title: Diabetogenic milieus induce specific changes in mitochondrial transcriptome and differentiation of human pancreatic islets.
abstract: 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.
authors.affiliation: Department of Cell Physiology and Metabolism, University of Geneva, Medical Center, Geneva, Switzerland, thierry.brun@unige.ch pierre.maechler@unige.ch.
authors.forename: Thierry
authors.initials: T
authors.lastname: Brun
authors.affiliation: Department of Cell Physiology and Metabolism, University of Geneva, Medical Center, Geneva, Switzerland.
authors.forename: Ning
authors.initials: N
authors.lastname: Li
authors.affiliation: Department of Cell Biology, University of Geneva, Sciences III, Geneva, Switzerland.
authors.forename: Alexis A
authors.initials: AA
authors.lastname: Jourdain
authors.affiliation: Swiss Institute of Bioinformatics (SIB), Geneva, Switzerland, University of Geneva, Medical Center, Geneva, Switzerland and.
authors.forename: Pascale
authors.initials: P
authors.lastname: Gaudet
authors.affiliation: Department of Cell Physiology and Metabolism, University of Geneva, Medical Center, Geneva, Switzerland.
authors.forename: Dominique
authors.initials: D
authors.lastname: Duhamel
authors.affiliation: Cell Isolation and Transplantation Center, Department of Surgery, Geneva University Hospital, Geneva, Switzerland.
authors.forename: Jérémy
authors.initials: J
authors.lastname: Meyer
authors.affiliation: Cell Isolation and Transplantation Center, Department of Surgery, Geneva University Hospital, Geneva, Switzerland.
authors.forename: Domenico
authors.initials: D
authors.lastname: Bosco
authors.affiliation: Department of Cell Physiology and Metabolism, University of Geneva, Medical Center, Geneva, Switzerland, thierry.brun@unige.ch pierre.maechler@unige.ch.
authors.forename: Pierre
authors.initials: P
authors.lastname: Maechler
mesh_terms: D017209:Apoptosis / Q000235:genetics; D002454:Cell Differentiation / Q000235:genetics*; D002460:Cell Line; D002470:Cell Survival / Q000235:genetics; D004272:DNA, Mitochondrial / Q000235:genetics; D003920:Diabetes Mellitus / Q000235:genetics* / Q000378:metabolism; D004579:Electron Transport; D015870:Gene Expression; D005947:Glucose / Q000378:metabolism; D006801:Humans; D007328:Insulin / Q000378:metabolism; D007515:Islets of Langerhans / Q000166:cytology* / Q000378:metabolism*; D008928:Mitochondria / Q000235:genetics* / Q000378:metabolism; D017494:Proton Pumps / Q000378:metabolism; D013481:Superoxides / Q000378:metabolism; D059467:Transcriptome
chemical_list: D004272:DNA, Mitochondrial; D007328:Insulin; D017494:Proton Pumps; D013481:Superoxides; D005947:Glucose