Mode of Action of Clonidine Upon Islet Function: Dissociated Effects Upon the Time Course and Magnitude of Insulin Release

Clonidine (0.08 to 80.0 ng/ml) caused a dose-related inhibition of glucose-stimulated insulin release, but failed to affect glucose oxidation, glucose-stimulated ⁴⁵Ca net uptake, and adenylate cyclase activity in isolated rat islets. Phentolamine antagonized the effect of clonidine upon insulin release. Despite profound inhibition of insulin secretion, the drug failed to affect the time course for the changes evoked by glucose in either ⁴⁵Ca fractional outflow rate from perifused islets or insulin release from the isolated perfused pancreas. The latter changes were multiphasic, revealing an initial secretory peak, a period of low secretory activity, and a second secretory elevation before establishing a period characterized by a steadily and slowly increasing insulin output. In the clonidine-treated islets, the secretory rate was not significantly different from the basal value during the period after the initial secretory response. Thus, despite continuous stimulation with glucose, insulin release appears as a discontinuous phenomenon, even when little insulin is secreted during the initial phase of stimulation.