Increased β‐site APP cleaving enzyme 1‐mediated insulin receptor cleavage in type 2 diabetes mellitus with cognitive impairment

Patients with type 2 diabetes mellitus (T2DM) are at a high risk of cognitive impairment, with insulin resistance playing a pivotal role. β-site amyloid precursor protein cleaving enzyme 1 (BACE1) is considered a predictor of Alzheimer's disease. However, the potential roles of BACE1 in insulin resistance and the risk of cognitive impairment in T2DM remain unclear.We measured plasma BACE1 levels, BACE1 cleavage activities for Swedish mutant amyloid precursor protein (APPsw) and insulin receptor β subunit (INSR-β), and soluble INSR (sINSR) levels in a clinical cohort study.T2DM patients with or without cognitive impairment exhibited elevated plasma BACE1 levels and BACE1 enzymatic activities for APPsw and INSR-β, and sINSR levels. Moreover, the glycemic status correlated with elevated BACE1 levels and BACE1-mediated INSR cleavage, which was associated with insulin resistance.The elevated BACE1 levels in T2DM may contribute to increasing the cognitive impairment risk through both amyloidogenesis and insulin resistance.