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Pharmacological stimulation and inhibition of insulin secretion in mouse islets lacking ATP‐sensitive K + channels
Author(s) -
Szollosi A,
Nenquin M,
Henquin JC
Publication year - 2010
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.2009.00588.x
Subject(s) - diazoxide , sulfonylurea receptor , tolbutamide , verapamil , medicine , phentolamine , endocrinology , chemistry , potassium channel , pinacidil , channel blocker , stimulation , insulin , calcium , glibenclamide , biology , diabetes mellitus
Background and purpose: ATP‐sensitive potassium channels (K ATP 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 K ATP 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 K ATP channels in their beta cells ( Sur1 KO). 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 Sur1 KO islets. Of two non‐selective blockers of potassium channels, quinine was inactive, whereas tetraethylammonium was more active in Sur1 KO compared with control islets. Phentolamine, efaroxan and alinidine, three imidazolines binding to K IR 6.2 (pore of K ATP channels), stimulated control islets, but only phentolamine retained weaker stimulatory effects on [Ca 2+ ] c and IS in Sur1 KO islets. Neither K ATP channel opener (diazoxide, pinacidil) inhibited Sur1 KO 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 Sur1 KO islets. Activation of α 2 ‐adrenoceptors or dopamine receptors strongly inhibited IS while partially (clonidine > dopamine) lowering [Ca 2+ ] c (control > Sur1 KO islets). Conclusions and implications: Those drugs retaining effects on IS in islets lacking K ATP channels, also affected [Ca 2+ ] c , indicating actions on other ionic channels. The greater effects of some inhibitors in Sur1 KO than in control islets might be relevant to medical treatment of congenital hyperinsulinism caused by inactivating mutations of K ATP channels.