Nuclear Factor-κB Activity in β-Cells Is Required for Glucose-Stimulated Insulin Secretion

Norlin, Stefan; Ahlgren, Ulf; Edlund, Helena

doi:10.2337/diabetes.54.1.125

Cited by 105 publications

(87 citation statements)

References 51 publications

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“…However, recent data obtained in rat beta cells demonstrate that a transient and moderate increase in NF-κB (nuclear factor-κB) activity improves beta cell function and insulin secretion [36]. Furthermore, attenuation of NF-κB activation in transgenic mice impairs GSIS and decreases the expression of genes involved in glucose metabolism and insulin exocytosis [37]. Taken together, these data indicate that moderate activity of NF-κB could be beneficial to the beta cell.…”

Section: Discussionmentioning

confidence: 92%

Increasing uncoupling protein-2 in pancreatic beta cells does not alter glucose-induced insulin secretion but decreases production of reactive oxygen species

Produit-Zengaffinen¹,

Davis-Lameloise²,

Perreten³

et al. 2006

Diabetologia

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Aims/hypothesis Levels of uncoupling protein-2 (UCP2) are regulated in the pancreatic beta cells and an increase in the protein level has been associated with mitochondrial uncoupling and alteration in glucose-stimulated insulin secretion. However, it is not clear whether an increase in uncoupling protein-2 per se induces mitochondrial uncoupling and affects ATP generation and insulin secretion. Materials and methods Transgenic mice with beta cell-specific overexpression of the human UCP2 gene and INS-1 cells with doxycycline-inducible overproduction of the protein were generated and the consequences of increased levels of UCP2 on glucose-induced insulin secretion and on parameters reflecting mitochondrial uncoupling were determined.Results In transgenic mice, an increase in beta cell UCP2 protein concentration did not significantly modify plasma glucose and insulin levels. Glucose-induced insulin secretion and elevation in the ATP/ADP ratio were unaltered by an increase in UCP2 level. In INS-1 cells, a similar increase in UCP2 level did not modify glucose-induced insulin secretion, cytosolic ATP and ATP/ADP ratio, or glucose oxidation. Increased levels of UCP2 did not modify the mitochondrial membrane potential and oxygen consumption. Increased UCP2 levels decreased cytokine-induced production of reactive oxygen species. Conclusion/interpretation The results obtained in transgenic mice and in the beta cell line do not support the hypothesis that an increase in UCP2 protein per se uncouples the mitochondria and decreases glucose-induced insulin secretion. In contrast, the observation that increased UCP2 levels decrease cytokine-induced production of reactive oxygen species indicates a potential protective effect of the protein on beta cells, as observed in other cell types.

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Section: Discussionmentioning

confidence: 92%

Increasing uncoupling protein-2 in pancreatic beta cells does not alter glucose-induced insulin secretion but decreases production of reactive oxygen species

Produit-Zengaffinen¹,

Davis-Lameloise²,

Perreten³

et al. 2006

Diabetologia

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“…This activation step has been demonstrated to occur in MIN6 cells in response to Ca 2+ influx (Bernal-Mizrachi et al, 2001). Attenuation of NF-kB activation in β cells by overexpression of IκBα under control of the PDX-1 promoter leads to glucose intolerance and a downregulation of GLUT2, uncoupling protein 2 and the vesicle protein Rab3c (Norlin et al, 2005). Therefore it seems that NF-κB plays a positive role in insulin secretion; however whether it mediates or prevents cytokineinduced β cell death is subject to debate and further investigation (Baker et al, 2001;Chang et al, 2003;Heimberg et al, 2001;Park et al, 2003).…”

Section: β Cell Toxicity and Death: Protective Effects Of Glp-1r Agonmentioning

confidence: 99%

Mechanisms of action of glucagon-like peptide 1 in the pancreas

Doyle

Egan

2007

Pharmacology & Therapeutics

561

465

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Glucagon-like peptide-1 is a hormone that is encoded in the proglucagon gene. It is mainly produced in enteroendocrine L cells of the gut and is secreted into the blood stream when food containing fat, protein hydrolysate and/or glucose enters the duodenum. Its particular effects on insulin and glucagon secretion have generated a flurry of research activity over the past twenty years culminating in a naturally occurring GLP-1 receptor agonist, exendin-4, now being used to treat type 2 diabetes. GLP-1 engages a specific G-protein coupled receptor that is present in tissues other than the pancreas (brain, kidney, lung, heart, major blood vessels). The most widely studied cell activated by GLP-1 is the insulin-secreting beta cell where its defining action is augmentation of glucose-induced insulin secretion. Upon GLP-1 receptor activation, adenylyl cyclase is activated and cAMP generated, leading, in turn, to cAMP-dependent activation of second messenger pathways, such as the PKA and Epac pathways. As well as short-term effects of enhancing glucose-induced insulin secretion, continuous GLP-1 receptor activation also increases insulin synthesis, and beta cell proliferation and neogenesis. Although these latter effects cannot be currently monitored in humans, there are substantial improvements in glucose tolerance and increases in both first phase and plateau phase insulin secretory responses in type 2 diabetic patients treated with exendin-4. This review we will focus on the effects resulting from GLP-1 receptor activation in islets of Langerhans

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“…Although follicular B-cell numbers are normal, this population turns over more rapidly 'in vivo' (Grumont et al, 1998), a phenotype linked to an accelerated rate of quiescent B-cell apoptosis (Grumont et al, 1998). Although the tumor necrosis factor-receptor (TNF-R) superfamily ligand BAFF has been shown to promote the survival of follicular B cells by inducing p52 expression (Claudio Pancreatic islets Impaired glucose tolerance and mild diabetes Norlin et al (2005) Abbreviations: Con A, concanavalin A; NK cells, natural killer cells; TNF-a, tumor necrosis factor-a.…”

Section: Nf-kb P50/p105mentioning

confidence: 99%

“…Transgenic expression of degradation-resistant IkBa and IkBb isoforms Degradation-resistant IkBa and IkBb mutants (IkBm) that function as dominant inhibitors of NF-kB activation when expressed under the control of tissue-specific or developmentally restricted promoters have been used to probe NF-kB function in a range of cell types in mice, including B (Bendall et al, 1999) and T lymphocytes (Boothby et al, 1997;Esslinger et al, 1997;Attar et al, 1998;Ferreira et al, 1999;Hettmann et al, 1999;Voll et al, 2000;Hettmann and Leiden, 2000), muscle (Cai et al, 2004), neurons (Fridmacher et al, 2003), hepatocytes (Lavon et al, 2000;Cai et al, 2005), heart (Dawn et al, 2001), pancreas (Norlin et al, 2005) and skin (Seitz et al, 1998;van Hogerlinden et al, 1999). Although this approach has been highly successful, IkBm expression targeted to a particular tissue has been documented to generate distinct phenotypes, or a phenotype of varying severity in different transgenic founder lines.…”

Section: Ijb Proteinsmentioning

confidence: 99%

Unravelling the complexities of the NF-κB signalling pathway using mouse knockout and transgenic models

et al. 2006

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The nuclear factor-jB (NF-jB) signalling pathway serves a crucial role in regulating the transcriptional responses of physiological processes that include cell division, cell survival, differentiation, immunity and inflammation. Here we outline studies using mouse models in which the core components of the NF-jB pathway, namely the IjB kinase subunits (IKKa, IKKb and NEMO), the IjB proteins (IjBa, IjBb, IjBe and Bcl-3) and the five NF-jB transcription factors (NF-jB1, NF-jB2, c-Rel, RelA and RelB), have been genetically manipulated using transgenic and knockout technology.

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Nuclear Factor-κB Activity in β-Cells Is Required for Glucose-Stimulated Insulin Secretion

Cited by 105 publications

References 51 publications

Increasing uncoupling protein-2 in pancreatic beta cells does not alter glucose-induced insulin secretion but decreases production of reactive oxygen species

Increasing uncoupling protein-2 in pancreatic beta cells does not alter glucose-induced insulin secretion but decreases production of reactive oxygen species

Mechanisms of action of glucagon-like peptide 1 in the pancreas

Unravelling the complexities of the NF-κB signalling pathway using mouse knockout and transgenic models

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