide supplementation on the improvement of DKD (24–26). A clinical trial included twenty-one normotensive patients with microalbuminuria demonstrated that combined human C-peptide (600 nmol/24 h) and insulin administration for 3 months might improve the kidney function by decreasing the urinary albumin excretion in patients with type 1 diabetes mellitus (24). An animal model study showed the similar findings that the supplementation of exogenous C-peptide could reduce the urinary albumin excretion and inhibit the upregulation of type IV collagen via interaction with the TGF-beta signal in glomerular podocytes in mouses with type 1 diabetes mellitus (25). However, Samnegård B et al. conducted an animal study of 9 rats without diabetes and 22 rats with type 1 diabetes mellitus, they found that neither the albuminuria level nor the glomerular basement membrane had statistically significant improvement after the supplementation of exogenous C-peptide for 4 weeks (26). Most these previous study for C-peptide effects on DKD were conducted in patients or animals with type 1 diabetes mellitus (24–26). In addition, the C-peptide levels fluctuated greatly in different stages of T2DM (27), therefore, the role of C-peptide in renal injury in patients with T2DM is still controversial and needs more studies.

In the present study, the association of C-peptide with the renal dysfunction odds in patients with T2DM was investigated. Compared with 2h postprandial C-peptide, fasting C-peptide was independently and significantly related with the renal dysfunction prevalence. Although on the whole the odds of renal impairment raised with increase of fasting C-peptide in the multivariate regression analysis using the continuous values, a non-linear relationship was showed between the renal dysfunction odds and the different stratification of fasting C-peptide. The study of Huang Y, et al. (23) demonstrated that among the patients with T2DM, these one with 1.71 ≤ C-peptide < 2.51 ng/mL had a higher glycemic control rate, however, it did not clarify the specific relationships between the stratified C-peptide levels and the renal dysfunction odds. In this study, our findings showed that the patients with 0.28 ≤ fasting C-peptide ≤ 0.56 nmol/L had lower renal impairment chance compared with the patients with fasting C-peptide < 0.28 nmol/L or fasting C-peptide > 0.56 nmol/L. It indicated that moderate level of fasting C-peptide might be a clinically protective factor for renal impairment, on the contrary, low-level and excessive fasting C-peptide might be the risk factors for renal dysfunction in patients with T2DM. In addition, to a certain extent, the changes between fasting and postprandial C-peptide levels were correlated with the improvement of patient prognosis after intensive therapy, which reflected the reserve function of pancreatic β cell (28). Therefore, in the present study the correlation between C2/C0 ratio and renal dysfunction odds was also analyzed. Unlike fasting C-peptide, C2/C0 ratio did not show a statistically significant non-linear relationship with the odds of renal dysfunction.

A number of previous studies had shown the association between the UA levels and the kidney disease (6, 29). The mechanisms of UA induced kidney disease had been identified by several preclinical studies (29, 30). High UA levels induced and accelerated renal disease on their own without the deposition of UA crystals (29). Reducing the UA level by using xanthine oxidase inhibitor or a uricosuric agent in rats could prevent renal hypertrophy, and proteinuria (30). However, the clinical trials showed the divergent findings of the UA effects for predicting the incidence and development of chronic kidney disease in patients with diabetes (15, 16). In the present study, we found that on the whole, the higher UA level was correlated with increased incidence of renal dysfunction, with a 49% increase in renal dysfunction odds for each SD (1 SD = 91.45 μmol/L) increment independently of potential confounders. In addition, to the best of our knowledge, there are no studies that have reported the U-shape association of serum UA level with renal dysfunction odds in patients with T2DM. Our findings showed the non-linear relationship between them, indicating that in a proper range, the renal impairment incidence did not rise with the increment of UA levels. Additionally, the previous studies had indicated that fasting C-peptide was significantly associated with UA in patients with T2DM (31, 32), however, no multiplication interaction effect between these two clinical factors for the renal dysfunction odds was found in the present study.

The highlights of the present study were that we conducted a real-world study and clarified the non-linear associations of fasting C-peptide and UA with the incidence of renal impairment in patients with T2DM. However, several potential limitations of this study are worth noting. First, we did not assess post-hoc statistical power and the statistical power achieved for the main outcome measure in the present study. Second, this was a cross-sectional observational study, these findings could not provide strong evidences of the non-linear associations of the new-onset occurrence odds of renal dysfunction with the C-peptide and UA levels. Generally, this exploratory study highlighted and paved the way for the need to design and conduct a prospective confirmatory study in a random sample with the proper dimension that demonstrated evidence of a non-linear association of new cases of renal dysfunction with C-peptide and UA levels.

In conclusion, the odds of renal dysfunction was non-linearly associated with the levels of serum fasting C-peptide and UA. When 0.28 ≤ fasting C-peptide ≤ 0.56 nmol/L and/or when 276 ≤ UA ≤ 409 μmol/L, patients with T2DM might have the relatively lower renal dysfunction odds. Our results suggested that fasting C-peptide and UA might have the potential role in odds stratification of renal dysfunction, and provided laboratory evidence for prevention and treatment of renal disease in patients with T2DM and no primary kidney diseases, serious autoimmune diseases, liver diseases and/or infectious diseases.

The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

The studies involving human participants were reviewed and approved by Ethics Committee of Affiliated Jinhua Hospital, Zhejiang University School of Medicine. The patients/participants provided their written informed consent to participate in this study.

Study design: LC, YH, and HW; Statistical analysis: HW and YM; Manuscript writing: LC and HW; Data collection: LC and YH. All authors contributed to the article and approved the submitted version.