Carbohydrate response element‐binding protein (ChREBP) mediates decreased SNAP25 expression in islets from diabetic Goto‐Kakizaki (GK) rats

SNAP25 plays an essential role in the glucose‐stimulated insulin secretion (GSIS) of pancreatic β‐cells. Carbohydrate response element‐binding protein (ChREBP) is an important transcription factor in β‐cells and, in this study, we aimed to explore whether ChREBP regulates SNAP25 expression in β‐cells. We show that diabetic Goto‐Kakizaki (GK) rats exhibited impaired insulin secretion and hyperglycemia, along with decreased SNAP25 expression and ChREBP phosphorylation in islets. SNAP25 knockdown decreased GSIS in β‐cells, while SNAP25 overexpression increased GSIS in β‐cells. Activation or overexpression of ChREBP led to reduced SNAP25 expression and subsequent suppression of GSIS. Conversely, ChREBP knockdown mitigated the reduction in SNAP25 expression caused by high glucose. Mechanistically, the activation of ChREBP by high glucose increased its occupancy and decreased the level of H3K4me3 at the Snap25 promoter. Our findings reveal the novel regulatory mechanisms of SNAP25 expression in β‐cells and suggest that SNAP25 may be involved in the regulation of β‐cell secretory function controlled by ChREBP. SNAP25 plays an essential role in the glucose‐stimulated insulin secretion of pancreatic β‐cells. Diabetic hyperglycemia suppresses SNAP25 expression in β‐cells, an effect associated with the activation of ChREBP, leading to increased ChREBP recruitment to the promoter of Snap25, and subsequently reducing the tri‐methylation of histone H3 at lysine 4 (H3K4me3) at the promoter.