Parathyroid hormone-related protein enhances human ß-cell proliferation and function with associated induction of cyclin-dependent kinase 2 and cyclin E expression.
Diabetes
; 59(12): 3131-8, 2010 Dec.
Article
em En
| MEDLINE
| ID: mdl-20876711
ABSTRACT
OBJECTIVE:
Inducing human ß-cell growth while enhancing function is a major goal in the treatment of diabetes. Parathyroid hormone-related protein (PTHrP) enhances rodent ß-cell growth and function through the parathyroid hormone-1 receptor (PTH1R). Based on this, we hypothesized that PTH1R is expressed in human ß-cells and that PTHrP has the potential to enhance human ß-cell proliferation and/or function. RESEARCH DESIGN ANDMETHODS:
PTH1R expression, ß-cell proliferation, glucose-stimulated insulin secretion (GSIS), and expression of differentiation and cell-cycle genes were analyzed in human islets transduced with adenoviral PTHrP constructs or treated with PTHrP peptides. The effect of overexpression of late G1/S cell cycle molecules was also assessed on human ß-cell proliferation.RESULTS:
We found that human ß-cells express PTH1R. More importantly, overexpression of PTHrP causes a significant approximately threefold increase in human ß-cell proliferation. Furthermore, the amino terminus PTHrP(1-36) peptide is sufficient to increase replication as well as expression of the late G1/S cell-cycle proteins cyclin E and cyclin-dependent kinase 2 (cdk2) in human islets. Notably, PTHrP(1-36) also enhances GSIS. Finally, overexpression of cyclin E alone, but not cdk2, augments human ß-cell proliferation, and when both molecules are expressed simultaneously there is a further marked synergistic increase in replication.CONCLUSIONS:
PTHrP(1-36) peptide enhances human ß-cell proliferation as well as function, with associated upregulation of two specific cell-cycle activators that together can induce human ß-cell proliferation several fold. The future therapeutic potential of PTHrP(1-36) for the treatment of diabetes is especially relevant given the complementary therapeutic efficacy of PTHrP(1-36) in postmenopausal osteoporosis.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Ciclina E
/
Proteína Relacionada ao Hormônio Paratireóideo
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Receptor Tipo 1 de Hormônio Paratireóideo
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Células Secretoras de Insulina
/
Quinase 2 Dependente de Ciclina
Tipo de estudo:
Risk_factors_studies
Limite:
Adolescent
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Adult
/
Aged
/
Child
/
Child, preschool
/
Female
/
Humans
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Male
/
Middle aged
Idioma:
En
Revista:
Diabetes
Ano de publicação:
2010
Tipo de documento:
Article