| First Author | Nguyen-Tu MS | Year | 2018 |
| Journal | J Biol Chem | Volume | 293 |
| Issue | 36 | Pages | 14178-14189 |
| PubMed ID | 29967064 | Mgi Jnum | J:270684 |
| Mgi Id | MGI:6222523 | Doi | 10.1074/jbc.RA118.003613 |
| Citation | Nguyen-Tu MS, et al. (2018) Transcription factor-7-like 2 (TCF7L2) gene acts downstream of the Lkb1/Stk11 kinase to control mTOR signaling, beta cell growth, and insulin secretion. J Biol Chem 293(36):14178-14189 |
| abstractText | 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 beta cell in mice has previously been shown to cause glucose intolerance and to lower beta cell mass. Deletion of the tumor suppressor liver kinase B1 (LKB1/STK11) leads to beta cell hyperplasia and enhanced glucose-stimulated insulin secretion, providing a convenient genetic model for increased beta 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 beta 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 beta 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 beta cell proliferation, increased beta cell mass, and caused changes in polarity as revealed by the "rosette-like" arrangement of beta 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 beta cell to restrict insulin secretion. |
