Role of phosphodiesterase in the biology and pathology of diabetes

Abstract

Glucose metabolism is the initiator of a large number of molecular secretory processes in β cells. Cyclic nucleotides as a second messenger are the main physiological regulators of these processes and are functionally divided into compartments in pancreatic cells. Their intracellular concentration is limited by hydrolysis led by one or more phosphodiesterase (PDE) isoenzymes. Literature data confirmed multiple expressions of PDEs subtypes, but the specific roles of each in pancreatic β-cell function, particularly in humans, are still unclear. Isoforms present in the pancreas are also found in various tissues of the body. Normoglycemia and its strict control are supported by the appropriate release of insulin from the pancreas and the action of insulin in peripheral tissues, including processes related to homeostasis, the regulation of which is based on the PDE-cyclic AMP (cAMP) signaling pathway. The challenge in developing a therapeutic solution based on GSIS (glucose-stimulated insulin secretion) enhancers targeted at PDEs is the selective inhibition of their activity only within β cells. Undeniably, PDEs inhibitors have therapeutic potential, but some of them are burdened with certain adverse effects. Therefore, the chance to use knowledge in this field for diabetes treatment has been postulated for a long time.