The inhibition of multiple PI3K isoforms mimics the effect of wortmannin on GSIS and exocytosis. A, GSIS was measured from mouse islets treated with DMSO (0.1%) (open bars), PIK-75 (100 nM) alone (light grey), PIK-75 (100 nM) together with TGX-221 (100 nM) (dark grey), or wortmannin (100 nM) (black bars). B, GSIS was measured from mouse islets treated with DMSO (open bars) or with increasing concentrations of A66 (1 nM–10 μM) (grey bars) C, GSIS was measured from mouse islets treated with DMSO (open bars), wortmannin (100 nM) (black bars), DMSO together with A66 (10 μM) (open bars, dots), or wortmannin (100 nM) together with A66 (10 μM) (black bars, dots). D, (left) Representative capacitance recordings from mouse beta cells expressing siScram (grey lines) or siPI3K-C2β (black lines). (right) Average cumulative capacitance response during each depolarization step) are shown. E, (left) Representative VGCC recordings from mouse beta cells expressing siScram or siPI3K-C2β are shown. (right) Average cumulative VGCC responses during each voltage-step were measured in mouse beta cells expressing siScram (white circles) or siPI3K-C2β (100 nM) (black circles). *-p < 0.05, **-p < 0.01, ***, ###-p < 0.001, ns- non significant.