title: TCF1 links GIPR signaling to the control of beta cell function and survival.
abstract: The glucagon-like peptide-1 (GLP-1) receptor and the glucose-dependent insulinotropic polypeptide (GIP) receptor transduce nutrient-stimulated signals to control beta cell function. Although the GLP-1 receptor (GLP-1R) is a validated drug target for diabetes, the importance of the GIP receptor (GIPR) for the function of beta cells remains uncertain. We demonstrate that mice with selective ablation of GIPR in beta cells (MIP-Cre:Gipr(Flox/Flox); Gipr(-/-βCell)) exhibit lower levels of meal-stimulated insulin secretion, decreased expansion of adipose tissue mass and preservation of insulin sensitivity when compared to MIP-Cre controls. Beta cells from Gipr(-/-βCell) mice display greater sensitivity to apoptosis and markedly lower islet expression of T cell-specific transcription factor-1 (TCF1, encoded by Tcf7), a protein not previously characterized in beta cells. GIP, but not GLP-1, promotes beta cell Tcf7 expression via a cyclic adenosine monophosphate (cAMP)-independent and extracellular signal-regulated kinase (ERK)-dependent pathway. Tcf7 (in mice) or TCF7 (in humans) levels are lower in islets taken from diabetic mice and in humans with type 2 diabetes; knockdown of TCF7 in human and mouse islets impairs the cytoprotective responsiveness to GIP and enhances the magnitude of apoptotic injury, whereas restoring TCF1 levels in beta cells from Gipr(-/-βCell) mice lowers the number of apoptotic cells compared to that seen in MIP-Cre controls. Tcf7(-/-) mice show impaired insulin secretion, deterioration of glucose tolerance with either aging and/or high-fat feeding and increased sensitivity to beta cell injury relative to wild-type (WT) controls. Hence the GIPR-TCF1 axis represents a potential therapeutic target for preserving both the function and survival of vulnerable, diabetic beta cells.
authors.affiliation: Lunenfeld-Tanenbaum Research Institute, Mt. Sinai Hospital, Toronto, Ontario, Canada.
authors.forename: Jonathan E
authors.initials: JE
authors.lastname: Campbell
authors.affiliation: Lunenfeld-Tanenbaum Research Institute, Mt. Sinai Hospital, Toronto, Ontario, Canada.
authors.forename: John R
authors.initials: JR
authors.lastname: Ussher
authors.affiliation: Lunenfeld-Tanenbaum Research Institute, Mt. Sinai Hospital, Toronto, Ontario, Canada.
authors.forename: Erin E
authors.initials: EE
authors.lastname: Mulvihill
authors.affiliation: Department of Pharmacology, University of Alberta, Edmonton, Alberta, Canada.|Alberta Diabetes Institute, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Jelena
authors.initials: J
authors.lastname: Kolic
authors.affiliation: Lunenfeld-Tanenbaum Research Institute, Mt. Sinai Hospital, Toronto, Ontario, Canada.
authors.forename: Laurie L
authors.initials: LL
authors.lastname: Baggio
authors.affiliation: Lunenfeld-Tanenbaum Research Institute, Mt. Sinai Hospital, Toronto, Ontario, Canada.
authors.forename: Xiemen
authors.initials: X
authors.lastname: Cao
authors.affiliation: Lunenfeld-Tanenbaum Research Institute, Mt. Sinai Hospital, Toronto, Ontario, Canada.
authors.forename: Yu
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Lunenfeld-Tanenbaum Research Institute, Mt. Sinai Hospital, Toronto, Ontario, Canada.
authors.forename: Benjamin J
authors.initials: BJ
authors.lastname: Lamont
authors.affiliation: Lunenfeld-Tanenbaum Research Institute, Mt. Sinai Hospital, Toronto, Ontario, Canada.
authors.forename: Tsukasa
authors.initials: T
authors.lastname: Morii
authors.affiliation: St. Michael's Hospital, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Catherine J
authors.initials: CJ
authors.lastname: Streutker
authors.affiliation: Department of Medicine, Kovler Diabetes Center, University of Chicago, Chicago, USA.
authors.forename: Natalia
authors.initials: N
authors.lastname: Tamarina
authors.affiliation: Department of Medicine, Kovler Diabetes Center, University of Chicago, Chicago, USA.
authors.forename: Louis H
authors.initials: LH
authors.lastname: Philipson
authors.affiliation: Lunenfeld-Tanenbaum Research Institute, Mt. Sinai Hospital, Toronto, Ontario, Canada.
authors.forename: Jeffrey L
authors.initials: JL
authors.lastname: Wrana
authors.affiliation: Department of Pharmacology, University of Alberta, Edmonton, Alberta, Canada.|Alberta Diabetes Institute, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Patrick E
authors.initials: PE
authors.lastname: MacDonald
authors.affiliation: Lunenfeld-Tanenbaum Research Institute, Mt. Sinai Hospital, Toronto, Ontario, Canada.|Department of Medicine, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Drucker
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics; D015153:Blotting, Western; D003921:Diabetes Mellitus, Experimental / Q000235:genetics* / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics* / Q000378:metabolism; D055786:Gene Knockout Techniques; D005951:Glucose Tolerance Test; D051538:Hepatocyte Nuclear Factor 1-alpha / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D007333:Insulin Resistance / Q000235:genetics; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000378:metabolism*; D007515:Islets of Langerhans / Q000378:metabolism; D008297:Male; D051379:Mice; D012333:RNA, Messenger / Q000378:metabolism*; D060888:Real-Time Polymerase Chain Reaction; D011964:Receptors, Gastrointestinal Hormone / Q000235:genetics* / Q000378:metabolism; D017423:Sequence Analysis, RNA; D015398:Signal Transduction; D051822:T Cell Transcription Factor 1 / Q000235:genetics* / Q000378:metabolism
chemical_list: D051538:Hepatocyte Nuclear Factor 1-alpha; C496488:Hnf1a protein, mouse; D007328:Insulin; D012333:RNA, Messenger; D011964:Receptors, Gastrointestinal Hormone; D051822:T Cell Transcription Factor 1; C497576:TCF7 protein, human; C041086:gastric inhibitory polypeptide receptor