Beta cell proliferation and growth factors

Nielsen, Jens Høiriis; Svensson, Christoffer; Galsgaard, Elisabeth D.; Møldrup, Annette; Billestrup, Nils

doi:10.1007/s001090050302

Cited by 122 publications

(17 citation statements)

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“…It is noteworthy, however, that treatment with prolactin, which is also known to stimulate β cell proliferation, did not significantly enhance proliferation in Ffar2 −/− β cells (Fig. 3a)1638. This observation is especially important in light of our recent findings that adaptive β cell mass expansion during pregnancy is compromised in Ffar2 −/− female mice32, as this adaptive expansion is regulated in large part by prolactin receptor (PRLR) signaling39.…”

Section: Resultsmentioning

confidence: 87%

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Loss of Free Fatty Acid Receptor 2 leads to impaired islet mass and beta cell survival

Villa

Priyadarshini

Fuller

et al. 2016

Sci Rep

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The regulation of pancreatic β cell mass is a critical factor to help maintain normoglycemia during insulin resistance. Nutrient-sensing G protein-coupled receptors (GPCR) contribute to aspects of β cell function, including regulation of β cell mass. Nutrients such as free fatty acids (FFAs) contribute to precise regulation of β cell mass by signaling through cognate GPCRs, and considerable evidence suggests that circulating FFAs promote β cell expansion by direct and indirect mechanisms. Free Fatty Acid Receptor 2 (FFA2) is a β cell-expressed GPCR that is activated by short chain fatty acids, particularly acetate. Recent studies of FFA2 suggest that it may act as a regulator of β cell function. Here, we set out to explore what role FFA2 may play in regulation of β cell mass. Interestingly, Ffar2−/− mice exhibit diminished β cell mass at birth and throughout adulthood, and increased β cell death at adolescent time points, suggesting a role for FFA2 in establishment and maintenance of β cell mass. Additionally, activation of FFA2 with Gαq/11-biased agonists substantially increased β cell proliferation in in vitro and ex vivo proliferation assays. Collectively, these data suggest that FFA2 may be a novel therapeutic target to stimulate β cell growth and proliferation.

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Section: Resultsmentioning

confidence: 87%

“…Subsequent experiments were carried out with acetate, 2-BA, and CPCA at the indicated concentrations, as determined by dose response curve. Placental lactogen (PL) at 0.5 ug/ml served as a positive control for β cell proliferation38. β cell proliferation was visualized by insulin and Ki67 immunolabeling in mildly dissociated islets.…”

Section: Methodsmentioning

confidence: 99%

Loss of Free Fatty Acid Receptor 2 leads to impaired islet mass and beta cell survival

Villa

Priyadarshini

Fuller

et al. 2016

Sci Rep

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“…Among the more striking examples are Prlr , Ghr and Cntfr , three related receptors that respond to structurally similar ligands [42], that are abundantly and selectively expressed by mouse beta cells, with only nominal expression in human islets. Co-stimulation of CNTF and EGF promotes acinar to beta cell transdifferentiation in diabetic mice [50] and GH and PRL are potent inducers of mouse beta cell proliferation [51] and implicated in the expansion of maternal beta cell mass during pregnancy in mice [43, 44]. However, efforts to use PRL or GH to induce human beta cell proliferation in vitro have been largely unsuccessful [52, 53] and expansion of human beta cell mass during pregnancy is modest compared to mouse and driven by neogenesis instead of beta cell proliferation [54].…”

Section: Discussionmentioning

confidence: 99%

The transcriptional landscape of mouse beta cells compared to human beta cells reveals notable species differences in long non-coding RNA and protein-coding gene expression

et al. 2014

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BackgroundInsulin producing beta cell and glucagon producing alpha cells are colocalized in pancreatic islets in an arrangement that facilitates the coordinated release of the two principal hormones that regulate glucose homeostasis and prevent both hypoglycemia and diabetes. However, this intricate organization has also complicated the determination of the cellular source(s) of the expression of genes that are detected in the islet. This reflects a significant gap in our understanding of mouse islet physiology, which reduces the effectiveness by which mice model human islet disease.ResultsTo overcome this challenge, we generated a bitransgenic reporter mouse that faithfully labels all beta and alpha cells in mouse islets to enable FACS-based purification and the generation of comprehensive transcriptomes of both populations. This facilitates systematic comparison across thousands of genes between the two major endocrine cell types of the islets of Langerhans whose principal hormones are of cardinal importance for glucose homeostasis. Our data leveraged against similar data for human beta cells reveal a core common beta cell transcriptome of 9900+ genes. Against the backdrop of overall similar beta cell transcriptomes, we describe marked differences in the repertoire of receptors and long non-coding RNAs between mouse and human beta cells.ConclusionsThe comprehensive mouse alpha and beta cell transcriptomes complemented by the comparison of the global (dis)similarities between mouse and human beta cells represent invaluable resources to boost the accuracy by which rodent models offer guidance in finding cures for human diabetes.Electronic supplementary materialThe online version of this article (doi:10.1186/1471-2164-15-620) contains supplementary material, which is available to authorized users.

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“…The hormones GLP-1, CCKA, PRL, and GH are involved in mitotic and functional activation of rodent β-cells (33,34). Due to these characteristics, GLP-1 analogs are being presently tested as an adjuvant therapy in early type 1 diabetes (35).…”

Section: Discussionmentioning

confidence: 99%

Cytokines Interleukin-1β and Tumor Necrosis Factor-α Regulate Different Transcriptional and Alternative Splicing Networks in Primary β-Cells

et al. 2009

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OBJECTIVECytokines contribute to pancreatic β-cell death in type 1 diabetes. This effect is mediated by complex gene networks that remain to be characterized. We presently utilized array analysis to define the global expression pattern of genes, including spliced variants, modified by the cytokines interleukin (IL)-1β + interferon (IFN)-γ and tumor necrosis factor (TNF)-α + IFN-γ in primary rat β-cells.RESEARCH DESIGN AND METHODSFluorescence-activated cell sorter–purified rat β-cells were exposed to IL-1β + IFN-γ or TNF-α + IFN-γ for 6 or 24 h, and global gene expression was analyzed by microarray. Key results were confirmed by RT-PCR, and small-interfering RNAs were used to investigate the mechanistic role of novel and relevant transcription factors identified by pathway analysis.RESULTSNearly 16,000 transcripts were detected as present in β-cells, with temporal differences in the number of genes modulated by IL-1β + IFNγ or TNF-α + IFN-γ. These cytokine combinations induced differential expression of inflammatory response genes, which is related to differential induction of IFN regulatory factor-7. Both treatments decreased the expression of genes involved in the maintenance of β-cell phenotype and growth/regeneration. Cytokines induced hypoxia-inducible factor-α, which in this context has a proapoptotic role. Cytokines also modified the expression of >20 genes involved in RNA splicing, and exon array analysis showed cytokine-induced changes in alternative splicing of >50% of the cytokine-modified genes.CONCLUSIONSThe present study doubles the number of known genes expressed in primary β-cells, modified or not by cytokines, and indicates the biological role for several novel cytokine-modified pathways in β-cells. It also shows that cytokines modify alternative splicing in β-cells, opening a new avenue of research for the field.

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Beta cell proliferation and growth factors

Cited by 122 publications

References 0 publications

Loss of Free Fatty Acid Receptor 2 leads to impaired islet mass and beta cell survival

Loss of Free Fatty Acid Receptor 2 leads to impaired islet mass and beta cell survival

The transcriptional landscape of mouse beta cells compared to human beta cells reveals notable species differences in long non-coding RNA and protein-coding gene expression

Cytokines Interleukin-1β and Tumor Necrosis Factor-α Regulate Different Transcriptional and Alternative Splicing Networks in Primary β-Cells

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