Uncoupling protein 2 and aldolase B impact insulin release by modulating mitochondrial function and Ca2+ release from the ER

Uncoupling protein 2 (UCP2), a mitochondrial protein, is known to be upregu-lated in pancreatic islets of patients with type 2 diabetes (T2DM); however, the pathological significance of this increase in UCP2 expression is unclear. In this study, we highlight the molecular link between the increase in UCP2 expression in beta -cells and beta-cell failure by using genetically engineered mice and human islets. beta-cell-specific UCP2-overexpressing transgenic mice (beta UCP2Tg) exhibited glucose intolerance and a reduction in insulin secretion. Decreased mitochondrial function and increased aldolase B (AldB) expression through oxidative-stress -mediated pathway were observed in beta UCP2Tg islets. AldB, a glycolytic enzyme, was associated with reduced insulin secretion via mitochondrial dysfunction and impaired calcium release from the endoplasmic reticulum (ER). Taken together, our findings provide a new mechanism of beta-cell dysfunction by UCP2 and AldB. Targeting the UCP2/AldB axis is a promising approach for the recovery of beta-cell function.

Automated summary

This study highlights the molecular link between the increase in UCP2 expression in beta-cells and beta-cell failure, and suggests that targeting the UCP2/AldB axis may be a promising approach for the recovery of beta-cell function.