title: Direct effect of glucocorticoids on glucose-activated adult rat β-cells increases their cell number and their functional mass for transplantation.
abstract: Compounds that increase β-cell number can serve as β-cell replacement therapies in diabetes. In vitro studies have identified several agents that can activate DNA synthesis in primary β-cells but only in small percentages of cells and without demonstration of increases in cell number. We used whole well multiparameter imaging to first screen a library of 1,280 compounds for their ability to recruit adult rat β-cells into DNA synthesis and then assessed influences of stimulatory agents on the number of living cells. The four compounds with highest β-cell recruitment were glucocorticoid (GC) receptor ligands. The GC effect occurred in glucose-activated β-cells and was associated with increased glucose utilization and oxidation. Hydrocortisone and methylprednisolone almost doubled the number of β-cells in 2 wk. The expanded cell population provided an increased functional β-cell mass for transplantation in diabetic animals. These effects are age dependent; they did not occur in neonatal rat β-cells, where GC exposure suppressed basal replication and was cytotoxic. We concluded that GCs can induce the replication of adult rat β-cells through a direct action, with intercellular differences in responsiveness that have been related to differences in glucose activation and in age. These influences can explain variability in GC-induced activation of DNA synthesis in rat and human β-cells. Our study also demonstrated that β-cells can be expanded in vitro to increase the size of metabolically adequate grafts.
authors.affiliation: Diabetes Research Center, Brussels Free University-VUB, University Hospital Brussels, and Center for Beta Cell Therapy, Brussels, Belgium.
authors.forename: Zerihun
authors.initials: Z
authors.lastname: Assefa
authors.affiliation: Diabetes Research Center, Brussels Free University-VUB, University Hospital Brussels, and Center for Beta Cell Therapy, Brussels, Belgium.
authors.forename: Sarah
authors.initials: S
authors.lastname: Akbib
authors.affiliation: Diabetes Research Center, Brussels Free University-VUB, University Hospital Brussels, and Center for Beta Cell Therapy, Brussels, Belgium.
authors.forename: Astrid
authors.initials: A
authors.lastname: Lavens
authors.affiliation: Diabetes Research Center, Brussels Free University-VUB, University Hospital Brussels, and Center for Beta Cell Therapy, Brussels, Belgium.
authors.forename: Geert
authors.initials: G
authors.lastname: Stangé
authors.affiliation: Diabetes Research Center, Brussels Free University-VUB, University Hospital Brussels, and Center for Beta Cell Therapy, Brussels, Belgium.
authors.forename: Zhidong
authors.initials: Z
authors.lastname: Ling
authors.affiliation: Diabetes Research Center, Brussels Free University-VUB, University Hospital Brussels, and Center for Beta Cell Therapy, Brussels, Belgium.
authors.forename: Karine H
authors.initials: KH
authors.lastname: Hellemans
authors.affiliation: Diabetes Research Center, Brussels Free University-VUB, University Hospital Brussels, and Center for Beta Cell Therapy, Brussels, Belgium Daniel.Pipeleers@vub.ac.be.
authors.forename: Daniel
authors.initials: D
authors.lastname: Pipeleers
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D002452:Cell Count; D002469:Cell Separation; D004247:DNA / Q000096:biosynthesis / Q000235:genetics; D005938:Glucocorticoids / Q000494:pharmacology*; D005947:Glucose / Q000494:pharmacology*; D006801:Humans; D050417:Insulin-Secreting Cells / Q000187:drug effects*; D016381:Islets of Langerhans Transplantation / Q000379:methods*; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D051381:Rats; D017208:Rats, Wistar; D011965:Receptors, Glucocorticoid / Q000096:biosynthesis / Q000235:genetics
chemical_list: D005938:Glucocorticoids; D011965:Receptors, Glucocorticoid; D004247:DNA; D005947:Glucose
keywords: diabetes; drug screening; insulin; islet; transplantation