Glucose-stimulated insulin secretion correlates with changes in mitochondrial and cytosolic Ca2+ in aequorin-expressing INS-1 cells.

Kennedy, Eleanor D.; Rizzuto, Rosario; Théler, Jean-Marc; Pralong, William; Bastianutto, Carlo; Pozzan, Tullio; Wollheim, Claes B.

doi:10.1172/jci119071

Cited by 139 publications

(186 citation statements)

References 49 publications

(48 reference statements)

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“…This in turn generates a mitochondrial factor which activates the exocytotic release of insulin. The same sequence of events is seen in intact cells stimulated with glucose, i. e. hyperpolarisation of Dy m and increased mitochondrial Ca 2+ and TCA cycle-dependent generation of a coupling factor distinct from ATP [32,48,49,56]. The mitochondrial factor was subsequently identified as glutamate [57].…”

Section: Mitochondrial Activation Directly Stimulates Insulin Exocytosismentioning

confidence: 81%

“…Do INS-1 r 0 cells secrete insulin? Glucose-stimulated insulin secretion was completely abolished in the r 0 cells, whereas depolarisation with potassium, which raises cytosolic Ca 2+ independent of cellular metabolism [48,51], still evoked insulin secretion (Fig. 13).…”

Section: Beta-cell Model Of Mitochondrial Diabetesmentioning

confidence: 93%

“…These cells respond to an increase in the glucose concentration from 2.8 to 10 mmol/l with a biphasic insulin secretion (Fig. 7) [47,48]. For assessment of signal transduction, the cells were stably transfected with proteins permitting the monitoring of intracellular messengers.…”

Section: Consensus Model For the Mechanism Of Insulin Secretionmentioning

confidence: 99%

“…This precedes the rise in cytosolic Ca 2+ measured with the Ca 2+ -sensitive photoprotein aequorin. The biphasic increase in cytosolic Ca 2+ is associated with a biphasic increase in the Ca 2+ concentration inside the mitochondria [48,49]. Leucine, like glucose, raises the cytosolic and mitochondrial Ca 2+ concentrations [49].…”

Section: Consensus Model For the Mechanism Of Insulin Secretionmentioning

confidence: 99%

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Beta-cell mitochondria in the regulation of insulin secretion: a new culprit in Type II diabetes

Wollheim¹

2000

Diabetologia

175

148

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In previous lectures, Claude Bernard's many scientific contributions have been highlighted. Among others he suggested in 1850 that the liver stores glucose and 7 years later, in 1857, he finally isolated glycogen [2]. Before that, in 1849, Claude Bernard reported his ªPiqßre sucrØeº to the SociØtØ de Biologie, Paris [3]. In analogy to his experiments in which stimulation of the fifth cranial nerve caused saliva secretion, he assumed that stimulation of the vagus nerve would elicit glucose secretion from the liver. In unanaesthetised rabbits and dogs, the pricking of the bottom of the fourth ventricle resulted in pronounced hyperglycaemia and glucosuria within 20 min. The ªdiabetesº was transient and disappeared after a few hours. He later showed that this effect was mediated, not by the vagus, but by sympathetic nerves. His discovery of glycogen made Claude Bernard the true father of Diabetologia (2000) AbstractInsulin is stored in secretory granules in the beta-cell and is secreted by exocytosis. This process is precisely controlled to achieve blood glucose homeostasis. Many forms of diabetes mellitus display impaired glucose-induced insulin secretion. This has been shown to be the primary cause of the disease in the various forms of maturity-onset diabetes of the young (MODY) and has also been implicated in adult-onset Type II (non-insulin-dependent) diabetes mellitus. Glucose generates ATP and other metabolic coupling factors in the beta-cell mitochondria. By plasma membrane depolarisation ATP promotes Ca 2+ influx, which raises cytosolic Ca 2+ and triggers insulin exocytosis. Through hyperpolarisation of the mitochondrial membrane glucose also increases the Ca 2+ concentration in the mitochondrial matrix activating Ca 2+ -sensitive dehydrogenases in the tricarboxylic acid cycle. The resulting generation of glutamate participates in Ca 2+ -stimulated exocytosis. Mitochondrial DNA (mtDNA) encodes some of the polypeptides of the respiratory chain enzyme complexes. Mutations in mtDNA lead to maternally inherited diabetes mellitus characterised by impaired insulin secretion. The impact of altered mtDNA on insulin secretion has been shown in mtDNA-deficient beta-cell lines which have lost glucose-stimulated insulin secretion but retain a Ca 2+ -induced insulin secretion. A cellular model of MODY3 expressing dominant-negative hepatocyte nuclear factor-1a (HNF-1a) also displayed deletion of glucose-induced but not Ca 2+ -induced insulin secretion. Reduced mitochondrial metabolism explains this secretory pattern. Thus, genetically manipulated beta-cell lines are essential tools in the investigation of the molecular basis of beta-cell dysfunction in diabetes and should explain the role of other transcription factors in the disease. [Diabetologia (2000) 43: 265±277]

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Section: Mitochondrial Activation Directly Stimulates Insulin Exocytosismentioning

confidence: 81%

Section: Beta-cell Model Of Mitochondrial Diabetesmentioning

confidence: 93%

Section: Consensus Model For the Mechanism Of Insulin Secretionmentioning

confidence: 99%

Section: Consensus Model For the Mechanism Of Insulin Secretionmentioning

confidence: 99%

See 2 more Smart Citations

Beta-cell mitochondria in the regulation of insulin secretion: a new culprit in Type II diabetes

Wollheim¹

2000

Diabetologia

175

148

View full text Add to dashboard Cite

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“…While the majority of these subunits are encoded by the nuclear genome, thirteen subunits are encoded by a circular M a n u s c r i p t double stranded DNA molecule, the 16.6-kb mitochondrial genome. Depletion of mitochondrial DNA (mtDNA) from β-cells results in impaired mitochondrial metabolism and loss of fuel-stimulated insulin secretion (Kennedy et al, 1996).…”

Section: Genetic and Epigenetic Regulation Of Mitochondria And Associmentioning

confidence: 99%

Mitochondrial dysfunction in pancreatic β-cells in Type 2 Diabetes

Mulder

Ling

2009

Molecular and Cellular Endocrinology

105

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Mitochondrial metabolism controls insulin secretion from the pancreatic β-cell. Type 2 Diabetes evolves when the β-cells fail to release appropriate amounts of insulin, causing metabolic dysregulation and hyperglycemia. It is attractive to assume that mitochondrial dysfunction plays a decisive role in these processes. Indeed, while being a rare condition, genetically determined dysfunction of mitochondria causes a Type 2 Diabetes-like syndrome.Here, we review what is known about mitochondrial dysfunction in the β-cell in Type 2Diabetes. The focus is on observations in humans but relevant studies in animal models of the disease are discussed. A particular emphasis is placed on changes in metabolic enzymes and function in β-cell mitochondria and how altered structure of the organelle appears to facilitate its function. These molecular processes are subject to tight genetic as well as epigenetic control. Variations and implications of these mechanisms are reviewed. The emerging picture is that alterations in mitochondria may be a culprit in the pathogenetic processes culminating in Type 2 Diabetes. Such processes may prove to be targets for therapeutic interventions in the disease.

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Probing cellular function with bioluminescence imaging

Rutter

Xavier

Tsuboi

et al. 2004

Encyclopedia of Genetics, Genomics, Proteomics and Bioinformatics

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Glucose-stimulated insulin secretion correlates with changes in mitochondrial and cytosolic Ca2+ in aequorin-expressing INS-1 cells.

Abstract: Nutrient-stimulated insulin secretion is dependent upon the generation of metabolic coupling factors in the mitochondria of the pancreatic B cell.

Cited by 139 publications

References 49 publications

Beta-cell mitochondria in the regulation of insulin secretion: a new culprit in Type II diabetes

Beta-cell mitochondria in the regulation of insulin secretion: a new culprit in Type II diabetes

Mitochondrial dysfunction in pancreatic β-cells in Type 2 Diabetes

Probing cellular function with bioluminescence imaging

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