Mitochondrial Reactive Oxygen Species Are Obligatory Signals for Glucose-Induced Insulin Secretion
Corinne Leloup 1 ,
Cécile Tourrel-Cuzin 2 ,
Christophe Magnan 2 ,
Melis Karaca 2 ,
Julien Castel 2 ,
Lionel Carneiro 1 ,
Anne-Laure Colombani 1 ,
Alain Ktorza 2 ,
Louis Casteilla 1 and
Luc Pénicaud 1
1 Department of Metabolism, Plasticity, and Mitochondria, Unité Mixte de Recherche 5241, Centre National de la Recherche Scientifique-Université
Paul Sabatier, Institut Fédératif de Recherche 31, Institut Fédératif de Recherche 109, Toulouse, France
2 Unité Mixte de Recherche 7059, Centre National de la Recherche Scientifique, Paris, France
Corresponding author: Corinne Leloup, coleloup{at}toulouse.inserm.fr
Abstract
OBJECTIVE— Insulin secretion involves complex events in which the mitochondria play a pivotal role in the generation of signals that
couple glucose detection to insulin secretion. Studies on the mitochondrial generation of reactive oxygen species (ROS) generally
focus on chronic nutrient exposure. Here, we investigate whether transient mitochondrial ROS production linked to glucose-induced
increased respiration might act as a signal for monitoring insulin secretion.
RESEARCH DESIGN AND METHODS— ROS production in response to glucose was investigated in freshly isolated rat islets. ROS effects were studied using a pharmacological
approach and calcium imaging.
RESULTS— Transient glucose increase from 5.5 to 16.7 mmol/l stimulated ROS generation, which was reversed by antioxidants. Insulin
secretion was dose dependently blunted by antioxidants and highly correlated with ROS levels. The incapacity of β-cells to
secrete insulin in response to glucose with antioxidants was associated with a decrease in ROS production and in contrast
to the maintenance of high levels of ATP and NADH. Then, we investigated the mitochondrial origin of ROS (mROS) as the triggering
signal. Insulin release was mimicked by the mitochondrial-complex blockers, antimycin and rotenone, that generate mROS. The
adding of antioxidants to mitochondrial blockers or to glucose was used to lower mROS reversed insulin secretion. Finally,
calcium imaging on perifused islets using glucose stimulation or mitochondrial blockers revealed that calcium mobilization
was completely reversed using the antioxidant trolox and that it was of extracellular origin. No toxic effects were present
using these pharmacological approaches.
CONCLUSIONS— Altogether, these complementary results demonstrate that mROS production is a necessary stimulus for glucose-induced insulin
secretion.
Footnotes
Published ahead of print at http://diabetes.diabetesjournals.org on 10 December 2008.
Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work
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Mitochondrial Reactive Oxygen Species Are Obligatory Signals for Glucose-Induced Insulin Secretion

10.2337/db07-1056