Advantages of PDE5i in the Management of Glucose Metabolism Disorders

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Advantages of Phosphodiesterase Type 5 Inhibitors in the Management of Glucose Metabolism Disorders: A Clinical and Translational Issue




Among metabolic diseases, carbohydrate metabolism disorders are the most widespread. The most common glucose pathological conditions are acquired and may increase the risk of type 2 diabetes, obesity, heart diseases, stroke, and kidney insufficiency. Phosphodiesterase type 5 inhibitors (PDE5i) have long been used as an effective therapeutic option for the treatment of erectile dysfunction (ED). Different studies have demonstrated that PDE5i, by sensitizing insulin target tissues to insulin, plays an important role in controlling the action of insulin and glucose metabolism, highlighting the protective action of these drugs against metabolic diseases. In this review, we report the latest knowledge about the role of PDE5i in the metabolic diseases of insulin resistance and type 2 diabetes, highlighting clinical aspects and potential treatment approaches. Although various encouraging data are available, further in vivo and in vitro studies are required to elucidate the mechanism of action and their clinical application in humans.








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Conclusions

Besides their well-known effects on ED, different preclinical, and clinical studies on the use of PDE5 inhibitors for metabolic disease treatment have been conducted. Indeed, PDE5 enzymes are highly expressed in all insulin-sensitive tissues, such as endothelium, muscle, adipocytes, and hepatocytes. Moreover, PDE5i interferes with the NO/cGMP signaling, an important pathway that controls glucose metabolism regulation. Thus, by regulating NO/cGMP pathways, PDE5i administration could provide a good strategy to promote glucose uptake and may be a new pharmacological approach to treat metabolic diseases (Figure 2). Given the safety record of these drugs, it is desirable to speculate on the use of PDE5 inhibition as a potential approach in the prevention of diet-induced IR and metabolic imbalances. Although different encouraging data are available, further in vivo and in vitro indications are mandatory.
 

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Figure 1: Schematic representation of PDE5i action in insulin-related pathways. PKG activated by cGMP exerts positive effects on IRS downstream effectors. The phosphorylation of PKB/AKT induces the translocation of GLUT4 vesicles on the plasma membrane, favoring glucose uptake and activation of downstream signaling involved in protein synthesis, cell growth, and differentiation. The balance between cGMP synthesis (induced by the interaction of NO with sGC) and cGMP hydrolysis (by PDE5) regulates cGMP levels. The action of the PDE5i promotes the accumulation of cGMP. IR: insulin receptor; NO: nitric oxide; sGC: guanylyl cyclase; PDE5: phosphodiesterase type 5; GMP: guanosine monophosphate; cGMP: cyclic guanosine monophosphate; IRS: insulin receptor substrate; PI3K: phosphatidylinositol 3- kinase; PKB/AKT: protein kinase B/AKT; and mTOR: mammalian target of rapamycin.
 

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Figure 2: Pivotal roles of PDE5i in glucose metabolic disorders. Schematic image summarizing the main effects of PDE5 inhibitors in insulin resistance and diabetes. LDL: low-density lipoprotein and T2DM: type 2 diabetes mellitus.
 
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