To understand the role cAMP phosphodiesterases (PDEs) play in the regulation of insulin secretion, we analyzed cyclic nucleotide PDEs of a pancreatic ␤-cell line and used family and isozyme-specific PDE inhibitors to identify the PDEs that counteract glucose-stimulated insulin secretion. We demonstrate the presence of soluble PDE1C, PDE4A and 4D, a cGMP-specific PDE, and of particulate PDE3, activities in ␤TC3 insulinoma cells. Selective inhibition of PDE1C, but not of PDE4, augmentedglucose-stimulatedinsulinsecretioninadosedependent fashion thus demonstrating that PDE1C is the major PDE counteracting glucose-dependent insulin secretion from ␤TC3 cells. In pancreatic islets, inhibition of both PDE1C and PDE3 augmented glucose-dependent insulin secretion. The PDE1C of ␤TC3 cells is a novel isozyme possessing a K m of 0.47 M for cAMP and 0.25 M for cGMP. The PDE1C isozyme of ␤TC3 cells is sensitive to 8-methoxymethyl isobutylmethylxanthine and zaprinast (IC 50 ‫؍‬ 7.5 and 4.5 M, respectively) and resistant to vinpocetine (IC 50 > 100 M). Increased responsiveness of PDE1C activity to calcium/calmodulin is evident upon exposure of cells to glucose. Enhanced cAMP degradation by PDE1C, due to increases in its responsiveness to calcium/calmodulin and in intracellular calcium, constitutes a glucose-dependent feedback mechanism for the control of insulin secretion.

No abstract

No abstract

No abstract