Mitochondrial reactive oxygen species are obligatory signals for glucose-induced insulin secretion

Leloup, Corinne; Tourrel-Cuzin, Cécile; Magnan, Christophe; Karaca, Melis; Castel, Julien; Carneiro, Lionel; Colombani, Anne-Laure; Ktorza, Alain; Casteilla, Louis; Pénicaud, Luc

doi:10.2337/db07-1056

Cited by 362Pancreatic function and diabetesMitochondrial Function and PathologyCardiac Ischemia and Reperfusion

Mitochondrial reactive oxygen species are obligatory signals for glucose-induced insulin secretion

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Leloup, Corinne, Tourrel-Cuzin, Cécile, Magnan, Christophe, Karaca, Melis, Castel, Julien, Carneiro, Lionel, Colombani, Anne-Laure, Ktorza, Alain +2 more·2009·Diabetes

DOI 10.2337/db07-1056PMC PMC2646066

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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 beta-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.

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In the rat insulinoma cell line INS-1E and in primary mouse and rat pancreatic beta cells, use of FCCP/CCCP inhibits glucose-stimulated insulin release (GSIS).
“In the rat insulinoma cell line INS-1E and in primary mouse and rat pancreatic beta cells, use of FCCP/CCCP inhibits glucose-stimulated insulin release (GSIS) [168,169,170].”
From Mitochondrial Uncoupling: A Key Controller of Biological Processes in Physiology and Diseases (2019) · cites this paper as [169]
In rat insulinoma cells and primary mouse and rat pancreatic beta cells, FCCP/CCCP inhibits glucose-stimulated and Ca2+-dependent insulin release.
“In rat insulinoma cells and primary mouse and rat pancreatic beta cells, FCCP/CCCP inhibits glucose-stimulated (and Ca2+-dependent) insulin release (GSIS) [168,169,170].”
From Mitochondrial Uncoupling: A Key Controller of Biological Processes in Physiology and Diseases (2019) · cites this paper as [169]
Mitochondrial metabolism is also required for the transient, controlled production of ROS, which is required for the mitochondrial signaling pathways that trigger granule exocytosis.
“Mitochondrial metabolism is also required for the transient, controlled production of ROS, which is required for the mitochondrial signaling pathways that trigger granule exocytosis (239, 240).”
From The role of mitochondria in the pathogenesis of type 2 diabetes (2010) · cites this paper as [240]

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Authors: Leloup, C., Tourrel-Cuzin, C., Magnan, C., Karaca, M., Castel, J., Carneiro, L., Colombani, A.-L., Ktorza, A., Casteilla, L., & Pénicaud, L.
Affiliations: Centre National de la Recherche Scientifique (FR)
Unité Mixte de Recherche 7059, Centre National de la Recherche Scientifique, Paris, France
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
Corresponding author: Leloup, Corinne
ORCID: Leloup, Corinne
Castel, Julien
Carneiro, Lionel
Casteilla, Louis
Venue: Diabetes
Publisher: American Diabetes Association
Published: 2009-03-01
Volume: 58
Issue: 3
Pages: 673-681
ISSN: 0012-1797 (ISSN-L)
1939-327X
DOI: 10.2337/db07-1056
PMC: PMC2646066
OpenAlex: W2128342607
Cited by: 361
References: 33
Citations by year: 2026: 10 · 2025: 16 · 2024: 16 · 2023: 11 · 2022: 20 · 2021: 23 · 2020: 13 · 2019: 20 · 2018: 19 · 2017: 32 · 2016: 27 · 2015: 22 · 2014: 23 · 2013: 21 · 2012: 22
FWCI: 23.24
Type: journal article
Language: en
Open access: hybrid
doi.org
Licence: cc-by-nc-nd
Locations: Diabetes (publishedVersion, cc-by-nc-nd)
PubMed Central (publishedVersion, cc-by-nc-nd)
PubMed (publishedVersion)
HAL (submittedVersion)
Funders: Centre National de la Recherche Scientifique
Topics: Health Sciences › Medicine › Surgery › Pancreatic function and diabetes
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
Health Sciences › Medicine › Pathology and Forensic Medicine › Cardiac Ischemia and Reperfusion
Keywords: mitochondrial reactive oxygen species, glucose-stimulated insulin secretion, pancreatic beta cells, islets, mitochondrial respiration, antioxidants, calcium mobilization, antimycin, rotenone, ATP, NADH
MeSH terms: Insulin Secretion, Adenosine Triphosphate, Animals, Calcium, Chromans, Glucose, Insulin, Islets of Langerhans, Kinetics, Male, Mitochondria, NAD, Superoxides, Superoxide Dismutase, Signal Transduction, Rats, Wistar, Reactive Oxygen Species, Thapsigargin, Rats

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Mitochondrial reactive oxygen species are obligatory signals for glucose-induced insulin secretion

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