Direct effect of glucocorticoids on glucose-activated adult rat ß-cells increases their cell number and their functional mass for transplantation.
Am J Physiol Endocrinol Metab
; 311(4): E698-E705, 2016 10 01.
Article
em En
| MEDLINE
| ID: mdl-27555297
ABSTRACT
Compounds that increase ß-cell number can serve as ß-cell replacement therapies in diabetes. In vitro studies have identified several agents that can activate DNA synthesis in primary ß-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 ß-cells into DNA synthesis and then assessed influences of stimulatory agents on the number of living cells. The four compounds with highest ß-cell recruitment were glucocorticoid (GC) receptor ligands. The GC effect occurred in glucose-activated ß-cells and was associated with increased glucose utilization and oxidation. Hydrocortisone and methylprednisolone almost doubled the number of ß-cells in 2 wk. The expanded cell population provided an increased functional ß-cell mass for transplantation in diabetic animals. These effects are age dependent; they did not occur in neonatal rat ß-cells, where GC exposure suppressed basal replication and was cytotoxic. We concluded that GCs can induce the replication of adult rat ß-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 ß-cells. Our study also demonstrated that ß-cells can be expanded in vitro to increase the size of metabolically adequate grafts.
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Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Transplante das Ilhotas Pancreáticas
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Células Secretoras de Insulina
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Glucocorticoides
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Glucose
Limite:
Animals
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Humans
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Male
Idioma:
En
Ano de publicação:
2016
Tipo de documento:
Article