Transcription factor-7-like 2 (TCF7L2) gene acts downstream of the Lkb1/Stk11 kinase to control mTOR signaling, ß cell growth, and insulin secretion.
J Biol Chem
; 293(36): 14178-14189, 2018 09 07.
Article
em En
| MEDLINE
| ID: mdl-29967064
ABSTRACT
Variants in the transcription factor-7-like 2 (TCF7L2/TCF4) gene, involved in Wnt signaling, are associated with type 2 diabetes. Loss of Tcf7l2 selectively from the ß cell in mice has previously been shown to cause glucose intolerance and to lower ß cell mass. Deletion of the tumor suppressor liver kinase B1 (LKB1/STK11) leads to ß cell hyperplasia and enhanced glucose-stimulated insulin secretion, providing a convenient genetic model for increased ß cell growth and function. The aim of this study was to explore the possibility that Tcf7l2 may be required for the effects of Lkb1 deletion on insulin secretion in the mouse ß cell. Mice bearing floxed Lkb1 and/or Tcf7l2 alleles were bred with knockin mice bearing Cre recombinase inserted at the Ins1 locus (Ins1Cre), allowing highly ß cell-selective deletion of either or both genes. Oral glucose tolerance was unchanged by the further deletion of a single Tcf7l2 allele in these cells. By contrast, mice lacking both Tcf7l2 alleles on this background showed improved oral glucose tolerance and insulin secretion in vivo and in vitro compared with mice lacking a single Tcf7l2 allele. Biallelic Tcf7l2 deletion also enhanced ß cell proliferation, increased ß cell mass, and caused changes in polarity as revealed by the "rosette-like" arrangement of ß cells. Tcf7l2 deletion also increased signaling by mammalian target of rapamycin (mTOR), augmenting phospho-ribosomal S6 levels. We identified a novel signaling mechanism through which a modifier gene, Tcf7l2, lies on a pathway through which LKB1 acts in the ß cell to restrict insulin secretion.
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Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Transdução de Sinais
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Células Secretoras de Insulina
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Serina-Treonina Quinases TOR
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Proteína 2 Semelhante ao Fator 7 de Transcrição
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Secreção de Insulina
Tipo de estudo:
Prognostic_studies
Limite:
Animals
Idioma:
En
Ano de publicação:
2018
Tipo de documento:
Article