Effects of glucose on the cytosolic ration of reduced/oxidized nicotinamide-adenine dinucleotide phosphate in rat islets of Langerhans

Ashcroft, S. J. H.; Christie, Michael R.

doi:10.1042/bj1840697

Cited by 44 publications

(29 citation statements)

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“…Both ratios rose in parallel in the presence of glucose. Glucose also raised the cytosolic NADPH/NADP + ratio [32,33]. These findings allow conclusions to be drawn from the whole-islet NADPH/ NADP + ratio about the mitochondrial and the cytosolic NADPH/NADP + ratios.…”

Section: Discussionmentioning

confidence: 71%

Fuel-induced amplification of insulin secretion in mouse pancreatic islets exposed to a high sulfonylurea concentration: role of the NADPH/NADP+ ratio

Panten

Rustenbeck

2007

Diabetologia

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Aims/hypothesis The aim of this study was to examine whether the cytosolic NADPH/NADP + ratio of beta cells serves as an amplifying signal in fuel-induced insulin secretion and whether such a function is mediated by cytosolic α-ketoglutarate. Methods Pancreatic islets and islet cells were isolated from albino mice by collagenase digestion. Insulin secretion of incubated or perifused islets was measured by ELISA. The NADPH and NADP + content of incubated islets was determined by enzymatic cycling. The cytosolic Ca 2+ concentration ([Ca 2+ ] c ) in islets was measured by microfluorimetry and the activity of ATP-sensitive K + channels in islet cells by patch-clamping. Results Both 30 mmol/l glucose and 10 mmol/l α-ketoisocaproate stimulated insulin secretion and elevated the NADPH/NADP + ratio of islets preincubated in the absence of fuel. The increase in the NADPH/NADP + ratio was abolished in the presence of 2.7 μmol/l glipizide (closing all ATP-sensitive K + channels). However, α-ketoisocaproate, but not glucose, still stimulated insulin secretion. That glipizide did not inhibit α-ketoisocaproate-induced insulin secretion was not the result of elevated [Ca 2+ ] c , as glucose caused a more marked [Ca 2+ ] c increase. Insulin release triggered by glipizide alone was moderately amplified by dimethyl α-ketoglutarate (which is cleaved to produce cytosolic α-ketoglutarate), but there was no indication of a signal function of cytosolic α-ketoglutarate. Conclusions/interpretationThe results strongly suggest that the NADPH/NADP + ratio in the beta cell cytosol does not serve as an amplifying signal in fuel-induced insulin release. The study supports the view that amplification results from the intramitochondrial production of citrate by citrate synthase and from the associated export of citrate into the cytosol.

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Section: Discussionmentioning

confidence: 71%

Fuel-induced amplification of insulin secretion in mouse pancreatic islets exposed to a high sulfonylurea concentration: role of the NADPH/NADP+ ratio

Panten

Rustenbeck

2007

Diabetologia

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“…Because the pentose-P pathway is slow in beta cells, it would be left to malic enzyme and isocitrate dehydrogenase to generate NADPH. The mitochondrial energy-dependent NADP reductase, which transfers hydrogen from NADH to NADP, is not in equilibrium with the cytosolic NAD(P)/NAD(P)H system because of absolute permeability barriers for pyridine nucleotides (23,24). It is striking that pyruvate in SUR1 Ϫ/Ϫ islets is more effectively labeled than in the controls when glucose is at low levels of 5 mM, consistent with a higher rate of 13 CO 2 production and strongly suggests pyruvate cycling in SUR1 Ϫ/Ϫ cells.…”

Section: Discussionmentioning

confidence: 99%

Elimination of KATP Channels in Mouse Islets Results in Elevated [U-13C]Glucose Metabolism, Glutaminolysis, and Pyruvate Cycling but a Decreased γ-Aminobutyric Acid Shunt

Nissim

Chen

et al. 2008

Journal of Biological Chemistry

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Pancreatic beta cells are hyper-responsive to amino acids but have decreased glucose sensitivity after deletion of the sulfonylurea receptor 1 (SUR1) both in man and mouse. It was hypothesized that these defects are the consequence of impaired integration of amino acid, glucose, and energy metabolism in beta cells. We used gas chromatography-mass spectrometry methodology to study intermediary metabolism of SUR1 knock-out (SUR1 ؊/؊ ) and control mouse islets with D-[U-13 C]glucose as substrate and related the results to insulin secretion. The levels and isotope labeling of alanine, aspartate, glutamate, glutamine, and ␥-aminobutyric acid (GABA) served as indicators of intermediary metabolism. We found that the GABA shunt of SUR1 ؊/؊ islets is blocked by about 75% and showed that this defect is due to decreased glutamate decarboxylase synthesis, probably caused by elevated free intracellular calcium. Glutaminolysis stimulated by the leucine analogue D,L-␤-2-amino-2-norbornane-carboxylic acid was, however, enhanced in SUR1 ؊/؊ and glyburide-treated SUR1 ؉/؉ islets. Glucose oxidation and pyruvate cycling was increased in SUR1 ؊/؊ islets at low glucose but was the same as in controls at high glucose. Malic enzyme isoforms 1, 2, and 3, involved in pyruvate cycling, were all expressed in islets. High glucose lowered aspartate and stimulated glutamine synthesis similarly in controls and SUR1 ؊/؊ islets. The data suggest that the interruption of the GABA shunt and the lack of glucose regulation of pyruvate cycling may cause the glucose insensitivity of the SUR1 ؊/؊ islets but that enhanced basal pyruvate cycling, lowered GABA shunt flux, and enhanced glutaminolytic capacity may sensitize the beta cells to amino acid stimulation.The pancreatic beta cells function as the predominant sensors and regulators of glucose, amino acid, and fatty acid levels of the mammalian organism, including man, by adjusting the minute to minute rate of insulin secretion such that these fuels are maintained at physiologically optimal blood concentrations under all nutritional conditions including feeding and fasting. This process of fuel-sensing and stimulation of insulin secretion requires that the various stimuli are transported into the beta cells and are metabolized to generate coupling factors that trigger and sustain the secretion of the hormone from large stores of insulin granules (1-4). The diverse specific pathways that allow access to metabolism for glucose, amino acids, and fatty acids converge to a complex network of intermediary metabolism represented by the citric acid cycle, a considerable variety of metabolite and cofactor shuttles including the GABA 2 shunt, and the processes of electron transport and oxidative phosphorylation, to mention just a few outstanding features of the biochemical maze of the beta cell.In the present study we have used uniformly labeled D-[13 C]glucose and GC-MS methods to explore the role of intermediary metabolism of pancreatic islets isolated from normal and sulfonylurea receptor 1 (SUR1) knock-out...

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“…Recent studies have strongly suggested that NADPH production via the malate-aspartate shuttle [162,163,164], also called pyruvate cycling [165], might be an important metabolic signal. Indeed, metabolisable insulin secretagogues increase the NADPH/NADP + ratio in rodent islets [166,167] and inhibition of NADPH formation reduces glucose-stimulated insulin secretion from rat islets [168,169]. Recent evidence suggests the existence of membrane associated aldehyde oxidoreductase-like enzyme activity in rat islets [170] and, as mentioned above, a number of oxidoreductase-like Kvβ subunits (Kvβ1, 2 and 3) are expressed in human and rat islets and INS-1 insulinoma cells [93].…”

Section: Regulation Of Kv Channel Activity In Beta Cellsmentioning

confidence: 99%

Voltage-dependent K + channels in pancreatic beta cells: Role, regulation and potential as therapeutic targets

2003

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Insulin secretion from pancreatic islet beta cells is acutely regulated by a complex interplay of metabolic and electrogenic events. The electrogenic mechanism regulating insulin secretion from beta cells is commonly referred to as the ATP-sensitive K + (K ATP ) channel dependent pathway. Briefly, an increase in ATP and, perhaps more importantly, a decrease in ADP stimulated by glucose metabolism depolarises the beta cell by closing K ATP channels. Membrane depolarisation results in the opening of voltage-dependent Ca 2+ channels, and influx of Ca 2+ is the main trigger for insulin secretion. Repolarisation of pancreatic beta cell action potential is mediated by the activation of voltage-dependent K + (Kv) channels. Various Kv channel homologues have been detected in insulin secreting cells, and recent studies have shown a role for specific Kv channels as modulators of insulin secretion. Here we review the evidence supporting a role for Kv channels in the regulation of insulin secretion and discuss the potential and the limitations for beta-cell Kv channels as therapeutic targets. Furthermore, we review recent investigations of mechanisms regulating Kv channels in beta cells, which suggest that Kv channels are active participants in the regulation of beta-cell electrical activity and insulin secretion. [Diabetologia (2003[Diabetologia ( ) 46:1046[Diabetologia ( -1062

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Effects of glucose on the cytosolic ration of reduced/oxidized nicotinamide-adenine dinucleotide phosphate in rat islets of Langerhans

Cited by 44 publications

References 23 publications

Fuel-induced amplification of insulin secretion in mouse pancreatic islets exposed to a high sulfonylurea concentration: role of the NADPH/NADP+ ratio

Fuel-induced amplification of insulin secretion in mouse pancreatic islets exposed to a high sulfonylurea concentration: role of the NADPH/NADP+ ratio

Elimination of KATP Channels in Mouse Islets Results in Elevated [U-13C]Glucose Metabolism, Glutaminolysis, and Pyruvate Cycling but a Decreased γ-Aminobutyric Acid Shunt

Voltage-dependent K + channels in pancreatic beta cells: Role, regulation and potential as therapeutic targets

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