Cyclic nucleotide phosphodiesterases in pancreatic islets

Abstract

Cyclic nucleotide phosphodiesterases (PDEs) comprise a family of enzymes (PDE1-PDE11) which hydrolyse cyclic AMP and cyclic GMP to their biologically inactive 5′ derivatives. Cyclic AMP is an important physiological amplifier of glucose-induced insulin secretion. As PDEs are the only known mechanism for inactivating cyclic nucleotides, it is important to characterise the PDEs present in the pancreatic islet beta cells. Several studies have shown pancreatic islets or beta cells to contain PDE1C, PDE3B and PDE4, with some evidence for PDE10A. Most evidence suggests that PDE3B is the most important in relation to the regulation of insulin release, although PDE1C could have a role. PDE3-selective inhibitors augment glucose-induced insulin secretion. In contrast, activation of beta-cell PDE3B could mediate the inhibitory effect of IGF-1 and leptin on insulin secretion. In vivo, although PDE3 inhibitors augment glucose-induced insulin secretion, concomitant inhibition of PDE3B in liver and adipose tissue induce insulin resistance and PDE3 inhibitors do not induce hypoglycaemia. The development of PDE3 inhibitors as anti-diabetic agents would require differentiation between PDE3B in the beta cell and that in hepatocytes and adipocytes. Through their effects in regulating beta-cell cyclic nucleotide concentrations, PDEs could modulate beta-cell growth, differentiation and survival; some work has shown that selective inhibition of PDE4 prevents diabetes in NOD mice and that selective PDE3 inhibition blocks cytokine-induced nitric oxide production in islet cells. Further work is required to understand the mechanism of regulation and role of the various PDEs in islet-cell function and to validate them as targets for drugs to treat and prevent diabetes. [Diabetologia (2003[Diabetologia ( ) 46:1179[Diabetologia ( -1189

Interplay of Ca2+ and cAMP Signaling in the Insulin-secreting MIN6 β-Cell Line

“…IBMX blocked the cAMP oscillations and increased [cAMP] c , but did not inhibit the Ca 2ϩ transients. Reverse transcription-PCR analysis demonstrated expression of multiple PDE isoforms in MIN6 cells, including PDE1C, which is activated by calmodulin in a Ca 2ϩ -dependent fashion (41,47). Taken together, our findings suggest that dynamic interplay between Ca 2ϩ -dependent AC-I and AC-VIII and PDE1C differentially encodes oscillatory Ca 2ϩ signal inputs to generate cAMP oscillations in electrically excitable cells.…”

RNA-binding protein CUGBP1 regulates insulin secretion via activation of phosphodiesterase 3B in mice

“…Indeed, accumulating evidence indicates that intracellular cAMP is an important regulator of insulin secretion either dependent or independent of Ca 2+ [4,5,41]. Although several PDE proteins regulate insulin secretion [7][8][9][10]45], only PDE3B can be activated by CUGBP1. Actually, PDE3B OE results in reduced insulin secretion by islets and beta cells [9,46,47]; conversely, GSIS is enhanced in islets from Pde3b-null mice [8].…”

Oscillatory control of insulin secretion

“…This was interpreted as Ca 2+ -dependent activation of the PDE1 family of phosphodiesterases (Landa et al, 2005). Islets and insulinsecreting cells express both Ca 2+ -regulated phosphodiesterases (Pyne and Furman, 2003;Landa et al, 2005) and adenylyl cyclases (Leech et al, 1999;Guenifi et al, 2000;Delmeire et al, 2003), and among the cyclases certain isoforms are stimulated, whereas others are suppressed by Ca 2+ (Willoughby and Cooper, 2007). It is therefore likely that the phase relationship between cAMP and Ca 2+ signals varies depending on the relative expression levels of different adenylyl cyclases and phosphodiesterases as well as on the type of stimulus (Fridlyand et al, 2007).…”