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

Hellman, Bo MD, PhD; Dansk, Heléne; Grapengiesser, Eva PhD

doi: 10.1097/MPA.0000000000000777
Original Articles

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.

From the Department of Medical Cell Biology, Uppsala University, Uppsala, Sweden.

Received for publication May 6, 2015; accepted October 7, 2016.

Address correspondence to: Bo Hellman, MD, PhD, Biomedicum, Box 571, Husargatan 3, SE-75123 Uppsala, Sweden (e-mail: bo.hellman@mcb.uu.se).

This study was supported by the Swedish Research Council (55x-06240) and the Swedish Diabetes Association.

The authors declare no conflict of interest.

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