Sulfonylurea Blockade of KATP Channels Unmasks a Distinct Type of Glucose-Induced Ca2+ Decrease in Pancreatic β-Cells

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Abstract

Objectives

This study aimed to explore how sulfonylurea blockade of KATP channels affects the early Ca2+ signals for glucose generation of insulin release.

Methods

Cytoplasmic Ca2+ was measured with ratiometric microfluorometry in isolated mouse islets loaded with Fura-PE3.

Results

After sulfonylurea blockade of the KATP channels (50 μM-1 mM tolbutamide or 1 μM-1 mM gliclazide), increase of glucose from 3 to 20 mM resulted in suppression of elevated Ca2+ during a 3- to 5-minute period. The Ca2+ decrease was shorter after inhibition of the Na/K pump with ouabain (10 and 100 μM) but prolonged when the α2A adrenoceptors were activated with clonidine (1 and 10 nM) or epinephrine (10 nM). Inhibition of the sarco/endoplasmic reticulum Ca2+-ATPase pump with 10 μM cyclopiazonic acid counteracted the action of 10 nM clonidine, making the Ca2+ decrease shorter than in controls. Extended superfusion of islets with a medium containing 20 mM glucose and 1 mM tolbutamide sometimes resulted in delayed appearance of Ca2+ oscillations mediated by periodic interruption of elevated Ca2+.

Conclusions

Increase of glucose generates prompt suppression of cytoplasmic Ca2+ in β-cells lacking functional KATP channels. Activation of α2A adrenoceptors markedly prolongs the period of glucose-induced Ca2+ decrease, an effect counteracted by cyclopiazonic acid.

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