Glucose stimulates proinsulin biosynthesis by a dose-dependent recruitment of pancreatic beta cells.

Schuit, Frans; Veld, Pieter In 'T; Pipeleers, Daniël

doi:10.1073/pnas.85.11.3865

Cited by 294 publications

(261 citation statements)

References 37 publications

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“…Under stimulatory conditions, production of insulin may represent up to 50% of total protein production, placing an enormous burden on the ER [50]. As a consequence, beta cells are in a constant state of mild ER-stress, characterised by high basal expression of UPR transducers such as IRE1α, allowing them to adapt efficiently to the ever changing insulin demand [3].…”

Section: Discussionmentioning

confidence: 99%

Sustained production of spliced X-box binding protein 1 (XBP1) induces pancreatic beta cell dysfunction and apoptosis

et al. 2010

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Aims/hypothesis Pro-inflammatory cytokines involved in the pathogenesis of type 1 diabetes deplete endoplasmic reticulum (ER) Ca 2+ stores, leading to ER-stress and beta cell apoptosis. However, the cytokine-induced ER-stress response in beta cells is atypical and characterised by induction of the pro-apoptotic PKR-like ER kinase (PERK)-C/EBP homologous protein (CHOP) branch of the unfolded protein response, but defective X-box binding protein 1 (XBP1) splicing and activating transcription factor 6 activation. The purpose of this study was to overexpress spliced/active Xbp1 (XBP1s) to increase beta cell resistance to cytokine-induced ER-stress and apoptosis.Methods Xbp1s was overexpressed using adenoviruses and knocked down using small interference RNA in rat islet cells. In selected experiments, Xbp1 was also knocked down in FACS-purified rat beta cells and rat fibroblasts. Expression and production of XBP1s and key downstream genes and proteins was measured and beta cell function and viability were evaluated.

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Section: Discussionmentioning

confidence: 99%

Sustained production of spliced X-box binding protein 1 (XBP1) induces pancreatic beta cell dysfunction and apoptosis

et al. 2010

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“…Half-maximal synthesis occurred at 5.4 mM glucose and the V max was 42.971.4 Â 10 3 cpm/mg DNA (n¼6), not significantly different from that for human islets. 21,22 The ratio of (pro)insulin synthesis to total protein synthesis was 0.065 at 2.5 mM glucose, 0.196 at 10 mM glucose and 0.213 at 20 mM glucose. …”

Section: (Pro)insulin Synthesismentioning

confidence: 97%

“…6 In contrast to the dose-response curve for insulin secretion, that for insulin synthesis was exactly the same as that which occurs in pancreatic b cells. 21,22 This implies that different metabolites of glucose are responsible for the secretion of insulin and translation of the insulin message from the nucleus. …”

Section: Insulin-producing Liver Cells Be Tuch Et Almentioning

confidence: 99%

Function of a genetically modified human liver cell line that stores, processes and secretes insulin

Tuch

Szymańska

et al. 2003

Gene Ther

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An alternative approach to the treatment of type I diabetes is the use of genetically altered neoplastic liver cells to synthesize, store and secrete insulin. To try and achieve this goal we modified a human liver cell line, HUH7, by transfecting it with human insulin cDNA under the control of the cytomegalovirus promoter. The HUH7-ins cells created were able to synthesize insulin in a similar manner to that which occurs in pancreatic b cells. They secreted insulin in a regulated manner in response to glucose, calcium and theophylline, the dose-response curve for glucose being near-physiological. Perifusion studies showed that secretion was rapid and tightly controlled. Removal of calcium resulted in loss of glucose stimulation while addition of brefeldin A resulted in a 30% diminution of effect, indicating that constitutive release of insulin occurred to a small extent. Insulin was stored in granules within the cytoplasm. When transplanted into diabetic immunoincompetent mice, the cells synthesized, processed, stored and secreted diarginyl insulin in a rapid regulated manner in response to glucose.Constitutive release of insulin also occurred and was greater than regulated secretion. Blood glucose levels of the mice were normalized but ultimately became subnormal due to continued proliferation of cells. Examination of the HUH7-ins cells as well as the parent cell line for b cell transcription factors showed the presence of NeuroD but not PDX-1. PC1 and PC2 were also present in both cell types. Thus, the parent HUH7 cell line possessed a number of endocrine pancreatic features that reflect the common endodermal ancestry of liver and pancreas, perhaps as a result of ontogenetic regression of the neoplastic liver cell from which the line was derived. Introduction of the insulin gene under the control of the CMV promoter induced changes in these cells to make them function to some extent like pancreatic b cells. Our results support the view that neoplastic liver cells can be induced to become substitute pancreatic b cells and become a therapy for the treatment of type I diabetes.

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“…For instance, beta cells respond unequally to glucose stimulation in terms of insulin secretion and biosynthetic activity [12,14,15]. It has been suggested that intercellular contacts coordinate the functioning of beta cells by homogenising and synchronising their activities.…”

Section: Introductionmentioning

confidence: 99%

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

Wojtusciszyn

Armanet²,

Morel³

et al. 2008

Diabetologia

133

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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Glucose stimulates proinsulin biosynthesis by a dose-dependent recruitment of pancreatic beta cells.

Cited by 294 publications

References 37 publications

Sustained production of spliced X-box binding protein 1 (XBP1) induces pancreatic beta cell dysfunction and apoptosis

Sustained production of spliced X-box binding protein 1 (XBP1) induces pancreatic beta cell dysfunction and apoptosis

Function of a genetically modified human liver cell line that stores, processes and secretes insulin

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

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