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Pharmacological stimulation and inhibition of insulin secretion in mouse islets lacking ATP-sensitive K+ channels

A Szollosi1, M Nenquin, J C Henquin

  • 1Unité d'Endocrinologie et Métabolisme, Faculty of Medicine, University of Louvain, Brussels, Belgium.

British Journal of Pharmacology
|February 5, 2010
PubMed
Abstract

Insights

Pharmacological agents targeting ATP-sensitive potassium (K(ATP)) channels in beta cells show varied effects in their absence. Some drugs retain activity by acting on other ionic channels, offering potential for treating congenital hyperinsulinism.

Area of Science:

  • Endocrinology
  • Pharmacology
  • Ion Channel Physiology

Background:

  • ATP-sensitive potassium (K(ATP)) channels in pancreatic beta cells are crucial targets for drugs that stimulate insulin secretion.
  • Understanding drug mechanisms independent of K(ATP) channels is vital for developing new therapeutic strategies.

Purpose of the Study:

  • To investigate the effects of various pharmacological agents on insulin secretion and calcium signaling in beta cells lacking K(ATP) channels.
  • To identify drug actions mediated by targets other than K(ATP) channels.

Main Methods:

  • Comparison of insulin secretion and cytosolic calcium changes in islets from control mice and mice lacking the sulfonylurea receptor 1 (SUR1), which abolishes K(ATP) channel function.
  • Testing a range of stimulatory and inhibitory agents, including sulfonylureas, meglitinides, potassium channel blockers, K(ATP) channel openers, calcium channel blockers, and receptor agonists.

Main Results:

  • Drugs targeting SUR1 binding sites (tolbutamide, meglitinide) were ineffective in K(ATP) channel-deficient islets.
  • Non-selective potassium channel blockers showed differential activity, with tetraethylammonium being more potent in K(ATP) channel-null islets.
  • Imidazolines binding to K(IR)6.2 retained weaker stimulatory effects in K(ATP) channel-null islets, with phentolamine showing residual activity.
  • Calcium channel blockers and diphenylhydantoin decreased insulin secretion and calcium levels in both islet types, with enhanced efficacy in K(ATP) channel-null islets.
  • Alpha(2)-adrenoceptor and dopamine receptor agonists inhibited insulin secretion, with varying effects on calcium levels depending on the K(ATP) channel status.

Conclusions:

  • Drugs retaining effects on insulin secretion in K(ATP) channel-null islets act on alternative ionic channels.
  • The enhanced effects of certain inhibitors in K(ATP) channel-null islets may have therapeutic implications for congenital hyperinsulinism caused by K(ATP) channel mutations.

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