Clinical significance of detection of serum C-reactive protein-fasting C-peptide product, remnant cholesterol and 25-hydroxyvitamin D in type 2 diabetes mellitus

Abstract

C-reactive protein (CRP) and fasting C-peptide (FCP) have been determined together by various publications to assess cardiovascular risk and metabolic health, particularly in relation to insulin resistance and type 2 diabetes mellitus (T2DM). CRP-FCP product may provide a more comprehensive assessment of the cardiovascular risk burden than CRP or FCP alone in patients with T2DM. Remnant cholesterol (RC) is an independent predictor of cardiovascular events in people with T2DM. The detection of RC should be regarded as a complementary marker for diabetes risk stratification rather than a replacement for triglycerides, especially in individuals with relatively low baseline metabolic risk. Low 25-hydroxyvitamin D (25[OH]D) levels common in T2DM, are also strongly linked with increased cardiovascular disease risk. In euthyroid adults with T2DM, higher 25[OH]D is associated with a higher free triiodothyronine-to-free thyroxine ratio, mainly at low 25[OH]D levels. In conclusion, elevated levels of CRP-FCP product and RC and low levels of 25[OH]D “in combination” are strong promising and emerging predictors for T2DM and for cardiovascular disease and other complications in T2DM. This editorial highlights the clinical significance of detection of serum CRP-FCP product, RC and 25[OH]D in T2DM in light of the recent studies of Zhu et al, Jun et al and Zhang et al published in the World Journal of Diabetes.

Key Words: C-reactive protein; Fasting C-peptide; 25-hydroxyvitamin D; Type 2 diabetes mellitus; Cardiovascular risk

Core Tip: The elevated levels of C-reactive protein and fasting C-peptide product and remnant cholesterol and the low levels of 25-hydroxyvitamin D in combination are strong promising and emerging predictors for type 2 diabetes mellitus and for cardiovascular disease and other complications in type 2 diabetes mellitus. This integrative approach allows for better identification of high-risk patients, more accurate prognosis forecasting, and tailored therapeutic strategies.

This editorial refers to “Product of C-reactive protein and fasting C-peptide indicates cardiovascular risk in type 2 diabetes: A real-world study” by Zhang et al, 2026; https://doi.org/10.4239/wjd.v17.i4.117063; “Remnant cholesterol and the risk of incident type 2 diabetes: A community-based 14-year prospective cohort study” by Jun et al, 2026; https://doi.org/10.4239/wjd.v17.i4.117215; and “Serum 25-hydroxyvitamin D and peripheral thyroid hormone sensitivity in euthyroid type 2 diabetes: Linear estimates and low-range threshold” by Zhu et al, 2026; https://doi.org/10.4239/wjd.v17.i4.117489.

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INTRODUCTION

C-reactive protein (CRP) is a non-specific indicator of low-grade inflammation, meaning it indicates that inflammation is present, but not where or why[1]. CRP induces insulin resistance (IR) by impairing the insulin signaling pathway[2]. It has been reported to be increased in many disorders such cardiovascular diseases, diabetes mellitus, dyslipidemia, metabolic syndrome, arthritis and malignancies[3]. Thus, an elevated CRP test necessitates further diagnostic testing to determine the precise source of inflammation[4]. In 2019, CRP and incident type 2 diabetes mellitus (T2DM) were found to be positively correlated by Kanmani et al[5] in a large Korean population-based cohort study. Fasting C-peptide (FCP) level, on the other hand, is a critical clinical marker for assessing endogenous insulin production by pancreatic β-cells[6]. Because C-peptide is secreted in equimolar amounts to insulin but has a longer half-life and negligible hepatic clearance compared to insulin, it provides a more accurate, stable measure of β-cell function[7,8]. High FCP level in serum is a strong indicator of IR and is linked to a greater possibility of cardiovascular disease[9].

C-REACTIVE PROTEIN-FASTING C-PEPTIDE PRODUCT

Recently, CRP and FCP have been analyzed together to assess cardiovascular risk and metabolic health, particularly in relation to IR and T2DM. In 2023, Gedebjerg et al[10] reported that high sensitivity-CRP may help with better early detection and prevention of deadly diseases other than cardiovascular events (CVEs) because it is a stronger prognostic biomarker of all-cause mortality than CVEs. The need to address hyperinsulinemia and IR in the prevention of T2DM, on the other hand, is supported by elevated C-peptide as a potent biomarker for CVEs. The study of Zhang et al[11] published in the World Journal of Diabetes found that the CRP-FCP product was linked to an increased risk of CVEs, cerebrovascular events and cardio-cerebrovascular events. Thus, it can be stated that the CRP-FCP product offers a superior, cost-effective, and highly feasible combined metric for assessing cardiovascular risk in T2DM patients by uniting systemic inflammation (CRP) with metabolic dysfunction (FCP). As Zhang et al[11] have investigated patients with T2DM from Shanghai Sixth People’s Hospital affiliated to Shanghai Jiao Tong University School of Medicine, they highlights the necessity of increasing diversity in clinical trials to ensure generalizability. One major limitation of this study is its single-center design, which restricted the generalizability of the findings across different ethnic and geographical populations by focusing only on patients from a specific institution. Thus, future research should include more diverse cohorts to validate these results across broader demographics.

REMNANT CHOLESTEROL

Remnant cholesterol (RC) refers to the cholesterol content of triglyceride-rich lipoproteins, specifically chylomicron remnants in the postprandial state and both very-low-density lipoproteins and intermediate-density lipoproteins while fasting[12]. In T2DM, IR creates a state of selective resistance where the liver remains responsive to insulin-stimulated lipid synthesis but not to insulin-mediated suppression of glucose production. This impairment drives a triad of overproduction of large and triglyceride-rich subfraction of very-low-density lipoproteins particles, impaired clearance of these particles, and the subsequent accumulation of atherogenic cholesterol-dense remnants[13]. RC is an independent predictor of CVEs in people with T2DM[14]. In support to these findings, Drexel et al[15] in 2024 revealed that RC in individuals who already have coronary artery disease is higher in T2DM individuals than in non-diabetic individuals. The study of Jun et al[16] published in the World Journal of Diabetes concluded that detection of RC should be regarded as a complementary marker for diabetes risk stratification rather than a replacement for triglycerides, especially in individuals with relatively low baseline metabolic risk.

25-HYDROXYVITAMIN D

There is proof that vitamin D increases the production of insulin and evidence that low vitamin D level is associated with reduced insulin sensitivity[17]. Vitamin D receptors are present in pancreatic beta-cells, skeletal muscle, and adipose tissue, suggesting its direct involvement in insulin secretion and sensitivity. 25-Hydroxyvitamin D (25[OH]D), the primary circulating form of vitamin D in the blood, influences beta-cell function by regulating insulin gene expression and secretion. It may also enhance insulin sensitivity in peripheral tissues by modulating receptor expression and downstream signaling pathways. Low vitamin D status has been linked to impaired glycemic control in individuals with T2DM[18]. Moreover, low serum 25[OH]D level (a crucial indicator of vitamin D deficiency) has been stated to be significantly linked with a higher risk of T2DM, IR, and, notably, diabetic peripheral neuropathy[19,20]. Low 25[OH]D levels common in T2DM, are strongly linked with increased cardiovascular disease risk[21]. Vitamin D deficiency accelerates atherosclerosis, increases arterial stiffness, and impairs heart function, acting as an independent predictor of adverse CVEs in T2DM[21,22]. It has been reported that vitamin D supplementation significantly lowered glycosylated hemoglobin, serum fasting plasma glucose, and homeostatic model assessment of IR, alongside increasing 25[OH]D levels[23]. As indicated the article by Zhu et al[24] in the World Journal of Diabetes, it was demonstrated that in euthyroid adults with T2DM, higher 25[OH]D is associated with a higher free triiodothyronine-to-free thyroxine ratio, mainly at low 25[OH]D levels. Experimental studies have shown that vitamin D has a direct effect on iodothyronine deiodinase 2, the enzyme necessary for converting the inactive thyroid prohormone T4 into the active T3 hormone in target tissues. Vitamin D deficiency is linked to higher thyroid-stimulating hormone levels and lower T3/T4 ratio, which is associated with higher blood sugar and impaired glycemic control[25].

CONCLUSION

In conclusion, the elevated levels of CRP-FCP product and RC and the low levels of 25[OH]D in combination are strong promising and emerging predictors for T2DM and for cardiovascular disease and other complications in T2DM. Integrating serum CRP-FCP product and RC and low levels of 25[OH]D into current T2DM clinical guidelines offers significant potential to enhance risk stratification, prognosis, and treatment personalization, according to recent research.