Betacellulin and activin A coordinately convert amylase-secreting pancreatic AR42J cells into insulin-secreting cells.

Mashima, Hirosato; Ohnishi, Hirohide; Wakabayashi, Keiji; Mine, Tetsuya; Miyagawa, Jun Ichiro; Hanafusa, Toshiaki; Seno, Masaharu; Yamada, Hidenori; Kojima, Itaru

doi:10.1172/jci118591

Cited by 279 publications

(228 citation statements)

References 37 publications

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“…It has also been demonstrated that the acinar exocrine cell line AR42J can transdifferentiate in vitro into the beta cell phenotype [31] or into hepatocytes [32]. We recently found that normal acinar cells can transdifferentiate into hepatocytes [15] and in the present study we provide evidence for a transdifferentiation into beta cells.…”

Section: Discussionsupporting

confidence: 80%

In vitro generation of insulin-producing beta cells from adult exocrine pancreatic cells

Baeyens¹,

Breuck²,

Lardon³

et al. 2004

Diabetologia

291

224

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Aims/hypothesis: Transplantation of insulinproducing beta cells from donors can cure diabetes, but they are available in insufficient quantities. In this study, we investigated the possibility of generating insulinproducing cells from adult rat exocrine cells cultured in the presence of growth factors. Methods: Rat exocrine pancreatic cells were isolated and treated in vitro with epidermal growth factor (EGF) and leukaemia inhibitory factor (LIF). Analysis was performed by immunocytochemistry, DNA measurement and radioimmunoassay. Cells were transplanted to alloxan-treated (70 mg/kg) nude mice and glycaemia was monitored for 21 days. Nephrectomy was performed on day 15. Results: In a 3-day culture period, addition of LIF plus EGF to the medium resulted in an 11-fold increase of the beta cell mass. This could not be attributed to the very low mitotic activity of contaminating beta cells. Furthermore, when contaminating beta cells were initially destroyed with alloxan, this effect was even more pronounced. The newly formed cells secreted insulin in response to glucose and were immunoreactive for C-peptide-I, Pdx-1 and GLUT-2, which are characteristics of mature beta cells. Electron microscopy showed that they also contained insulinimmunoreactive secretory granules. Some insulin-positive cells were immunoreactive for amylase and cytokeratin-20, or were binucleated, which are characteristics of exocrine cells. The cells were able to restore normoglycaemia when transplanted to alloxan-diabetic mice, and hyperglycaemia recurred upon removal of the graft. Conclusions/interpretation: Our study shows that functional beta cells can be generated from exocrine tissue by transdifferentiation and thereby may offer a new perspective for beta cell therapy.

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Section: Discussionsupporting

confidence: 80%

In vitro generation of insulin-producing beta cells from adult exocrine pancreatic cells

Baeyens¹,

Breuck²,

Lardon³

et al. 2004

Diabetologia

291

224

View full text Add to dashboard Cite

show abstract

“…Surprisingly, levels of Foxa2 (HNF3β) a known transcription factor regulator of pdx-1 (Wu et al, 1997), were suppressed in response to Ex-4 treatment, indicating that it is not necessary for expression of pdx-1 in this context (vide infra). The combination of activin and betacellulin has also been shown to induce differentiation of the AR42J cells (Mashima et al, 1996). Activin binds to and activates the transforming growth factor-β (TGFβ) receptors (Fleisch et al, 2006).…”

Section: In Vitro Determination Of the Mechanism Of β Cell Differentimentioning

confidence: 99%

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

Doyle

Egan

2007

Pharmacology & Therapeutics

584

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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“…Currently, there is little evidence that any other cell type contributes to β cell neogenesis. Although some studies had suggested the potential role of Pdx1 in promoting β cell transdifferentiation from acinar tissue [83,[104][105][106], a recent elegant lineage tracing analysis suggests that such cells do not contribute to new β cells in models of regeneration in vivo [107].…”

Section: Role Of Pdx1 In Adaptive β Cell Hyperplasia and β Cell Regenmentioning

confidence: 99%

A feat of metabolic proportions: Pdx1 orchestrates islet development and function in the maintenance of glucose homeostasis

Babu

Deering

Mirmira

2007

Molecular Genetics and Metabolism

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Emerging evidence over the past decade indicates a central role for transcription factors in the embryonic development of pancreatic islets and the consequent maintenance of normal glucose homeostasis. Pancreatic and duodenal homeobox 1 (Pdx1) is the best studied and perhaps most important of these factors. Whereas deletion or inactivating mutations of the Pdx1 gene causes whole pancreas agenesis in both mice and humans, even haploinsufficiency of the gene or alterations in its expression in mature islet cells causes substantial impairments in glucose tolerance and the development of a late-onset form of diabetes known as maturity onset diabetes of the young. The study of Pdx1 has revealed crucial phenotypic interrelationships of the varied cell types within the pancreas, particularly as these impinge upon cellular differentiation in the embryo and neogenesis and regeneration in the adult. In this review, we describe the actions of Pdx1 in the developing and mature pancreas and attempt to unify these actions with its known roles in modulating transcriptional complex formation and chromatin structure at the molecular genetic level.

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Betacellulin and activin A coordinately convert amylase-secreting pancreatic AR42J cells into insulin-secreting cells.

Cited by 279 publications

References 37 publications

In vitro generation of insulin-producing beta cells from adult exocrine pancreatic cells

In vitro generation of insulin-producing beta cells from adult exocrine pancreatic cells

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

A feat of metabolic proportions: Pdx1 orchestrates islet development and function in the maintenance of glucose homeostasis

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