The different mechanisms of action of GIP and GLP-1 explain their different efficacy as therapeutic agents in type 2 diabetes

By modelling a variety ofin vivoprotocols, the following cellular mechanisms of incretins emerge: 1) a transient rise in intracellular Ca2+, which underlies the early effects of incretins; and 2) a potentiation of the AP, which mediates the sustained ISR. Our analysis suggests that in T2D the incretin effect on Ca2+is preserved while the amplification of the AP is impaired, though not abolished. Finally, we found that saturation of GIP effects, more than impaired sensitivity, underlies the lack of insulinotropic activity of pharmacological doses of GIP in T2D.