The Pancreatic β-Cell: A Bioenergetic Perspective

Nicholls, David G.

doi:10.1152/physrev.00009.2016

Cited by 93 publications

(129 citation statements)

References 565 publications

(713 reference statements)

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“…However, β-cells are unique in their ability to modulate their metabolic rate according to the glucose concentration. This is usually presented as an ability to increase their NADH/NAD + ratio, mitochondrial proton motive force (depending on both mitochondrial membrane potential and pH gradient), and ATP/ADP ratio upon glucose stimulation, but it might be more correct to state, as recently pointed out in a review on β-cell mitochondria [4], that β-cells allow these parameters to drop below 10 mmol/l glucose. Such unusual behavior could be related to the low coupling efficiency of β-cell mitochondria [4], [32].…”

Section: Discussionmentioning

confidence: 99%

“…This is usually presented as an ability to increase their NADH/NAD + ratio, mitochondrial proton motive force (depending on both mitochondrial membrane potential and pH gradient), and ATP/ADP ratio upon glucose stimulation, but it might be more correct to state, as recently pointed out in a review on β-cell mitochondria [4], that β-cells allow these parameters to drop below 10 mmol/l glucose. Such unusual behavior could be related to the low coupling efficiency of β-cell mitochondria [4], [32]. A low NADH/NAD + ratio, mitochondrial proton motive force, and ATP/ADP ratio, as observed in β-cells at non-stimulating glucose, correspond to the conditions that activate NNT reverse mode of operation in mitochondria isolated from other tissues [33], [34].…”

Section: Discussionmentioning

confidence: 99%

“…The ensuing rise in the ATP/ADP ratio closes K ATP channels, thereby depolarizing the plasma membrane, opening voltage-dependent Ca 2+ channels and triggering Ca 2+ influx, rise in intracellular Ca 2+ concentration ([Ca 2+ ] i ) and insulin granule exocytosis. In addition, glucose-derived coupling factors play a role in the metabolic amplification of Ca 2+ -induced secretion [1], [2], [3], [4]. Among them, cytosolic NADPH together with glutaredoxin 1 (GRX1) acts as a regulatory or permissive factor for Ca 2+ -induced exocytosis [5], [6], [7], an effect which may result from protein deSUMOylation by redox-sensitive SENP-1 [8], [9].…”

Section: Introductionmentioning

confidence: 99%

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

Santos

Muller

Souza

et al. 2017

Molecular Metabolism

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ObjectiveThe 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.MethodsIslets 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.ResultsNNT 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.ConclusionThese results drastically modify current views on NNT operation and mitochondrial function in pancreatic β-cells.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

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

Santos

Muller

Souza

et al. 2017

Molecular Metabolism

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“…All these mechanisms combine to enhance insulin secretion in an efficacious fashion (Ahrén 2000). Here, mitochondria play a key role (Wollheim 2000, Nicholls 2016; oxidation of most cellular fuels produces reducing equivalents, driving the electron transport chain and subsequently ATP production via oxidative phosphorylation (OXPHOS). A rise in ATP:ADP ratio closes the ATP-sensitive K + channel (K ATP ), depolarizes the plasma membrane, opens voltage-gated Ca 2+ channels and subsequently triggers exocytosis of insulincontaining granules.…”

Section: Introductionmentioning

confidence: 99%

The pathogenetic role of β-cell mitochondria in type 2 diabetes

Fex

Nicholas

Vishnu

et al. 2018

Journal of Endocrinology

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Mitochondrial metabolism is a major determinant of insulin secretion from pancreatic β-cells. Type 2 diabetes evolves when β-cells fail to release appropriate amounts of insulin in response to glucose. This results in hyperglycemia and metabolic dysregulation. Evidence has recently been mounting that mitochondrial dysfunction plays an important role in these processes. Monogenic dysfunction of mitochondria is a rare condition but causes a type 2 diabetes-like syndrome owing to β-cell failure. Here, we describe novel advances in research on mitochondrial dysfunction in the β-cell in type 2 diabetes, with a focus on human studies. Relevant studies in animal and cell models of the disease are described. Transcriptional and translational regulation in mitochondria are particularly emphasized. The role of metabolic enzymes and pathways and their impact on β-cell function in type 2 diabetes pathophysiology are discussed. The role of genetic variation in mitochondrial function leading to type 2 diabetes is highlighted. We argue that alterations in mitochondria may be a culprit in the pathogenetic processes culminating in type 2 diabetes.

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“…Mitochondrial metabolism of glycolytic pyruvate plays a central role in insulin secretion [1]. The canonical pathway of glucose-stimulated insulin secretion (GSIS) relies on hyperpolarization of mitochondrial membrane potential (ΔψM) (more strictly, hyperpolarization of the protonmotive force) leading to increased mitochondrial production of ATP, and is largely responsible for the first phase of insulin secretion [2–7].…”

Section: Introductionmentioning

confidence: 99%

Positive Feedback Amplifies the Response of Mitochondrial Membrane Potential to Glucose Concentration in Clonal Pancreatic Beta Cells

Gerencser

Mookerjee

Jastroch

et al. 2017

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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Analysis of the cellular mechanisms of metabolic disorders, including type 2 diabetes mellitus, is complicated by the large number of reactions and interactions in metabolic networks. Metabolic control analysis with appropriate modularization is a powerful method for simplifying and analyzing these networks. To analyze control of cellular energy metabolism in adherent cell cultures of the INS-1 832/13 pancreatic β-cell model we adapted our microscopy assay of absolute mitochondrial membrane potential (ΔψM) to a fluorescence microplate reader format, and applied it in conjunction with cell respirometry. In these cells the sensitive response of ΔψM to extracellular glucose concentration drives glucose-stimulated insulin secretion. Using metabolic control analysis we identified the control properties that generate this sensitive response. Force-flux relationships between ΔψM and respiration were used to calculate kinetic responses to ΔψM of processes both upstream (glucose oxidation) and downstream (proton leak and ATP turnover) of ΔψM. The analysis revealed that glucose-evoked ΔψM hyperpolarization is amplified by increased glucose oxidation activity caused by factors downstream of ΔψM. At high glucose, the hyperpolarized ΔψM is stabilized almost completely by the action of glucose oxidation, whereas proton leak also contribute to the homeostatic control of ΔψM at low glucose. These findings suggest a strong positive feedback loop in the regulation of β-cell energetics, and a possible regulatory role of proton leak in the fasting state. Analysis of islet bioenergetics from published cases of type 2 diabetes suggests that disruption of this feedback can explain the damaged bioenergetic response of β-cells to glucose.

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The Pancreatic β-Cell: A Bioenergetic Perspective

Cited by 93 publications

References 565 publications

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

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

The pathogenetic role of β-cell mitochondria in type 2 diabetes

Positive Feedback Amplifies the Response of Mitochondrial Membrane Potential to Glucose Concentration in Clonal Pancreatic Beta Cells

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