Elevated circulating BACE2 captures chronic glycemic burden and enhances the clinical identification of type 2 diabetes

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.