Deficiency of SCAMP5 Triggers Pancreatic β‐Cell Secretory Dysfunction and Apoptosis

The late stage of type 2 diabetes is characterized by secretory dysfunction and increased β-cell apoptosis, but the underlying mechanisms are not fully understood. The expression and function of secretory carrier membrane protein 5 (SCAMP5) in β-cells are unclear. The aim is to explore the role of SCAMP5 in diabetic β-cell failure. SCAMP5 expression is reduced in β-cells under diabetic conditions. Notably, SCAMP5 deficiency diminishes insulin secretion, which is involved in reduced Ca_V1.2 expression. Additionally, decreased SCAMP5 triggers β-cell apoptosis, suggesting the anti-apoptotic role of SCAMP5 in β-cells. Mechanistically, SCAMP5 downregulates the protein expression of voltage-dependent anion channel (VDAC1) and interacts with it, thereby repressing VDAC1-recruited Bax to mitochondria, thus inhibiting the release of cytochrome c from mitochondria to the cytoplasm, culminating in preventing β-cell apoptosis. Furthermore, hyperglycemia-activated carbohydrate-responsive element-binding protein (ChREBP) epigenetically represses SCAMP5 expression by reducing trimethylation of histone H3 at lysine 4 (H3K4me3) within the Scamp5 promoter. These findings highlight the essential role of the ChREBP-controlled SCAMP5 in β-cell insulin secretion and apoptosis, revealing a previously unrecognized mechanism underlying the β-cell failure in diabetes.