Mitochondrial DNA Is Required for Regulation of Glucose-stimulated Insulin Secretion in a Mouse Pancreatic Beta Cell Line, MIN6

Soejima, Aki; Inoue, Kimiko; Takai, Daiya; Kaneko, Motohisa; Ishihara, Hideharu; Oka, Yoshitomo; Hayashi, Jun‐Ichi

doi:10.1074/jbc.271.42.26194

Cited by 145 publications

(98 citation statements)

References 43 publications

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“…Thus the chemical elimination of mitochondrial DNA leads to complete inhibition of glucose-stimulated insulin secretion [26]. Some experiments have, however, shown that formation of cybrids between enucleated donor cells containing normal mitochondria and r 0 cells of the mouse beta-cell line MIN6 permitted restoration of glucose-induced insulin secretion [70]. These experiments thus unequivocally show the pivotal role of the mitochondria in glucose-stimulated insulin secretion.…”

Section: Beta-cell Model Of Mitochondrial Diabetesmentioning

confidence: 70%

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

Wollheim¹

2000

Diabetologia

176

149

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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: Beta-cell Model Of Mitochondrial Diabetesmentioning

confidence: 70%

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

Wollheim¹

2000

Diabetologia

176

149

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“…29 Depletion of mtDNA in MIN6 cells resulted in loss of ability to release insulin by glucose stimulation which was restored by introduction of mtDNA into the knockout cells. 30 Thus high glucose exposure induced reduction in the expression of mitochondrial aconitase may result in Table 1 were incubated for 60 minutes. Immediately after incubation, aliquots of the medium were removed for assay of insulin by RIA as previously described.…”

Section: Discussionmentioning

confidence: 99%

Mitochondrial proteome analysis reveals altered expression of voltage dependent anion channels in pancreatic β-cells exposed to high glucose

Ahmed¹,

Muhammed²,

Kessler³

et al. 2010

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“…For example, a 0 line isolated from the mouse pancreatic beta cell line MIN6 was used for studying the influence of mtDNA depletion and its repopulation on phenotypic expression of glucose-stimulated insulin secretion (27).…”

Section: Discussionmentioning

confidence: 99%

“…A mouse pancreatic beta cell line (MIN6) was cultivated as described previously (27) Isolation of 0 Mouse Cells-Cells were plated at 1 ϫ 10 2 -5 ϫ 10 4 cells/dish, and beginning 24 h after plating they were treated with ditercalinium (DC, an antitumor bis-intercalating agent) for 1 month. C2 and NIH3T3 cells were treated with 1.5 g/ml DC, while MIN6 cells were treated with 56 ng/ml DC.…”

Section: Methodsmentioning

confidence: 99%

Isolation of Mitochondrial DNA-less Mouse Cell Lines and Their Application for Trapping Mouse Synaptosomal Mitochondrial DNA with Deletion Mutations

Inoue

Ito

Takai

et al. 1997

Journal of Biological Chemistry

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For isolation of mouse mtDNA-less ( 0 ) cell lines, we searched for various antimitochondrial drugs that were expected to decrease the mtDNA content and found that treatment with ditercalinium, an antitumor bis-intercalating agent, was extremely effective for completely excluding mtDNA in all the mouse cell lines we tested. The resulting 0 mouse cells were successfully used for trapping the mtDNA of living nerve cells into dividing cultured cells by fusion of the 0 cells with mouse brain synaptosomes, which represent synaptic endings isolated from nerve cells. With neuronal mtDNA obtained, all of the cybrid clones restored mitochondrial translation activity similarly regardless of whether the mtDNA was derived from young or aged mice, thus at least suggesting that defects in mitochondrial genomes are not involved in the age-associated mitochondrial dysfunction observed in the brain of aged mice. Furthermore, we could trap a very small amount of a common 5823-base pair deletion mutant mtDNA (⌬mtDNA 5823 ) that was detectable by polymerase chain reaction in the cybrid clones. As the amount of mutant mtDNA with large scale deletions was expected to increase during prolonged cultivation of the cybrids, these cells should be available for establishment of mice containing the deletion mutant mtDNA.

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Mitochondrial DNA Is Required for Regulation of Glucose-stimulated Insulin Secretion in a Mouse Pancreatic Beta Cell Line, MIN6

Cited by 145 publications

References 43 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 proteome analysis reveals altered expression of voltage dependent anion channels in pancreatic β-cells exposed to high glucose

Isolation of Mitochondrial DNA-less Mouse Cell Lines and Their Application for Trapping Mouse Synaptosomal Mitochondrial DNA with Deletion Mutations

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