Beneficial Effects of a Novel Fructose-1,6-Bisphosphatase Inhibitor Cpd96 on Insulin Secretion in Type 2 Diabetes

Fructose-1,6-bisphosphatase (FBPase) is a rate-limiting enzyme in gluconeogenesis, and its inhibition has the potential to improve glucose homeostasis. We characterize Cpd96, a novel inhibitor of FBPase, and demonstrate its multifaceted antidiabetic effects. In vivo, Cpd96 significantly improved glucose tolerance, enhanced insulin sensitivity, and promoted insulin secretion in type 2 diabetic (db/db and KKAy) mice. In vitro, Cpd96 potentiated insulin secretion in MIN6 cells and primary pancreatic islets by facilitating glucose uptake, elevating the ATP/ADP ratio, and activating the cAMP and AMPK/mTORC1/S6K signaling pathways. Notably, the insulinotropic effect of Cpd96 was FBPase-dependent, as it failed to promote insulin secretion in primary islets from β-cell-specific FBPase knockout mice. These findings suggest that Cpd96 improves insulin secretion through the metabolic reprogramming of β-cells and highlight its potential as a novel therapeutic strategy for diabetes treatment.