Phosphodiesterase inhibition mimics the effects of PI3K inhibition on GSIS and restores insulin secretion in islets from T2D donors. A, IBMX (100 μM)-amplified GSIS was measured from mouse islets treated with DMSO (0.1%) (open bars) or wortmannin (100 nM) (black bars). (inset) Effects of IBMX (100 μM) under low glucose conditions in the same islets. B, dipyridamole (50 μM)-amplified GSIS was measured from mouse islets treated with DMSO (open bars) or wortmannin (100 nM) (black bars). (inset) Effects of dipyridamole (50 μM) under low glucose conditions in the same islets. C, The effect of IBMX (100 μM) together with dipyridamole (50 μM) was examined on GSIS from mouse islets treated with DMSO (open bars) or wortmannin (100 nM) (black bars). (inset) Effects of IBMX (100 μM) together with dipyridamole (50 μM) under low glucose conditions in the same islets. D, shows the same as A, except in non-diabetic human islets. E, milrinone (10 μM)-amplified GSIS was measured from non-diabetic human islets treated with DMSO (open bars) or wortmannin (100 nM) (black bars). (inset) shows the effects of milrinone (10 μM) under low glucose conditions in the same islets. F, shows the same as D, except in human islets from T2D donors. *-p < 0.05, **, ##-p < 0.01, ***, ###-p < 0.001, ns- non significant.