Physiologic relevance of heterogeneity in the pancreatic beta-cell population

Pipeleers, Daniël; Kiekens, R; Ling, Zhidong; Wilikens, Ann; Schuit, Frans

doi:10.1007/bf00400827

Cited by 149 publications

(152 citation statements)

References 49 publications

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“…Beta cell heterogeneity in terms of insulin secretion has been described in rodents [10,21,26] and is described here for the first time in humans. In rodents, beta cell heterogeneity was also observed in terms of metabolic, signalling [27,28] and biosynthetic activities [12,29].…”

Section: Discussionmentioning

confidence: 80%

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Insulin secretion from human beta cells is heterogeneous and dependent on cell-to-cell contacts

Wojtusciszyn

Armanet²,

Morel³

et al. 2008

Diabetologia

127

102

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Aims/hypothesis We assessed the heterogeneity of insulin secretion from human isolated beta cells and its regulation by cell-to-cell contacts. Methods Insulin secretion from single and paired cells was assessed by a reverse haemolytic plaque assay. The percentage of plaque-forming cells, the mean plaque area and the total plaque development were evaluated after 1 h of stimulation with different secretagogues. Results Not all beta cells were surrounded by a haemolytic plaque under all conditions tested. A small fraction of the beta cell population (20%) secreted more than 90% and 70% of total insulin at 2.2 and 22.2 mmol/l glucose, respectively. Plaque-forming cells, mean plaque area and total plaque development were increased at 12.2 and 22.2 compared with 2.2 mmol/l glucose. Insulin secretion of single beta cells was similar at 12.2 and 22.2 mmol/l glucose. Insulin secretion of beta cell pairs was increased compared with that of single beta cells and was higher at 22.2 than at 12.2 mmol/l glucose. Insulin secretion of beta cells in contact with alpha cells was also increased compared with single beta cells, but was similar at 22.2 compared with 12.2 mmol/l glucose. Delta and other non-beta cells did not increase insulin secretion of contacting beta cells compared with that of single beta cells. Differences in insulin secretion between 22.2 and 12.2 mmol/l glucose were observed in murine but not in human islets. Conclusions/interpretation Human beta cells are highly heterogeneous in terms of insulin secretion so that a small fraction of beta cells contributes to the majority of insulin secreted. Homologous and heterologous intercellular contacts have a significant impact on insulin secretion and this could be related to the particular architecture of human islets.

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Section: Discussionmentioning

confidence: 80%

“…The importance of homologous contacts between beta cells is further supported by the observation in rodents that the functioning of isolated beta cells is heterogeneous [9][10][11][12][13]. For instance, beta cells respond unequally to glucose stimulation in terms of insulin secretion and biosynthetic activity [12,14,15].…”

Section: Introductionmentioning

confidence: 95%

Insulin secretion from human beta cells is heterogeneous and dependent on cell-to-cell contacts

Wojtusciszyn

Armanet²,

Morel³

et al. 2008

Diabetologia

127

102

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“…Grodsky (1972) mentioned briefly that the insulin 'packages' did not necessarily represent the granules but could also represent the cells (see also Pipeleers et al 1994). This idea is in line with the model presented here, and supported by calcium data (Hellman et al 1994;Jonkers & Henquin 2001;Heart et al 2006) not available at the time of Grodsky's paper.…”

Section: Discussionmentioning

confidence: 99%

A subcellular model of glucose-stimulated pancreatic insulin secretion

Pedersen

Corradin

Toffolo

et al. 2008

Phil. Trans. R. Soc. A.

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When glucose is raised from a basal to stimulating level, the pancreatic islets respond with a typical biphasic insulin secretion pattern. Moreover, the pancreas is able to recognize the rate of change of the glucose concentration. We present a relatively simple model of insulin secretion from pancreatic b-cells, yet founded on solid physiological grounds and capable of reproducing a series of secretion patterns from perfused pancreases as well as from stimulated islets. The model includes the notion of distinct pools of granules as well as mechanisms such as mobilization, priming, exocytosis and kiss-and-run. Based on experimental data, we suggest that the individual b-cells activate at different glucose concentrations. The model reproduces most of the data it was tested against very well, and can therefore serve as a general model of glucose-stimulated insulin secretion. Simulations predict that the effect of an increased frequency of kissand-run exocytotic events is a reduction in insulin secretion without modification of the qualitative pattern. Our model also appears to be the first physiology-based one to reproduce the staircase experiment, which underlies 'derivative control', i.e. the pancreatic capacity of measuring the rate of change of the glucose concentration.

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“…functionally relevant, in particular for generating its doseresponse curves to glucose [1]. The intercellular differences in glucose sensitivity can be altered by culture at low or high glucose concentrations with subsequent changes in functional responsiveness [2].…”

mentioning

confidence: 99%

Glibenclamide activates translation in rat pancreatic beta cells through calcium-dependent mTOR, PKA and MEK signalling pathways

et al. 2008

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Aims/hypothesis Prolonged exposure of rat beta cells to the insulin secretagogue glibenclamide has been found to induce a sustained increase in basal insulin synthesis. This effect was calcium-dependent and localised in cells that had been degranulated by the drug. Since it was blocked by the translation inhibitor cycloheximide, we examined whether sustained exposure to glibenclamide activates translational factors by calcium-dependent signalling pathways. Methods Purified rat beta cells were cultured with and without glibenclamide in the presence or absence of inhibitors of calcium-dependent signalling pathways before measurement of basal and stimulated protein and insulin synthesis, and assessment of abundance of (phosphorylated) translation factors.Results A 24 h exposure to glibenclamide induced activation of four translation factors, i.e. phosphorylation of eukaryotic initiation factor (eIF) 4e binding protein 1 and ribosomal protein S6 (rpS6), and dephosphorylation of eIF-2α and eukaryotic elongation factor 2. The rise in phospho-rpS6 intensity was localised to a subpopulation of beta cells with low insulin content. This activation of translational factors and the associated elevation of insulin synthesis were completely blocked by the calcium channel blocker verapamil and partially blocked by the mammalian target of rapamycin (mTOR) inhibitor rapamycin, the protein kinase A (PKA) inhibitor Rp-8-Br-cAMPs and the mitogen-activated protein kinase/ extracellular signal-regulated kinase kinase (MEK) inhibitor U0126; a combination of inhibitors exhibited additive effects. Conclusions/interpretation Prolonged exposure to glibenclamide activates protein translation in pancreatic beta cells through the calcium-regulated mTOR, PKA and MEK signalling pathways. The observed intercellular differences in translation activation are proposed as underlying mechanism for functional heterogeneity in the pancreatic beta cell population.

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Physiologic relevance of heterogeneity in the pancreatic beta-cell population

Cited by 149 publications

References 49 publications

Insulin secretion from human beta cells is heterogeneous and dependent on cell-to-cell contacts

Insulin secretion from human beta cells is heterogeneous and dependent on cell-to-cell contacts

A subcellular model of glucose-stimulated pancreatic insulin secretion

Glibenclamide activates translation in rat pancreatic beta cells through calcium-dependent mTOR, PKA and MEK signalling pathways

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