Sildenafil, a phosphodiesterase-5 (PDE5) inhibitor, has been shown to improve insulin sensitivity in animal models and prediabetic patients. However, its other metabolic effects remain poorly investigated. This study examines the impact of sildenafil on insulin secretion in MIN6-K8 mouse clonal β cells. Sildenafil is shown to amplify insulin secretion by enhancing Ca 2+ influx, an effect that requires other depolarizing stimuli in MIN6-K8 cells but not in K ATP channel-deficient β cells, which are already depolarized. These results indicate that the action of sildenafil is dependent on depolarization and is independent of K ATP channels. Furthermore, sildenafil-amplified insulin secretion is not inhibited by nifedipine or PDE5 knockdown. Thus, sildenafil stimulates Ca 2+ influx independently of L-type voltage-dependent Ca 2+ channels (VDCCs) and PDE5, a mechanism that differs from the known pharmacology of sildenafil and conventional insulin secretory pathways. Our results reposition sildenafil as an insulinotropic agent that can be used as a potential anti-diabetic medicine or a tool to elucidate the molecular mechanism of insulin secretion.

Sildenafil amplifies calcium influx and insulin secretion in pancreatic β cells