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

Abstract

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]

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

“…Mice treated with 70 mg/kg alloxan remain permanently hyperglycaemic [8]. Engraftment resulted in normalisation of blood glycaemia, which was retained for at least 14 days, but promptly reverted to hyperglycaemia when the graft-bearing kidney was removed (Fig.…”

“…Despite much progress in our understanding of pancreas development during the last decade, the extracellular factors that specify islet cell differentiation in the embryo remain unknown [5]. In adult mammals, the endocrine pancreas can expand or regenerate under certain experimental conditions, either as a result of islet cell proliferation [4], or neogenesis from progenitor cells [3,[6][7][8]. In vitro, very few studies have been able to demonstrate the feasibility of inducing islet neogenesis from adult tissue.…”

Ngn3 expression during postnatal in vitro beta cell neogenesis induced by the JAK/STAT pathway

“…(b) Transient expression of Ngn3, Pdx1 and insulin at 24 h (1), 48 h (2) and 72 h (3) after growth factor addition. The mRNA levels after 48 h of growth factor addition were compared to cultures treated with inhibitors AG1478 (4), Pp-YLKTK-mts (5) or AG490 (6). (c) Cell cultures after 24 h of treatment with growth factors þ Pp-YLKTK-mts (STAT3 inhibitor) were compared to inhibitor-untreated cultures at the same time points infected with either a control virus expressing scrambled siRNA or one of two vectors containing silencing siRNA specifically directed against Ngn3.…”

“…1 However, numerous reports of alternative sources of beta-cell 'neogenesis' in response to severe tissue injury have been described. [2][3][4][5][6] The pancreas is composed of exocrine tissue, comprising acinar and duct cells, and of endocrine tissue that contains beta-, alpha-, delta-and pancreatic polypeptide cells. A possible source of progenitor cells is the acinar cell population that is the most abundant in adult pancreas and is known to retain a remarkable plasticity both in vivo and in vitro.…”

La thérapie cellulaire du diabète

“…Le potentiel de la transdifférenciation acinaire-vers-β n'en est pas négligé pour autant, comme le montrent les travaux de l'équipe de Heimberg. Actifs depuis longtemps dans les investigations visant à stimuler la conversion acinaire-β de manière pharmacologique, l'équipe avait montré l'utilité de facteurs de croissance (epidermal growth factor [EGF]) ou d'hormones (gastrine) dans la régénération des cellules β [47]. L'extension de ces recherches a permis d'identifier deux facteurs, l'EGF et le ciliary neurotrophic factor (CNTF) qui permettent d'induire une transdifférencia-tion acinaire-vers-β massive chez la plupart (65 %) des souris traitées [48].…”