Elevated Serum SERPINE2 Levels are Linked to Impaired Renal Function in Patients with Type 2 Diabetes Mellitus

Abstract

Introduction: Diabetic nephropathy (DN) is the primary complication associated with diabetes mellitus and is increasingly acknowledged as the leading cause of end-stage renal disease worldwide, placing a significant economic burden on society. This study determined how blood serpin peptidase inhibitor clade E member 2 (SERPINE2) levels affect DN in individuals with type 2 diabetes mellitus (T2DM).

Methods: We recruited 292 individuals diagnosed with T2DM and 120 healthy controls for this study. We employed comprehensive and systematic data collection methodologies to gather relevant biomarkers and information on biochemical parameters. We measured serum levels of neutrophil gelatinase-associated lipocalin (NGAL), kidney injury molecule 1 (KIM-1), transforming growth factor-β1 (TGFβ1), connective tissue growth factor (CTGF), and SERPINE2 by the enzyme-linked immunosorbent assay in control subjects and patients with T2DM. We calculated generalized odds ratios (OR) to estimate the risk of developing DN.

Results: Patients with diabetes had significantly higher levels of SERPINE2 (285.64 ± 56.58 pg/mL) than healthy controls (184.84 ± 23.54 pg/mL). Additionally, the multivariate logistic regression analysis indicated that patients with diabetes with DN possessed higher levels of serum SERPINE2 (OR 1.033, 95% confidence interval [CI] 1.013-1.053; P = 0.001), along with an increased body mass index (BMI), duration of diabetes, serum creatinine (Scr), NGAL, KIM-1, TGFβ1, and CTGF. Receiver operating characteristic (ROC) curve analysis indicated that patients with T2DM and serum SERPINE2 levels exceeding 278.94 pg/mL had a significantly higher risk of developing DN.

Conclusion: The results showed that patients with diabetes with DN have higher levels of serum SERPINE2. A more extensive population-based prospective study is needed to validate our findings.

Keywords: Biomarker; Diabetic nephropathy; Estimated glomerular filtration rate; SERPINE2; Type 2 diabetes mellitus.

Fig. 1

Flowchart of participant selection. A total of 441 patients with suspected type 2 diabetes mellitus (T2DM) were consecutively enrolled. Eleven patients had type 1 diabetes, 4 had infections, 3 had liver cirrhosis, 27 had acute or chronic nephritis, 16 had cardiovascular disorders, and 9 had a malignancy history were excluded. Thirty-two patients with no complete case data and 47 who refused to participate were also excluded. Finally, this study included 292 patients with T2DM who were divided into the normoalbuminuria group (n = 127), microalbuminuria group (n = 104), and macroalbuminuria group (n = 61) according to the urinary albumin excretion rate (UAER) over 24 h

Fig. 2

Serum serpin peptidase inhibitor clade E member 2 (SERPINE2) levels were compared between control subjects and patients with type 2 diabetes mellitus (T2DM). a Serum SERPINE2 levels in control subjects and patients with T2DM were detected by enzyme-linked immunosorbent assay (ELISA). The serum SERPINE2 concentration in patients with T2DM (n = 292) was significantly higher than that in control subjects (n = 120). Student t test was applied. b Comparison of serum SERPINE2 levels in patients with T2DM with normoalbuminuria, microalbuminuria, and macroalbuminuria. ANOVA was applied. ***P < 0.001

Fig. 3

Correlation between serum serpin peptidase inhibitor clade E member 2 (SERPINE2) and clinical indicators. Pearson correlation test was performed between SERPINE2 with a estimated glomerular filtration rate (eGFR), b serum creatinine (Scr), c neutrophil gelatinase-associated lipocalin (NGAL), d kidney injury molecule 1 (KIM-1), e transforming growth factor-β1 (TGFβ1), and f connective tissue growth factor (CTGF) in all patients with type 2 diabetes mellitus (T2DM)

Fig. 4

Receiver operating characteristic (ROC) curve was used to obtain the optimal cutoff value of serum serpin peptidase inhibitor clade E member 2 (SERPINE2) (278.94 pg/mL) that distinguishes the patients with type 2 diabetes mellitus (T2DM) with and without albuminuria. AUC area under the curve

Fig. 5

Schematic diagram of serpin peptidase inhibitor clade E member 2 (SERPINE2) in the development of diabetic nephropathy. Increased SERPINE2 in patients with type 2 diabetes mellitus (T2DM) with renal dysfunction promotes podocyte injury and albuminuria. SERPINE2 also enhances renal fibrosis by promoting fibrosis-related cytokines, such as transforming growth factor-β1 (TGFβ1) and connective tissue growth factor (CTGF). Therefore, the increase in SERPINE2 levels plays an aggravating role in injury of glomerular and tubular cells caused by hyperglycemia and advanced glycation end products (AGEs)