Transcription factor-7–like 2 (TCF7L2) gene acts downstream of the Lkb1/Stk11 kinase to control mTOR signaling, β cell growth, and insulin secretion
Year: 2018
Type: article
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 β cell in mice has previously been shown to cause glucose intolerance and to lower β cell mass. Deletion of the tumor suppressor liver kinase B1 (LKB1/STK11) leads to β cell hyperplasia and enhanced glucose-stimulated insulin secretion, providing a convenient genetic model for increased β 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 β 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 β 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 β cell proliferation, increased β cell mass, and caused changes in polarity as revealed by the "rosette-like" arrangement of β 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 β cell to restrict insulin secretion.
Source: Journal of Biological Chemistry
Institution: Imperial College London
Language: English
Subfield: Surgery
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $3,430
Awards: G1335979935, G1635243398, Genetic and nutritional control of pancreatic beta cell identity., Roles of GWA genes in controlling pancreatic beta cell function and mass., G2040450235, G3555667338, G4426574518, G4781795914, All-optical deconstruction of the islet wiring patterns underlying insulin secretion in health and disease, The impact of long non-coding RNA at the Pax6 locus on beta cell identity and function, Defining the molecular and physiological mechanisms of pancreatic islet dysfunction which lead to type 2 diabetes, Roles of the type 2 diabetes (T2D)-associated gene C2cd4a in regulating glucose homeostasis in the mouse, G8635620823
OpenAlex ID: W2810362401