Dapansutrile preserves pancreatic beta‐cell function by regulating insulin vesicle membrane fusion and mitochondrial homeostasis

AIMS/HYPOTHESIS: Pancreatic beta-cell dysfunction is pivotal in diabetes pathogenesis, with the NOD-like receptor protein 3 (NLRP3) inflammasome playing a crucial role. Dapansutrile (DAPA), a novel NLRP3 inhibitor, demonstrates promise in diabetes management. METHODS: The diabetic model of high-fat diet (HFD) + streptozotocin (STZ) mice was utilized to assess glucose metabolism indicators following DAPA intervention. Experiments involving pancreatic islets from normal mice or humans, as well as INS-1 cell lines, were conducted to evaluate CCK8, glucose-stimulated insulin secretion (GSIS), calcium ion imaging, vesicle fusion and mitochondrial function after exposure to palmitic acid (PA) and DAPA intervention. Additionally, the study explored the efficacy of islet transplantation in type 1 diabetes mice using islets treated with DAPA in vitro. RESULTS: This study showed that DAPA improved fasting blood glucose level, glucose tolerance and glucose metabolism in diabetes mice. The experimental work on pancreatic islets and INS-1 cells exposed to PA confirmed that DAPA enhanced GSIS, restored pancreatic function, improved calcium ion flux, mitochondrial dynamics and vesicle fusion. Notably, through the application of pancreatic islet transplantation technology, we illustrated that DAPA effectively addresses systemic glucose metabolism issues at the beta-cell level. CONCLUSIONS/INTERPRETATION: DAPA targets the NLRP3 inflammasome in pancreatic beta cells of diabetic mice to preserve function, maintain mitochondrial homeostasis and offer potential avenues for diabetes management strategies.