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

<h2>Summary</h2> Although β-site amyloid precursor protein-cleaving enzyme 2 (BACE2) is implicated in β-cell physiology, its clinical relevance in metabolic dysfunction remains unclear. Here, we investigated the clinical significance of circulating BACE2 in type 2 diabetes (T2D). Serum BACE2 was measured by enzyme-linked immunosorbent assay (ELISA) in 161 patients with T2D and 134 individuals with normal glucose tolerance. Circulating BACE2 was significantly elevated in T2D and independently associated with the presence of disease, with individuals in the highest quartile showing a 7.22-fold higher adjusted likelihood of T2D. BACE2 levels correlated positively with insulin resistance and dyslipidemia, with HbA1c emerging as the strongest determinant. Notably, BACE2 levels decreased following oral glucose loading in T2D, suggesting dynamic regulation in response to metabolic stimuli. Combining BACE2 with HOMA-IR markedly improved diagnostic performance (AUC 0.912 versus 0.712 for BACE2 alone). These findings identify circulating BACE2 as a biomarker reflecting chronic glycemic burden and metabolic stress in T2D.