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.

qPCR Analysis Reveals Association of Differential Expression of SRR, NFKB1, and PDE4B Genes With Type 2 Diabetes Mellitus

“…Similarly, we observed the association of the PDE4B gene with cyclic AMP and the SRC, INSRR, GRIN, DISC1, PRKACA, PRKACB, AK3, ADK, and APRT gene signatures, their dysregulation causing insulin resistance and type 2 diabetes (53)(54)(55). PDEs are a large family of phosphodiesterases that catalyze cAMP and cGMP to 5′-AMP and 5′-GMP, respectively.…”

Divergent acute versus prolonged pharmacological GLP-1R responses in adult beta cell-selective β-arrestin 2 knockout mice

“…Given the importance of phosphodiesterases in the control of cAMP degradation, and with phosphodiesterase 4 (PDE4) being one of the dominant forms expressed in beta cells (Kilanowska and Ziółkowska, 2020; Pyne and Furman, 2003), we next evaluated the effect of rolipram, a specific inhibitor of PDE4 activity (Zhu et al, 2001), on the capacity for cAMP generation from beta cell-specific β-arrestin 2 KO and control CAMPER animals. Addition of rolipram normalised the acute exendin-4-induced cAMP response in KO to that of control islets (Fig.…”

“…We reasoned that this could potentially result in changes in GLP-1R acute desensitisation, including, perhaps, differences in the control of cAMP degradation due to variations in the capacity for phosphodiesterase (PDE) recruitment to the receptor between the two β-arrestin isoforms (31). To test this hypothesis, and as PDE4 is the dominant isoform in beta cells (32, 33), we next evaluated the effect of rolipram, a specific PDE4 inhibitor (34), on the capacity for cAMP generation from beta cell-specific β-arrestin 2 KO and control CAMPER islets. Indeed, addition of rolipram normalised acute exendin-4-induced cAMP responses in KO islets (Figure 3E), implicating changes in PDE4 action in the acute cAMP defect under beta cell β-arrestin 2 KO conditions.…”

Apoptosis in Type 2 Diabetes: Can It Be Prevented? Hippo Pathway Prospects

“…Diabetes mellitus is a heterogeneous disorder with multiple etiologies [ 1 , 2 ]. The most prevalent in adults is type 2, a chronic metabolic illness with increasing medical and financial costs [ 3 , 4 ]. The incidence of diabetes in 2015 was 8.8%, and in 2040 it will probably increase to 10.4% [ 5 ].…”