Intracellular ATP directly blocks K+ channels in pancreatic B-cells

Cook, Daniel L.; Hales, C. N.

doi:10.1038/311271a0

Cited by 1,189 publications

(759 citation statements)

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“…An early key observation was that glucose-stimulated insulin secretion is prevented by mannoheptulose, a competitive inhibitor of glucose phosphorylation (Coore and Randle, 1964). It was not until 20 years later after the invention of the patch clamp technique that ATP (Ashcroft et al, 1984;Cook and Hales, 1984) or the ATP/ADP ratio (Ashcroft and Rorsman, 1989) could be identified as a primary factor coupling glucose metabolism to insulin secretion. ATP acts by inhibiting ATP-sensitive K + (K ATP ) channels, thus confirming the early and innovative proposal that glucose depolarizes the β-cells by inhibiting the K + permeability (Sehlin and Täljedal, 1975).…”

Section: Role Of Metabolism For Glucose-induced Insulin Secretionmentioning

confidence: 99%

“…However, the discovery that β-cell depolarization with increase of [Ca 2+ ] i depends on ATP (Ashcroft et al, 1984;Cook and Hales, 1984) shifts attention towards oxidative metabolism as most ATP is produced by mitochondria. Since secretion is pulsatile it is obvious that oscillations in metabolism and ATP generation may underlie this pattern.…”

Section: Role Of Metabolism For Glucose-induced Insulin Secretionmentioning

confidence: 99%

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Oscillatory control of insulin secretion

Tengholm

Gylfe

2009

Molecular and Cellular Endocrinology

162

169

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Pulsatile insulin secretionSince insulin is the only blood glucose-lowering hormone, its secretion is essential for glucose homeostasis, and disturbances are associated with glucose intolerance and diabetes.Glucose is the major stimulus for insulin release but secretion is enhanced also by other nutrients and is under stimulatory and inhibitory control by hormones and neurotransmitters.Although the external factors are essential determinants of insulin secretion, there are also input-independent variations in hormone release. Regular oscillations of the circulating insulin concentrations in normal subjects consequently occur without accompanying changes

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Section: Role Of Metabolism For Glucose-induced Insulin Secretionmentioning

confidence: 99%

Section: Role Of Metabolism For Glucose-induced Insulin Secretionmentioning

confidence: 99%

Oscillatory control of insulin secretion

Tengholm

Gylfe

2009

Molecular and Cellular Endocrinology

162

169

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“…Glucose is converted via glycolysis to pyruvate, which enters the mitochondria and is metabolised in the tricarboxylic acid (TCA) cycle. Pyruvate carbon metabolism leads to generation of ATP and hence to an increased cytosolic ATP : ADP ratio, which is crucial for insulin secretion [4,5] and biosynthesis [3]. Thus, the energetic state of the beta cell is an important component of the stimulus-secretion coupling mechanism of glucose-induced insulin production and secretion.…”

Section: Introductionmentioning

confidence: 99%

Mitochondrial regulation of insulin production in rat pancreatic islets

Leibowitz

Khaldi²,

Shauer

et al. 2005

Diabetologia

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Aims/hypothesis: The study was designed to identify the key metabolic signals of glucose-stimulated proinsulin gene transcription and translation, focusing on the mechanism of succinate stimulation of insulin production. Methods: Wistar rat islets were incubated in 3.3 mmol/l glucose with and without esters of different mitochondrial metabolites or with 16.7 mmol/l glucose. Proinsulin biosynthesis was analysed by tritiated leucine incorporation into newly synthesised proinsulin. Preproinsulin gene transcription was evaluated following transduction with adenoviral vectors expressing the luciferase reporter gene under the control of the rat I preproinsulin promoter. Steady-state preproinsulin mRNA was determined using relative quantitative PCR. The mitochondrial membrane potential was measured by microspectrofluorimetry using rhodamine-123. Results: Succinic acid monomethyl ester, but not other mitochondrial metabolites, stimulated preproinsulin gene transcription and translation. Similarly to glucose, succinate increased specific preproinsulin gene transcription and biosynthesis. The inhibitor of succinate dehydrogenase (SDH), 3-nitropropionate, abolished glucose-and succinate-stimulated mitochondrial membrane hyperpolarisation and proinsulin biosynthesis, indicating that stimulation of proinsulin translation depends on SDH activity. Partial inhibition of SDH activity by exposure to fumaric acid monomethyl ester abolished the stimulation of preproinsulin gene transcription, but only partially inhibited the stimulation of proinsulin biosynthesis by glucose and succinate, suggesting that SDH activity is particularly important for the transcriptional response to glucose. Conclusions/interpretation: Succinate is a key metabolic mediator of glucose-stimulated preproinsulin gene transcription and translation. Moreover, succinate stimulation of insulin production depends on its metabolism via SDH. The differential effect of fumarate on preproinsulin gene transcription and translation suggests that these processes have different sensitivities to metabolic signals.

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“…Since the discovery of these channels in the beta cell [1], their tides, where intracellular ATP plays a central role. It has been shown that ATP inhibits K ATP channel activity in excised membrane patches, with reported halfmaximal inhibitory concentrations between 5 and 15 µmol/l [1,2,3]. Because of the presence of ATP in the millimolar range in the intact beta cell, endogenous agents capable of modulating ATP-sensitivity of the K ATP channel must be of importance in the regulation of the channel.…”

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confidence: 99%

Long-Chain CoA esters activate human pancreatic beta-cell K ATP channels: potential role in Type 2 diabetes

et al. 2004

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Aims/hypothesis. The ATP-regulated potassium (K ATP ) channel in the pancreatic beta cell couples the metabolic state to electrical activity. The primary regulator of the K ATP channel is generally accepted to be changes in ATP/ADP ratio, where ATP inhibits and ADP activates channel activity. Recently, we showed that long-chain CoA (LC-CoA) esters form a new class of potent K ATP channel activators in rodents, as studied in inside-out patches. Methods. In this study we have investigated the effects of LC-CoA esters in human pancreatic beta cells using the inside-out and whole-cell configurations of the patch clamp technique. Results. Human K ATP channels were potently activated by acyl-CoA esters with a chain length exceeding 12 carbons. Activation by LC-CoA esters did not require the presence of Mg 2+ or adenine nucleotides. A detailed characterization of the concentration-dependent relationship showed an EC 50 of 0.7±0.1 µmol/l. Furthermore, in the presence of an ATP/ADP ratio of 10 (1.1 mmol/l total adenine nucleotides), whole-cell K ATP channel currents increased approximately sixfold following addition of 1 µmol/l LC-CoA ester. The presence of 1 µmol/l LC-CoA in the recording pipette solution increased beta-cell input conductance, from 0.5±0.2 nS to 2.5±1.3 nS. Conclusion/interpretation. Taken together, these results show that LC-CoA esters are potent activators of the K ATP channel in human pancreatic beta cells. The fact that LC-CoA esters also stimulate K ATP channel activity recorded in the whole-cell configuration, points to the ability of these compounds to have an important modulatory role of human beta-cell electrical activity under both physiological and pathophysiological conditions. [Diabetologia (2004) essential function has been included in the model of glucose-induced insulin secretion. In this model, increases in blood glucose levels lead to metabolism of glucose which generates an increase in the ATP/ADP ratio. The consensus view is that increases in the ATP/ADP ratio promote closure of the beta-cell K ATP channel, thereby depolarizing the cell membrane resulting in opening of voltage-dependent Ca 2+ channels. The subsequent rise in cytoplasmic free Ca 2+ concentration triggers a series of events leading to exocytosis of insulin. Hence, the K ATP channel provides a critical link between glucose metabolism, electrical activity and insulin secretion in the pancreatic beta cell.The most important molecular regulators of K ATP channel activity are believed to be adenine nucleo-ATP-sensitive potassium (K ATP ) channels play a key role in the coupling between cellular metabolism and electrical activity in a wide range of tissues. Since the discovery of these channels in the beta cell [1], their

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Intracellular ATP directly blocks K+ channels in pancreatic B-cells

Cited by 1,189 publications

References 20 publications

Oscillatory control of insulin secretion

Oscillatory control of insulin secretion

Mitochondrial regulation of insulin production in rat pancreatic islets

Long-Chain CoA esters activate human pancreatic beta-cell K ATP channels: potential role in Type 2 diabetes

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