Recombinant human betacellulin promotes the neogenesis of beta-cells and ameliorates glucose intolerance in mice with diabetes induced by selective alloxan perfusion.

Yamamoto, Keiji; Miyagawa, Jun Ichiro; Waguri, Masako; Sasada, Reiko; Igarashi, Koichi; Li, Ming; Nammo, Takao; Moriwaki, Masamitsu; Imagawa, Akihisa; Yamagata, Kazuya; Nakajima, Hitoshi; Namba, Mitsuyoshi; Tochino, Yoshihiro; Hanafusa, Toshiaki; Matsuzawa, Yūji

doi:10.2337/diabetes.49.12.2021

Cited by 101 publications

(63 citation statements)

References 16 publications

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“…In transgenic mice lacking functional EGF receptors, islet morphogenesis is impaired and beta cell differentiation is delayed [35]. Betacellulin, a growth factor which also operates via the EGF receptor, was found to promote islet regeneration in subtotally pancreatectomised rats [36] and in alloxan-diabetic mice [37]. In combination with gastrin hormone, EGF was shown to stimulate beta cell regeneration in alloxandiabetic mice [8].…”

Section: Discussionmentioning

confidence: 99%

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: Discussionmentioning

confidence: 99%

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

“…In a model of selective alloxan perfusion, betacellulin was reported to induce beta-cell neogenesis and improve glucose tolerance, but this effect could not be obtained before 8 weeks of treatment [24]. The approach outlined in our paper relies on the endogenous regenerative capacity of the diabetic pancreas.…”

Section: Discussionmentioning

confidence: 99%

Combined gastrin and epidermal growth factor treatment induces islet regeneration and restores normoglycaemia in C57Bl6/J mice treated with alloxan

2004

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Aims/hypothesis. Increasing beta-cell mass and/or function could restore glucose homeostasis in diabetes mellitus. Hitherto, trophic factors for beta-cell regeneration after toxic events have been difficult to identify. We evaluated the application of gastrin and epidermal growth factor after alloxan-induced pancreatic beta-cell damage. Methods. After alloxan treatment (70 mg/kg), mice were implanted with Alzet osmotic minipumps releasing gastrin and epidermal growth factor for one week. We monitored glycaemia, did histological analyses of the pancreata and quantified pancreatic beta-cell mass and insulin content. Results. Alloxan treatment alone resulted in a persisting hyperglycaemic state. Combined gastrin and epidermal growth factor treatment restored normoglycaemia in 3 days, an effect which seemed permanent. Glucose tolerance tests showed normal glucose responsiveness. Gastrin on its own and epidermal growth factor on its own did not alleviate hyperglycaemia. Islet mass, islet density and pancreatic insulin content were higher in mice treated with gastrin and epidermal growth factor than in untreated mice with persisting hyperglycaemia. In normoglycaemic control mice treatment with gastrin and epidermal growth factor did not affect these parameters. We detected transitional cytokeratin-positive ductal to endocrine insulinexpressing cells and noted increased ductal but not beta-cell proliferation. Conclusions/interpretation. Our results show that combined treatment with gastrin and epidermal growth factor can induce sufficient regeneration of a functional islet mass to restore glucose homeostasis. [Diabetologia (2004) 47:259-265]

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“…Paraffin-embedded sections (5-7 μm thick) cut at 500 μm intervals were stained with haematoxylin and eosin to observe mononuclear cell infiltration in and around the islet. Other sections were stained for insulin and BrdU using a polyclonal guinea pig anti-insulin and anti-BrdU antibodies, respectively, and were visualised with diaminobenzidine as described previously [21]. The grade of insulitis was scored on haematoxylin and eosin-stained sections.…”

Section: Immunohistochemical Studymentioning

confidence: 99%

Continuous stimulation of human glucagon-like peptide-1 (7–36) amide in a mouse model (NOD) delays onset of autoimmune type 1 diabetes

et al. 2007

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Aims/hypothesis We examined the effect of glucagon-like peptide-1 (GLP-1) on the development of diabetes and islet morphology in NOD mice by administering GLP-1 to prediabetic mice. Methods Eight-week-old female NOD mice were infused subcutaneously with human GLP-1 via a mini-osmotic pump for 4 or 8 weeks. In mice treated with GLP-1 for 4 weeks, blood glucose levels and body weight were measured. An intraperitoneal glucose tolerance test (IPGTT) and evaluation of insulitis score were also performed. Beta cell area, proliferation, apoptosis, neogenesis from ducts and subcellular localisation of forkhead box O1 (FOXO1) were examined by histomorphometrical, BrdU-labelling, TUNEL, insulin/cytokeratin and FOXO1/ insulin double-immunostaining methods, respectively.Results Mice treated with human GLP-1 for 4 weeks had lower blood glucose levels until 2 weeks after completion of treatment, showing improved IPGTT data and insulitis score. This effect continued even after cessation of the treatment. In addition to the increase of beta cell neogenesis, BrdU labelling index was elevated (0.24 vs 0.13%, p<0.001), while apoptosis was suppressed by 54.2% (p<0.001) in beta cells. Beta cell area was increased in parallel with the translocation of FOXO1 from the nucleus to the cytoplasm. The onset of diabetes was delayed in mice treated with GLP-1 for 4 weeks, while mice treated with GLP-1 for 8 weeks did not develop diabetes by age 21 weeks compared with a 60% diabetes incidence in control mice at this age. Conclusions/interpretation Continuous infusion of human GLP-1 to prediabetic NOD mice not only induces beta cell proliferation and neogenesis, but also suppresses beta cell apoptosis and delays the onset of type 1 diabetes.

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Recombinant human betacellulin promotes the neogenesis of beta-cells and ameliorates glucose intolerance in mice with diabetes induced by selective alloxan perfusion.

Cited by 101 publications

References 16 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

Combined gastrin and epidermal growth factor treatment induces islet regeneration and restores normoglycaemia in C57Bl6/J mice treated with alloxan

Continuous stimulation of human glucagon-like peptide-1 (7–36) amide in a mouse model (NOD) delays onset of autoimmune type 1 diabetes

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