The cyclic guanosine monophosphate (cGMP) signaling system is one of the most prominent regulators of many physiopathological processes in humans and rodents. It has been strongly established as an accomplished cellular signal involved in the regulation of energy homeostasis and cell metabolism, and pharmacological enhancement of cGMP has shown beneficial effects in metabolic disorders models. cGMP intracellular levels are finely regulated by phosphodiesterases (PDEs). The main enzyme responsible for the degradation of cGMP is PDE5. Preclinical and clinical studies have shown that PDE5 inhibitors (PDE5i) have beneficial effects on improving insulin resistance and glucose metabolism representing a promising therapeutic strategy for the treatment of metabolic disorders. This review aims to describe the molecular basis underlying the use of PDE5i to prompt cell metabolism and summarize current clinical trials assessing the effects of PDE5i on glucose metabolism.
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