2098-P: Transcriptomic Changes Associated with Oleate-Induced ß-Cell Proliferation in Rat Islets

Interleukin-1β (IL1B) is an important contributor to the autoimmune destruction of β-cells in type 1 diabetes, and it has been recently related to the development of type 2 diabetes. IGF2 stimulates β-cell proliferation and survival. We have determined the effect of IL1B on β-cell replication, and the potential modulation by IGF2 and glucose. Control-uninfected and adenovirus encoding for IGF2 (Ad-IGF2)-infected rat islets were cultured at 5.5 or 22.2 mmol/l glucose with or without 1, 10, 30, and 50 U/ml of IL1B. β-Cell replication was markedly reduced by 10 U/ml of IL1B and was almost nullified with 30 or 50 U/ml of IL1B. Higher concentrations of IL1B were required to increase β-cell apoptosis. Although IGF2 overexpression had a strong mitogenic effect on β-cells, IGF2 could preserve β-cell proliferation only in islets cultured with 10 U/ml IL1B, and had no effect with 30 and 50 U/ml of IL1B. In contrast, IGF2 overexpression induced a clear protection against IL1B-induced apoptosis, and higher concentrations of the cytokine were needed to increase β-cell apoptosis in Ad-IGF2-infected islets. These results indicate that β-cell replication is highly sensitive to the deleterious effects of the IL1B as shown by the inhibition of replication by relatively low IL1B concentrations, and the almost complete suppression of β-cell replication with high IL1B concentrations. Likewise, the inhibitory effects of IL-β on β-cell replication were not modified by glucose, and were only modestly prevented by IGF2 overexpression, in contrast with the higher protection against IL1B-induced apoptosis afforded by glucose and by IGF2 overexpression.

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Prolactin and oleic acid synergistically stimulate β-cell proliferation and growth in rat islets

Islets ◽

10.1080/19382014.2017.1330234 ◽

2017 ◽

Vol 9 (4) ◽

pp. e1330234 ◽

Cited By ~ 4

Author(s):

Todd Clark Brelje ◽

Nicholas V. Bhagroo ◽

Laurence E. Stout ◽

Robert L. Sorenson

Keyword(s):

Cell Proliferation ◽

Oleic Acid ◽

Β Cell ◽

Rat Islets

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Beneficial effects of growth hormone-releasing hormone agonists on rat INS-1 cells and on streptozotocin-induced NOD/SCID mice

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1518540112 ◽

2015 ◽

Vol 112 (44) ◽

pp. 13651-13656 ◽

Cited By ~ 15

Author(s):

Xianyang Zhang ◽

Tengjiao Cui ◽

Jinlin He ◽

Haibo Wang ◽

Renzhi Cai ◽

...

Keyword(s):

Growth Hormone ◽

Cell Proliferation ◽

Serum Insulin ◽

Severe Combined Immunodeficiency ◽

Scid Mice ◽

Growth Hormone Releasing Hormone ◽

Releasing Hormone ◽

Rat Islets ◽

Therapeutic Benefits ◽

Glucose Challenge

Agonists of growth hormone-releasing hormone (GHRH) have been previously reported to promote growth, function, and engraftment of islet cells following transplantation. Here we evaluated recently synthesized GHRH agonists on the proliferation and biological functions of rat pancreatic β-cell line (INS-1) and islets. In vitro treatment of INS-1 cells with GHRH agonists increased cell proliferation, the expression of cellular insulin, insulin-like growth factor-1 (IGF1), and GHRH receptor, and also stimulated insulin secretion in response to glucose challenge. Exposure of INS-1 cells to GHRH agonists, MR-356 and MR-409, induced activation of ERK and AKT pathways. Agonist MR-409 also significantly increased the levels of cellular cAMP and the phosphorylation of cAMP response element binding protein (CREB) in INS-1 cells. Treatment of rat islets with agonist, MR-409 significantly increased cell proliferation, islet size, and the expression of insulin. In vivo daily s.c. administration of 10 μg MR-409 for 3 wk dramatically reduced the severity of streptozotocin (STZ)-induced diabetes in nonobese diabetic severe combined immunodeficiency (NOD/SCID) mice. The maximal therapeutic benefits with respect to the efficiency of engraftment, ability to reach normoglycemia, gain in body weight, response to high glucose challenge, and induction of higher levels of serum insulin and IGF1 were observed when diabetic mice were transplanted with rat islets preconditioned with GHRH agonist, MR-409, and received additional treatment with MR-409 posttransplantation. This study provides an improved approach to the therapeutic use of GHRH agonists in the treatment of diabetes mellitus.

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Regulation of islet beta-cell proliferation by prolactin in rat islets

Diabetes ◽

10.2337/diabetes.43.2.263 ◽

1994 ◽

Vol 43 (2) ◽

pp. 263-273 ◽

Cited By ~ 13

Author(s):

T. C. Brelje ◽

J. A. Parsons ◽

R. L. Sorenson

Keyword(s):

Cell Proliferation ◽

Beta Cell ◽

Beta Cell Proliferation ◽

Islet Beta Cell ◽

Rat Islets

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A miR-375/YAP axis regulates neuroendocrine differentiation and tumorigenesis in lung carcinoid cells

Scientific Reports ◽

10.1038/s41598-021-89855-4 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Xiaojing Yang ◽

Jina Nanayakkara ◽

Duncan Claypool ◽

Sadegh Saghafinia ◽

Justin J. M. Wong ◽

...

Keyword(s):

Cell Proliferation ◽

Neural Differentiation ◽

Target Genes ◽

Neuroendocrine Differentiation ◽

Disease Models ◽

Neuroendocrine Neoplasms ◽

Wild Type ◽

Pathways Analysis ◽

Transcriptomic Changes ◽

Lung Carcinoid

AbstractLung carcinoids are variably aggressive and mechanistically understudied neuroendocrine neoplasms (NENs). Here, we identified and elucidated the function of a miR-375/yes-associated protein (YAP) axis in lung carcinoid (H727) cells. miR-375 and YAP are respectively high and low expressed in wild-type H727 cells. Following lentiviral CRISPR/Cas9-mediated miR-375 depletion, we identified distinct transcriptomic changes including dramatic YAP upregulation. We also observed a significant decrease in neuroendocrine differentiation and substantial reductions in cell proliferation, transformation, and tumor growth in cell culture and xenograft mouse disease models. Similarly, YAP overexpression resulted in distinct and partially overlapping transcriptomic changes, phenocopying the effects of miR-375 depletion in the same models as above. Transient YAP knockdown in miR-375-depleted cells reversed the effects of miR-375 on neuroendocrine differentiation and cell proliferation. Pathways analysis and confirmatory real-time PCR studies of shared dysregulated target genes indicate that this axis controls neuroendocrine related functions such as neural differentiation, exocytosis, and secretion. Taken together, we provide compelling evidence that a miR-375/YAP axis is a critical mediator of neuroendocrine differentiation and tumorigenesis in lung carcinoid cells.

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Stimulation of Human and Rat Islet β-Cell Proliferation with Retention of Function by the Homeodomain Transcription Factor Nkx6.1

Molecular and Cellular Biology ◽

10.1128/mcb.01791-07 ◽

2008 ◽

Vol 28 (10) ◽

pp. 3465-3476 ◽

Cited By ~ 64

Author(s):

Jonathan C. Schisler ◽

Patrick T. Fueger ◽

Daniella A. Babu ◽

Hans E. Hohmeier ◽

Jeffery S. Tessem ◽

...

Keyword(s):

Cell Proliferation ◽

Transcription Factor ◽

Thymidine Incorporation ◽

Cyclin E ◽

Cell Mass ◽

Control Level ◽

Brdu Incorporation ◽

Β Cell ◽

Homeodomain Transcription Factor ◽

Rat Islets

ABSTRACT The homeodomain transcription factor Nkx6.1 plays an important role in pancreatic islet β-cell development, but its effects on adult β-cell function, survival, and proliferation are not well understood. In the present study, we demonstrated that treatment of primary rat pancreatic islets with a cytomegalovirus promoter-driven recombinant adenovirus containing the Nkx6.1 cDNA (AdCMV-Nkx6.1) causes dramatic increases in [methyl-3H] thymidine and 5-bromo-2′-deoxyuridine (BrdU) incorporation and in the number of cells per islet relative to islets treated with a control adenovirus (AdCMV-βGAL), whereas suppression of Nkx6.1 expression reduces thymidine incorporation. Immunocytochemical studies reveal that >80% of BrdU-positive cells in AdCMV-Nkx6.1-treated islets are β cells. Microarray, real-time PCR, and immunoblot analyses reveal that overexpression of Nkx6.1 in rat islets causes concerted upregulation of a cadre of cell cycle control genes, including those encoding cyclins A, B, and E, and several regulatory kinases. Cyclin E is upregulated earlier than the other cyclins, and adenovirus-mediated overexpression of cyclin E is shown to be sufficient to activate islet cell proliferation. Moreover, chromatin immunoprecipitation assays demonstrate direct interaction of Nkx6.1 with the cyclin A2 and B1 genes. Overexpression of Nkx6.1 in rat islets caused a clear enhancement of glucose-stimulated insulin secretion (GSIS), whereas overexpression of Nkx6.1 in human islets caused an increase in the level of [3H]thymidine incorporation that was twice the control level, along with complete retention of GSIS. We conclude that Nkx6.1 is among the very rare factors capable of stimulating β-cell replication with retention or enhancement of function, properties that may be exploitable for expansion of β-cell mass in treatment of both major forms of diabetes.

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HB-EGF Signaling is Required for Glucose-Induced Pancreatic β-Cell Proliferation in Rats

10.1101/683003 ◽

2019 ◽

Author(s):

Hasna Maachi ◽

Grace Fergusson ◽

Melanie Ethier ◽

Gabriel N. Brill ◽

Liora S. Katz ◽

...

Keyword(s):

Cell Proliferation ◽

Growth Factor ◽

Proliferative Response ◽

Molecular Mechanisms ◽

Ex Vivo ◽

Cell Mass ◽

Mrna Levels ◽

Dependent Manner ◽

Β Cell ◽

Rat Islets

ABSTRACTThe molecular mechanisms of β-cell compensation to metabolic stress are poorly understood. We previously observed that nutrient-induced β-cell proliferation in rats is dependent on Epidermal Growth Factor Receptor (EGFR) signaling. The aim of this study was to determine the role of the EGFR ligand Heparin-Binding EGF-like Growth Factor (HB-EGF) in the β-cell proliferative response to glucose, a β-cell mitogen and key regulator of β-cell mass in response to increased insulin demand. We show that exposure of isolated rat and human islets to HB-EGF stimulates β-cell proliferation. In rat islets, inhibition of EGFR or HB-EGF blocks the proliferative response not only to HB-EGF but also to glucose. Furthermore, knockdown of HB-EGF in rat islets blocks β-cell proliferation in response to glucose ex vivo and in vivo in transplanted glucose-infused rats. Mechanistically, we demonstrate that HB-EGF mRNA levels are increased in β cells in response to glucose in a Carbohydrate Response Element Binding Protein (ChREBP)-dependent manner. In addition, chromatin-immunoprecipitation studies identified ChREBP binding sites in proximity to the HB-EGF gene. Finally, inhibition of Src family kinases, known to be involved in HB-EGF processing, abrogated glucose-induced β-cell proliferation. Our findings identify a novel glucose/HB-EGF/EGFR axis implicated in β-cell compensation to increased metabolic demand.

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Fibroblasts During Hypertrophic Scar Formation and Resolution

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s0424820100072587 ◽

1973 ◽

Vol 31 ◽

pp. 428-429

Author(s):

C. W. Kischer

Keyword(s):

Electron Microscopy ◽

Scanning Electron Microscopy ◽

Cell Proliferation ◽

Fine Structure ◽

Metabolic Activity ◽

Hypertrophic Scar ◽

Normal Skin ◽

Ground Substance ◽

Hypertrophic Scars ◽

Scanning Electron

The morphology of the fibroblasts changes markedly as the healing period from burn wounds progresses, through development of the hypertrophic scar, to resolution of the scar by a self-limiting process of maturation or therapeutic resolution. In addition, hypertrophic scars contain an increased cell proliferation largely made up of fibroblasts. This tremendous population of fibroblasts seems congruous with the abundance of collagen and ground substance. The fine structure of these cells should reflect some aspects of the metabolic activity necessary for production of the scar, and might presage the stage of maturation.A comparison of the fine structure of the fibroblasts from normal skin, different scar types, and granulation tissue has been made by transmission (TEM) and scanning electron microscopy (SEM).

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