Activation of protein kinase A (cAMP-dependent protein kinase; PKA) triggers insulin secretion in the β-cell. Adenylate cyclase toxin (ACT), a bacterial exotoxin with adenylate cyclase activity, and forskolin, an activator of adenylate cyclase, both dose-dependently increased insulin secretion in the presence, but not the absence, of glucose in insulin-secreting βTC3 cells. The stimulation of cAMP release by either agent was dose-dependent but glucose-independent. Omission of extracellular Ca2+ totally abolished the effects of ACT on insulin secretion and cytosolic cAMP accumulation. ACT and forskolin caused rapid and dramatic increases in cytosolic Ca2+, which were blocked by nifedipine and the omission of extracellular Ca2+. Omission of glucose completely blocked the effects of forskolin and partially blocked the effects of ACT on cytosolic Ca2+. PKA α, β and γ catalytic subunits (Cα, Cβ and Cγ respectively) were identified in βTC6 cells by confocal microscopy. Glucose and glucagon-like polypeptide-1 (GLP-1) caused translocation of Cα to the nucleus and of Cβ to the plasma membrane and the nucleus, but did not affect the distribution of Cγ. In conclusion, glucose and GLP-1 amplify insulin secretion via cAMP production and PKAβ activation.

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