RESEARCH PAPER Pharmacological stimulation and inhibition of insulin secretion in mouse islets lacking

Background and purpose: ATP-sensitive potassium channels (KATP channels) in beta cells are a major target for insulinotropic drugs. Here, we studied the effects of selected stimulatory and inhibitory pharmacological agents in islets lacking KATP channels. Experimental approach: We compared insulin secretion (IS) and cytosolic calcium ([Ca 2+ ]c) changes in islets isolated from control mice and mice lacking sulphonylurea receptor1 (SUR1), and thus KATP channels in their beta cells (Sur1KO). Key results: While similarly increasing [Ca 2+ ]c and IS in controls, agents binding to site A (tolbutamide) or site B (meglitinide) of SUR1 were ineffective in Sur1KO islets. Of two non-selective blockers of potassium channels, quinine was inactive, whereas tetraethylammonium was more active in Sur1KO compared with control islets. Phentolamine, efaroxan and alinidine, three imidazolines binding to KIR6.2 (pore of KATP channels), stimulated control islets, but only phentolamine retained weaker stimulatory effects on [Ca 2+ ]c and IS in Sur1KO islets. Neither KATP channel opener (diazoxide, pinacidil) inhibited Sur1KO islets. Calcium channel blockers (nimodipine, verapamil) or diphenylhydantoin decreased [Ca 2+ ]c and IS in both types of islets, verapamil and diphenylhydantoin being more efficient in Sur1KO islets. Activation of a2-adrenoceptors or dopamine receptors strongly inhibited IS while partially (clonidine > dopamine) lowering [Ca 2+ ]c (control > Sur1KO islets). Conclusions and implications: Those drugs retaining effects on IS in islets lacking KATP channels, also affected [Ca 2+ ]c,