Abstract
C-peptide measurement may represent a better index of pancreatic β-cell function compared to insulin. While insulin is mainly cleared by liver, C-peptide is mainly metabolized by kidneys. The aim of our study was to evaluate the association between baseline plasma C-peptide level and the development of type 2 diabetes independent of glucose and insulin levels and to examine potential effect-modification by variables related to kidney function. We included 5176 subjects of the Prevention of Renal and Vascular End-Stage Disease study without type 2 diabetes at baseline. C-peptide was measured in plasma with an electrochemiluminescent immunoassay. Cox proportional hazards regression was used to evaluate the association between C-peptide level and type 2 diabetes development. Median C-peptide was 722 (566–935) pmol/L. During a median follow-up of 7.2 (6.0–7.7) years, 289 individuals developed type 2 diabetes. In multivariable-adjusted Cox regression models, we observed a significant positive association of C-peptide with the risk of type 2 diabetes independent of glucose and insulin levels (hazard ratio (HR): 2.35; 95% confidence interval (CI): 1.49–3.70). Moreover, we found significant effect modification by hypertension and albuminuria (p < 0.001 and p = 0.001 for interaction, respectively), with a stronger association in normotensive and normo-albuminuric subjects and absence of an association in subjects with hypertension or albuminuria. In this population-based cohort, elevated C-peptide levels are associated with an increased risk of type 2 diabetes independent of glucose, insulin levels, and clinical risk factors. Elevated C-peptide level was not independently associated with an increased risk of type 2 diabetes in individuals with hypertension or albuminuria.
Highlights
The global number of people with diabetes was estimated 415 million in 2015 and it has been predicted to rise to 642 million by 2040 [1]
Higher C-peptide was positively associated with higher systolic and diastolic blood pressure, total cholesterol, triglyceride, glucose, insulin, HOMA-insulin resistance (IR), aspartate aminotransferase (ASAT), and alanine aminotransferase (ALAT)
In the analysis adjusted for age and sex, we found that family history of diabetes, body mass index (BMI), systolic blood pressure, diastolic blood pressure, total cholesterol, triglyceride, glucose, insulin, plasma ASAT, plasma ALAT, and urinary excretion of albumin were positively and significantly associated with C-peptide levels, whereas use of alcohol, High-density lipoprotein (HDL) cholesterol, and Estimated glomerular filtration rate (eGFR) were inversely associated with C-peptide levels
Summary
The global number of people with diabetes was estimated 415 million in 2015 and it has been predicted to rise to 642 million by 2040 [1]. Since IR is an important pathophysiological aspect underlying development of cardiovascular disease and even cancer, a considerable number of studies have prospectively investigated a potential association of C-peptide with development of cardiovascular and all-cause mortality [4,5,8,9,10,11]. To the best of our knowledge, only one study to date, prospectively investigated the association of C-peptide with development of type 2 diabetes [6]. This latter study only investigated 140 subjects, it suggested a much stronger association for a C-peptide based index than for an index based on insulin concentrations (area under receiver operating characteristic curve of 0.85 versus 0.73). One study that investigated potential interaction for the association of C-peptide with outcome, found kidney function to be the only significant effect-modifier among several factors evaluated [4]
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