Elevated circulating BACE2 captures chronic glycemic burden and enhances the clinical identification of type 2 diabetes
Description
This study investigated the clinical significance of circulating β-site amyloid precursor protein-cleaving enzyme 2 (BACE2) in a cohort of 161 newly diagnosed type 2 diabetes (T2D) patients and 134 individuals with normal glucose tolerance. Results detailed demonstrate that serum BACE2 concentrations were significantly elevated in the T2D group, alongside typical metabolic dysfunctions such as higher BMI, fasting glucose, and insulin resistance. Multivariable logistic regression identified BACE2 as a robust independent indicator of T2D; each 1 ng/mL increase doubled the odds of the disease, and individuals in the highest BACE2 quartile faced a 7.22-fold higher risk. Furthermore, correlation analyses showed that BACE2 levels positively correlated with fasting glucose, HOMA-IR, and adverse lipid profiles, with HbA1c emerging as the strongest independent determinant. Notably, BACE2 levels exhibited an acute decline during an oral glucose tolerance test specifically in T2D patients, highlighting a dynamic, nutrient-responsive regulation under metabolic stress. While BACE2 alone demonstrated moderate diagnostic utility (AUC 0.712), combining it with HOMA-IR yielded an excellent discriminatory performance (AUC 0.912). Collectively, these findings identify circulating BACE2 as a novel, non-invasive biomarker that captures chronic glycemic burden, subclinical β-cell stress, and systemic glucolipotoxicity, offering valuable complementary diagnostic information for T2D.
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This cross-sectional study enrolled 295 participants, comprising 161 newly diagnosed, treatment-naïve type 2 diabetes (T2D) patients and 134 age- and sex-matched healthy controls with normal glucose tolerance (NGT). Strict exclusion criteria were applied to rule out type 1 or gestational diabetes, severe cardiovascular or cerebrovascular diseases, infections, and organ dysfunction. Following a 10-12 hour overnight fast, anthropometric measurements (including BMI and waist-to-hip ratio) were recorded, and blood samples were collected, centrifuged, and stored at -80°C. Fasting blood glucose (FBG) was measured via the glucose oxidase method, and fasting insulin (FIns) was quantified using an electrochemiluminescence immunoassay (Roche E411, Switzerland). HbA1c was analyzed by high-performance liquid chromatography (Bio-Rad, USA), and serum lipid profiles (TC, HDL-C, LDL-C, TG) were assessed using enzymatic colorimetric assays (Siemens Advia 2400, Germany). HOMA-IR and HOMA-β were subsequently calculated to estimate insulin resistance and pancreatic β-cell function. To assess acute nutrient-responsive dynamics, all participants underwent a standard 75-g oral glucose tolerance test (OGTT). While baseline BACE2 was measured for the entire cohort, 2-hour post-load concentrations were analyzed in a random subgroup of 62 participants (24 NGT, 38 T2D). Fasting and post-load serum BACE2 levels were quantified in duplicate using a commercial sandwich ELISA kit (Novus Biologicals, USA, Cat. No. NBP2-66745), which specifically targets the shed, soluble extracellular domain of the protease. Absorbance was measured at 450 nm, and concentrations were calculated using a four-parameter logistic regression model. Standard statistical analyses were then conducted using GraphPad Prism and R to investigate the linear and non-linear associations, multivariable odds, and diagnostic performance of BACE2 relative to systemic metabolic parameters.
Institutions
- Chongqing Medical UniversitySichuan, Chongqing
- Chongqing City Hospital of Traditional Chinese MedicineChongqing, Chongqing