Inhibitory effect of D-myo-inositol-1,2,6-trisphosphate on glucose-stimulated insulin secretion in the mouse.

It has been demonstrated that D-myo-inositol-1,2,6-trisphosphate (PP56) antagonizes the effect of neuropeptide Y (NPY) in guinea pig basilar arteries. NPY is known to inhibit insulin secretion. We therefore examined whether PP56 is a NPY antagonist also on insulin secretion. Unanaesthetized mice were injected intraperitoneally with PP56. It was found that the plasma insulin response to a subsequent intravenous glucose challenge (500 mg/kg) was inhibited by PP56 at 20 but not at 2 mg/kg. Also NPY (8.5 nmol/kg) inhibited the glucose-induced increase in plasma insulin levels. When given together, PP56 and NPY exerted additive inhibitory effect. Thus, PP56 is not a NPY-antagonist on insulin secretion, but rather exerts a NPY-like effect. Furthermore, in isolated mouse islets, PP56 at 100 nmol/l, but not at lower dose levels, inhibited glucose (11.1 mM)-stimulated insulin secretion. Hence, PP-56 inhibits glucose-stimulated insulin secretion by a direct effect on the pancreatic islets.