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Dive into the research topics where Hilton Takahashi is active.

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Featured researches published by Hilton Takahashi.


Biochemical Journal | 2012

Dynamic measurements of mitochondrial hydrogen peroxide concentration and glutathione redox state in rat pancreatic β-cells using ratiometric fluorescent proteins : confounding effects of pH with HyPer but not roGFP1

Leticia Prates Roma; Jessica Duprez; Hilton Takahashi; Patrick Gilon; Andreas Wiederkehr; Jean-Christophe Jonas

Using the ROS (reactive oxygen species)-sensitive fluorescent dyes dichlorodihydrofluorescein and dihydroethidine, previous studies yielded opposite results about the glucose regulation of oxidative stress in insulin-secreting pancreatic β-cells. In the present paper, we used the ratiometric fluorescent proteins HyPer and roGFP1 (redox-sensitive green fluorescent protein 1) targeted to mitochondria [mt-HyPer (mitochondrial HyPer)/mt-roGFP1 (mitochondrial roGFP1)] to monitor glucose-induced changes in mitochondrial hydrogen peroxide concentration and glutathione redox state in adenovirus-infected rat islet cell clusters. Because of the reported pH sensitivity of HyPer, the results were compared with those obtained with the mitochondrial pH sensors mt-AlpHi and mt-SypHer. The fluorescence ratio of the mitochondrial probes slowly decreased (mt-HyPer) or increased (mt-roGFP1) in the presence of 10 mmol/l glucose. Besides its expected sensitivity to H2O2, mt-HyPer was also highly pH sensitive. In agreement, changes in mitochondrial metabolism similarly affected mt-HyPer, mt-AlpHi and mt-SypHer fluorescence signals. In contrast, the mt-roGFP1 fluorescence ratio was only slightly affected by pH and reversibly increased when glucose was lowered from 10 to 2 mmol/l. This increase was abrogated by the catalytic antioxidant Mn(III) tetrakis (4-benzoic acid) porphyrin but not by N-acetyl-L-cysteine. In conclusion, due to its pH sensitivity, mt-HyPer is not a reliable indicator of mitochondrial H2O2 in β-cells. In contrast, the mt-roGFP1 fluorescence ratio monitors changes in β-cell mitochondrial glutathione redox state with little interference from pH changes. Our results also show that glucose acutely decreases rather than increases mitochondrial thiol oxidation in rat β-cells.


Biochemical Journal | 2014

Acute nutrient regulation of the mitochondrial glutathione redox state in pancreatic β-cells

Hilton Takahashi; Laila R.B. Santos; Leticia Prates Roma; Jessica Duprez; Christophe Broca; Anne Wojtusciszyn; Jean-Christophe Jonas

The glucose stimulation of insulin secretion by pancreatic β-cells depends on increased production of metabolic coupling factors, among which changes in NADPH and ROS (reactive oxygen species) may alter the glutathione redox state (EGSH) and signal through changes in thiol oxidation. However, whether nutrients affect EGSH in β-cell subcellular compartments is unknown. Using redox-sensitive GFP2 fused to glutaredoxin 1 and its mitochondria-targeted form, we studied the acute nutrient regulation of EGSH in the cytosol/nucleus or the mitochondrial matrix of rat islet cells. These probes were mainly expressed in β-cells and reacted to low concentrations of exogenous H2O2 and menadione. Under control conditions, cytosolic/nuclear EGSH was close to -300 mV and unaffected by glucose (from 0 to 30 mM). In comparison, mitochondrial EGSH was less negative and rapidly regulated by glucose and other nutrients, ranging from -280 mV in the absence of glucose to -299 mV in 30 mM glucose. These changes were largely independent from changes in intracellular Ca(2+) concentration and in mitochondrial pH. They were unaffected by overexpression of SOD2 (superoxide dismutase 2) and mitochondria-targeted catalase, but were inversely correlated with changes in NAD(P)H autofluorescence, suggesting that they indirectly resulted from increased NADPH availability rather than from changes in ROS concentration. Interestingly, the opposite regulation of mitochondrial EGSH and NAD(P)H autofluorescence by glucose was also observed in human islets isolated from two donors. In conclusion, the present study demonstrates that glucose and other nutrients acutely reduce mitochondrial, but not cytosolic/nuclear, EGSH in pancreatic β-cells under control conditions.


Molecular metabolism | 2017

NNT reverse mode of operation mediates glucose control of mitochondrial NADPH and glutathione redox state in mouse pancreatic β-cells.

Laila R.B. Santos; Carole Muller; Arnaldo H. de Souza; Hilton Takahashi; Peter Spégel; Ian R. Sweet; Heeyoung Chae; Hindrik Mulder; Jean-Christophe Jonas

Objective The glucose stimulation of insulin secretion (GSIS) by pancreatic β-cells critically depends on increased production of metabolic coupling factors, including NADPH. Nicotinamide nucleotide transhydrogenase (NNT) typically produces NADPH at the expense of NADH and ΔpH in energized mitochondria. Its spontaneous inactivation in C57BL/6J mice was previously shown to alter ATP production, Ca2+ influx, and GSIS, thereby leading to glucose intolerance. Here, we tested the role of NNT in the glucose regulation of mitochondrial NADPH and glutathione redox state and reinvestigated its role in GSIS coupling events in mouse pancreatic islets. Methods Islets were isolated from female C57BL/6J mice (J-islets), which lack functional NNT, and genetically close C57BL/6N mice (N-islets). Wild-type mouse NNT was expressed in J-islets by adenoviral infection. Mitochondrial and cytosolic glutathione oxidation was measured with glutaredoxin 1-fused roGFP2 probes targeted or not to the mitochondrial matrix. NADPH and NADH redox state was measured biochemically. Insulin secretion and upstream coupling events were measured under dynamic or static conditions by standard procedures. Results NNT is largely responsible for the acute glucose-induced rise in islet NADPH/NADP+ ratio and decrease in mitochondrial glutathione oxidation, with a small impact on cytosolic glutathione. However, contrary to current views on NNT in β-cells, these effects resulted from a glucose-dependent reduction in NADPH consumption by NNT reverse mode of operation, rather than from a stimulation of its forward mode of operation. Accordingly, the lack of NNT in J-islets decreased their sensitivity to exogenous H2O2 at non-stimulating glucose. Surprisingly, the lack of NNT did not alter the glucose-stimulation of Ca2+ influx and upstream mitochondrial events, but it markedly reduced both phases of GSIS by altering Ca2+-induced exocytosis and its metabolic amplification. Conclusion These results drastically modify current views on NNT operation and mitochondrial function in pancreatic β-cells.


Diabetes | 2016

Nicotinamide nucleotide transhydrogenase and the glucose stimulation of insulin secretion

Laila Rb Santos; Carole Muller; Arnaldo H. Souza; Hilton Takahashi; Jean-Christophe Jonas


Archive | 2015

Pathophysiology of Metabolic Syndrome: Part II—Influence of Inflammatory Status and Oxidative Stress

Hilton Takahashi; Leticia Prates Roma; Mauricio da Silva


Diabetes & Metabolism | 2015

O58 Rôle de la « nicotinamide nucleotide transhydrogenase » dans la stimulation de la sécrétion d’insuline par le glucose dans les îlots pancréatiques de souris

Laila Rb Santos; Arnaldo H. de Souza; Carole Muller; Hilton Takahashi; Jean-Christophe Jonas


Diabetes & Metabolism | 2015

P162 Rôle de la « nicotinamide nucleotide transhydrogenase » dans la réduction rapide du glutathion mitochondrial dans les îlots pancréatiques de souris

Carole Muller; Laila Rb Santos; Hilton Takahashi; A.H. ouza; J.C. Jonas


51st Annual Meeting of the European Association for the Study of Diabetes | 2015

Nicotinamide nucleotide transhydrogenase and the glucose regulation of mitochondrial glutathione oxidation, NADPH concentration and insulin secretion in mouse islets

Laila R.B. Santos; Carole Muller; Arnaldo H. Souza; Hilton Takahashi; Jean-Christophe Jonas


EASD Islet Study Group 2014 "Pancreatic Islet Cels Plasticity in Health and Diabetes" | 2014

Impact of nicotinamide nucleotide transhydrogenase inactivation on the glucose stimulation of insulin secretion by mouse pancreatic beta‐cells

Jean-Christophe Jonas; Arnaldo H. Souza; Laila R.B. Santos; Hilton Takahashi


EASD Islet Study Group 2014 "Pancreatic Islet Cells Plasticity in Health and Diabetes" | 2014

Role of nicotinamide nucleotide transhydrogenase in the acute glucose regulation of glutathioneredox state in mouse pancreatic islets

Laila R.B. Santos; Hilton Takahashi; Arnaldo H. Souza; Jean-Christophe Jonas

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Jean-Christophe Jonas

Université catholique de Louvain

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Carole Muller

Université catholique de Louvain

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Laila R.B. Santos

Université catholique de Louvain

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Jessica Duprez

Université catholique de Louvain

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Laila Rb Santos

Université catholique de Louvain

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Leticia Prates Roma

Université catholique de Louvain

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Arnaldo H. de Souza

Université catholique de Louvain

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J.C. Jonas

Université catholique de Louvain

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A.H. ouza

Université catholique de Louvain

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