Diabetogenic milieus induce specific changes in mitochondrial transcriptome and differentiation of human pancreatic islets.

Détails

ID Serval
serval:BIB_455F5DE6CB47
Type
Article: article d'un périodique ou d'un magazine.
Collection
Publications
Institution
Titre
Diabetogenic milieus induce specific changes in mitochondrial transcriptome and differentiation of human pancreatic islets.
Périodique
Human molecular genetics
Auteur⸱e⸱s
Brun T., Li N., Jourdain A.A., Gaudet P., Duhamel D., Meyer J., Bosco D., Maechler P.
ISSN
1460-2083 (Electronic)
ISSN-L
0964-6906
Statut éditorial
Publié
Date de publication
15/09/2015
Peer-reviewed
Oui
Volume
24
Numéro
18
Pages
5270-5284
Langue
anglais
Notes
Publication types: Journal Article ; Research Support, Non-U.S. Gov't
Publication Status: ppublish
Résumé
In pancreatic β-cells, mitochondria play a central role in coupling glucose metabolism to insulin secretion. Chronic exposure of β-cells to metabolic stresses impairs their function and potentially induces apoptosis. Little is known on mitochondrial adaptation to metabolic stresses, i.e. high glucose, fatty acids or oxidative stress; being all highlighted in the pathogenesis of type 2 diabetes. Here, human islets were exposed for 3 days to 25 mm glucose, 0.4 mm palmitate, 0.4 mm oleate and transiently to H2O2. Culture at physiological 5.6 mm glucose served as no-stress control. Expression of mitochondrion-associated genes was quantified, including the transcriptome of mitochondrial inner membrane carriers. Targets of interest were further evaluated at the protein level. Three days after acute oxidative stress, no significant alteration in β-cell function or apoptosis was detected in human islets. Palmitate specifically increased expression of the pyruvate carriers MPC1 and MPC2, whereas the glutamate carrier GC1 and the aspartate/glutamate carrier AGC1 were down-regulated by palmitate and oleate, respectively. High glucose decreased mRNA levels of key transcription factors (HNF4A, IPF1, PPARA and TFAM) and energy-sensor SIRT1. High glucose also reduced expression of 11 mtDNA-encoded respiratory chain subunits. Interestingly, transcript levels of the carriers for aspartate/glutamate AGC2, malate DIC and malate/oxaloacetate/aspartate UCP2 were increased by high glucose, a profile suggesting important mitochondrial anaplerotic/cataplerotic activities and NADPH-generating shuttles. Chronic exposure to high glucose impaired glucose-stimulated insulin secretion, decreased insulin content, promoted caspase-3 cleavage and cell death, revealing glucotoxicity. Overall, expression profile of mitochondrion-associated genes was selectively modified by glucose, delineating a glucotoxic-specific signature.
Mots-clé
Apoptosis/genetics, Cell Differentiation/genetics, Cell Line, Cell Survival/genetics, DNA, Mitochondrial/genetics, Diabetes Mellitus/genetics, Diabetes Mellitus/metabolism, Electron Transport, Gene Expression, Glucose/metabolism, Humans, Insulin/metabolism, Islets of Langerhans/cytology, Islets of Langerhans/metabolism, Mitochondria/genetics, Mitochondria/metabolism, Proton Pumps/metabolism, Superoxides/metabolism, Transcriptome
Pubmed
Web of science
Open Access
Oui
Création de la notice
13/04/2021 17:25
Dernière modification de la notice
08/02/2022 7:36
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