The pentose cycle and insulin release in mouse pancreatic islets

Ashcroft, S. J. H.; Weerasinghe, L. C. C.; Bassett, J. M.; Randle, P. J.

doi:10.1042/bj1260525

Cited by 307 publications

(192 citation statements)

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“…The dependence of 3H20 production on D-(5-3H) -glucose concentration and the proportion between 3H20 and 14CO2 productions are in fair agreement with previous data on collagenase-isolated islets of normal mice [2]. The novel finding that anoxia inhibited the formation of 3H20 cannot be attributed to mobilization of B-cell glycogen with a resulting dilution of 3H in glucose-6-phosphate.…”

Section: Discussionsupporting

confidence: 91%

“…By using the method described by Ashcroft etaL [2], the production of 3H20 from D-(5-3H)glucose was measured as an index of the combined flux through the glycolytic and phosphogluconate pathways. Batches of 2 islets were incubated at 37 ~ in 15 gl of medium labelled with D-(5-3H)glucose (0.3-10.0 Ci/ mol); the glucose concentration varied between experiments as stated in the Results section.…”

Section: H20 Productionmentioning

confidence: 99%

“…In comparison with oxygenated islets, anoxic islets exhibited decreased concentrations of glucose-6-phosphate and increased concentrations of fructose-l,6-diphosphate. The concomitant inhibition of glycolytic flux may be due to a low lactate dehydrogenase activity in islets yielding a slow reoxidation of NADH and a slow phosphoglyceraldehyde oxidation under anaerobic conditions.Key words: Anoxia, glucose metabolism, pancreatic islets, Pasteur effect.Stimulation of insulin release by glucose may result from the production of a metabolic signal in the pancreatic B-cells [1][2][3][4]. The understanding of insulin secretion may thus be promoted by insight into the mechanisms that regulate glucose metabolism in these cells.…”

mentioning

confidence: 99%

“…Stimulation of insulin release by glucose may result from the production of a metabolic signal in the pancreatic B-cells [1][2][3][4]. The understanding of insulin secretion may thus be promoted by insight into the mechanisms that regulate glucose metabolism in these cells.…”

mentioning

confidence: 99%

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Influence of anoxia on glucose metabolism in pancreatic islets: Lack of correlation between fructose-1,6-diphosphate and apparent glycolytic flux

et al. 1975

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Summary. When equilibrated.with O2-CO 2 (95:5), pancreatic islets of non-inbred ob/ob-mice eXhibited a sigmoidal dependence of 3H20 production on D-(5-aH)-glucose cone, entration; the rate was most sensitive to changes of glucose concentration around 5mM and tended to be maximum above about 15 mM glucose. 3H20 production from more than 5 mM D-(5-3H)-glncose was about twice as fast as the production of 14CO z from equimolar D-(U-14Q) -glucose. Islets equilibrated with N2-CO 2 (95:5) did not exhibit a sigmoidal dose-response curve for 3H20 production, the process being inhibited by anoxia at glucose concentrations above 5mM. Pieces of exoerine pancreas had a slower aerobic 3HzO production than the islets and showed a clear enhancement of the process during anoxia. In comparison with oxygenated islets, anoxic islets exhibited decreased concentrations of glucose-6-phosphate and increased concentrations of fructose-l,6-diphosphate. The concomitant inhibition of glycolytic flux may be due to a low lactate dehydrogenase activity in islets yielding a slow reoxidation of NADH and a slow phosphoglyceraldehyde oxidation under anaerobic conditions.Key words: Anoxia, glucose metabolism, pancreatic islets, Pasteur effect.Stimulation of insulin release by glucose may result from the production of a metabolic signal in the pancreatic B-cells [1][2][3][4]. The understanding of insulin secretion may thus be promoted by insight into the mechanisms that regulate glucose metabolism in these cells. In most other tissues glycolysis is faster during anaerobic than under aerobic conditions. This effect of oxygen, the Pasteur effect, is probably due to the phosphofructokinase being inhibited by ATP and by a fall of ADP [5]. Matschinsky et al. [6] reported the inhibitory influence of ATP on phosphofructokinase in islet extracts. We have investigated the effects of anoxia on glycolysis in the B-cell-rich islets of non-inbred ob/ob-mice by measuring the transmembrane transport of glucose, the islet contents of glucose-6-phosphate and fructose-l,6-diphosphate and the production of 3H20 from D-(5-3H)glucose. Materials and Methods GeneralFresh islets were isolated by free-hand microdissection [7] of pancreatic glands from adult, non-inbred ob/ob-mice from the Ume~ colony; the isolation was performed at 2 ~ with the glands suspended in KrebsRinger bicarbonate buffer equilibrated with O2-CO 2 (95:5). In a few experiments pieces of exocrine pancreas were taken for comparison with the islets.Krebs-Ringer bicarbonate buffer equilibrated with O2-COz (95:5) or N2-CO2 (95:5) was used as basal medium in subsequent incubations at 37 ~ . Isolated islets were subjected to preliminary incubation for 30 min at 37 ~ in the absence or presence (5 raM) of glucose. Incubation was then continued in basal medium supplemented with D-glucose as required; the sugar was added as pure a-D-glucose, but this was done long. before the incubation to allow equlibration of the a and/3 anomers. The detailed incubation procedure depended on the aim of the experiment as follo...

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Section: Discussionsupporting

confidence: 91%

Section: H20 Productionmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Influence of anoxia on glucose metabolism in pancreatic islets: Lack of correlation between fructose-1,6-diphosphate and apparent glycolytic flux

et al. 1975

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“…Glucose utilisation was assayed as described by Ashcroft. 47 3 H 2 O production was by calculated by scintillation counting. Appropriate positive and negative (without cells) controls were performed alongside.…”

Section: Maldi-tof Mass Spectrometrymentioning

confidence: 99%

Carbonylation of glycolytic proteins is a key response to drug-induced oxidative stress and apoptosis

2003

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Recent work has highlighted the importance of protein posttranslational modifications such as phosphorylation (enzymatic) and nitrosylation (nonenzymatic) in the early stages of apoptosis. In this study, we have investigated the levels of protein carbonylation, a nonenzymatic protein modification that occurs in conditions of cellular oxidative stress, during etopside-induced apoptosis of HL60 cells. Within 1 h of VP16 treatment, a number of proteins underwent carbonylation due to oxidative stress. This was inhibited by the antioxidant N-acetyl-L-cysteine. Among the proteins found to be carbonylated were glycolytic enzymes. Subsequently, we found that the rate of glycolysis was significantly reduced, probably due to a carbonylation mediated reduction in enzymatic activity of glycolytic enzymes. Our work demonstrates that protein carbonylation can be rapidly induced through cytotoxic drug treatment and may specifically inhibit the glycolytic pathway. Given the importance of glycolysis as a source of cellular ATP, this has severe implications for cell function.

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Mitochondrial dysfunction in diabetes mellitus

Anderson¹

1999

Drug Dev. Res.

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This review discusses the hypothesis that mitochondrial dysfunction plays a role in the pathogenesis of the most common form of diabetes, type II diabetes mellitus. Mitochondrial mutations have been linked to the development of diabetes mellitus as part of several rare syndromes, accounting for approximately 1.5% of all cases of the disease (“classic” mitochondrial diabetes). The characteristics of classic mitochondrial diabetes are intermediate between those of type I and type II diabetes, more closely resembling the latter. By studying the biochemical, cellular, and physiologic consequences of mitochondrial DNA mutations that cause classic mitochondrial diabetes, we may also gain important insights into the pathogenesis of type II diabetes mellitus. Individuals with classic mitochondrial diabetes exhibit a variety of defects in mitochondrial electron transfer enzyme activities. Complex I and Complex IV activities in skeletal muscle are almost universally decreased in mitochondrial diabetics compared with control individuals. The major physiologic abnormality in classic mitochondrial diabetes is delayed and insufficient insulin secretion in response to a glucose load. Insulin resistance is less commonly observed in these patients. The link between mitochondrial function and insulin secretion is supported by cellular studies in which introduction of inhibitors of oxidative phosphorylation or depletion of mitochondrial DNA markedly impairs glucose mediated insulin secretion from pancreatic β‐cells. Evidence for mitochondrial dysfunction in the common form of type II diabetes includes excessive free radical levels in the plasma of diabetics, increased reactive oxygen species, and decreased ATP synthase activity in cybrids constructed from mitochondria of diabetic patients, and maternal inheritance of the disease. By using the occurrence of diabetes in rare mitochondrial syndromes as an example, evidence supporting a relationship between mitochondrial dysfunction and the common form of type II diabetes is discussed. Mitochondrial function may represent a novel area for the development of therapeutic and diagnostic strategies for type II diabetes mellitus. Drug Dev. Res. 46:67–79, 1999. © 1999 Wiley‐Liss, Inc.

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The pentose cycle and insulin release in mouse pancreatic islets

Cited by 307 publications

References 20 publications

Influence of anoxia on glucose metabolism in pancreatic islets: Lack of correlation between fructose-1,6-diphosphate and apparent glycolytic flux

Influence of anoxia on glucose metabolism in pancreatic islets: Lack of correlation between fructose-1,6-diphosphate and apparent glycolytic flux

Carbonylation of glycolytic proteins is a key response to drug-induced oxidative stress and apoptosis

Mitochondrial dysfunction in diabetes mellitus

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