Molecular Control of Cell Cycle Progression in the Pancreatic β-Cell

Cózar‐Castellano, Irene; Fiaschi-Taesch, Nathalie; Bigatel, Todd; Takane, Karen K.; Garcı́a-Ocaña, Adolfo; Vasavada, Rupangi C.; Stewart, Andrew F.

doi:10.1210/er.2006-0004

Cited by 192 publications

(203 citation statements)

References 72 publications

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“…Together, this evidence supports the notion that Sfrp5 can regulate the canonical Wnt pathway in beta cells. Correlating with these data, islets from CAF-fed rats exhibit upregulation of several genes involved in the Wnt pathway, as well as of well-known Wnt targets implicated in cell cycle progression such as cyclin D1 and Myc [32].…”

Section: Discussionsupporting

confidence: 53%

Downregulation of Sfrp5 promotes beta cell proliferation during obesity in the rat

et al. 2013

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Aims/hypothesis During obesity, the increment in beta cell mass in response to the rising demand for insulin is essential to maintain normal glucose homeostasis. However, the precise cellular and molecular mechanisms involved in beta cell mass plasticity remain poorly understood. The Wnt signalling pathway has been suggested as one possible modulator of beta cell proliferation, which represents the principal process involved in beta cell mass expansion. Here, we sought to determine the mechanisms involved in beta cell mass proliferation using diet-induced obese rats. Methods Wistar rats aged 8 weeks old were fed a standard or cafeteria diet. Global transcriptomic analysis of pancreatic rat islets was performed using microarray analysis. Genetic lossof-function approaches were performed in dispersed primary rat islets and the beta cell line INS1E. Gene expression was measured by real-time PCR, protein levels by immunoblot analysis, proliferation rates by ELISA and apoptosis by flow cytometry. Results Sfrp5, coding for secreted frizzled-related protein 5, is downregulated in the pancreatic islets of cafeteria-diet-fed rats as well as in the pancreatic islets of human obese patients. We demonstrate that silencing Sfrp5 increases beta cell proliferation, which correlates with activation of Wnt signalling and enhanced levels of proliferation markers. In addition, we show that expression of Sfrp5 in beta cells is modulated by IGF binding protein 3 (IGFBP3) secreted from visceral adipose tissue. Conclusions/interpretation Together, these findings reveal an important role for SFRP5 and Wnt signalling in the regulation of beta cell proliferation in obesity.

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Section: Discussionsupporting

confidence: 53%

Downregulation of Sfrp5 promotes beta cell proliferation during obesity in the rat

et al. 2013

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“…A recent review has discussed many of the important cell cycle proteins in the G 1 /S phase transition, the checkpoint in cell cycle progression critical for postnatal β cell growth hence maintenance of β cell mass (Cozar-Castellano et al, 2006). Two of the three Cyclin D proteins, namely Cyclin D1 and D2, are expressed in β cells and the absence of Cyclin D2 results eventually in overt diabetes in Cyclin D2−/− mice (Georgia and Bhushan, 2004;Kushner et al, 2005).…”

Section: β Cell Proliferationmentioning

confidence: 99%

“…Two of the three Cyclin D proteins, namely Cyclin D1 and D2, are expressed in β cells and the absence of Cyclin D2 results eventually in overt diabetes in Cyclin D2−/− mice (Georgia and Bhushan, 2004;Kushner et al, 2005). The cyclins coordinate with the cyclin-dependent kinases (cdks) to phosphorylate pRB, a member of the retinoblastoma family of proteins, thus releasing them from the E2F transcription factors (Cozar-Castellano et al, 2006). Members of E2F family of transcription factors are the effectors that control the G1/S transition and in particular transgenic mice lacking E2F1 display defective insulin secretion in response to a glucose challenge due to inadequate β cell mass and a disregulation in PDX-1 (Fajas et al, 2004).…”

Section: β Cell Proliferationmentioning

confidence: 99%

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

Doyle

Egan

2007

Pharmacology & Therapeutics

574

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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“…Among the pathways implicated, many transduce signals through the Raf-1/MEK/ERK cascade, including insulin, insulin-growth factor, hepatic growth factor, epidermal growth factor and PDGF [34][35][36], and thus could potentially be targeted by RKIP1. Yet, our data indicate that constitutive ERK1/2 activation may not be linked to enhanced beta cell proliferation in Rkip1 mutants.…”

Section: Discussionmentioning

confidence: 99%

The role of Raf-1 kinase inhibitor protein in the regulation of pancreatic beta cell proliferation in mice

et al. 2012

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Aims/hypothesis Manoeuvres aimed at increasing beta cell mass have been proposed as regenerative medicine strategies for diabetes treatment. Raf-1 kinase inhibitor protein 1 (RKIP1) is a common regulatory node of the mitogen-activated protein kinase (MAPK) and nuclear factor κB (NF-κB) pathways and therefore may be involved in regulation of beta cell homeostasis. The aim of this study was to investigate the involvement of RKIP1 in the control of beta cell mass and function. Methods Rkip1 (also known as Pebp1) knockout (Rkip1 −/− ) mice were characterised in terms of pancreatic and glucose homeostasis, including morphological and functional analysis. Glucose tolerance and insulin sensitivity were examined, followed by assessment of glucose-induced insulin secretion in isolated islets and beta cell mass quantification through morphometry. Further characterisation included determination of endocrine and exocrine proliferation, apoptosis, MAPK activation and whole genome gene expression assays. Capacity to reverse a diabetic phenotype was assessed in adult Rkip1 −/− mice after streptozotocin treatment. Results Rkip1 −/− mice exhibit a moderately larger pancreas and increased beta cell mass and pancreatic insulin content, which correlate with an overall improvement in whole body glucose tolerance. This phenotype is established in young postnatal stages and involves enhanced cellular proliferation without significant alterations in cell death. Importantly, adult Rkip1 −/− mice exhibit rapid reversal of streptozotocin-induced diabetes compared with control mice.Electronic supplementary material The online version of this article (doi:10.1007/s00125-012-2696-9) contains peer-reviewed but unedited supplementary material, which is available to authorised users. Conclusions/interpretation These data implicate RKIP1 in the regulation of pancreatic growth and beta cell expansion, thus revealing RKIP1 as a potential pharmacological target to promote beta cell regeneration.

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Molecular Control of Cell Cycle Progression in the Pancreatic β-Cell

Cited by 192 publications

References 72 publications

Downregulation of Sfrp5 promotes beta cell proliferation during obesity in the rat

Downregulation of Sfrp5 promotes beta cell proliferation during obesity in the rat

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

The role of Raf-1 kinase inhibitor protein in the regulation of pancreatic beta cell proliferation in mice

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