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TCF1 links GIPR signaling to the control of beta cell function and survival.

Publication ,  Journal Article
Campbell, JE; Ussher, JR; Mulvihill, EE; Kolic, J; Baggio, LL; Cao, X; Liu, Y; Lamont, BJ; Morii, T; Streutker, CJ; Tamarina, N; Philipson, LH ...
Published in: Nat Med
January 2016

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.

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Published In

Nat Med

DOI

EISSN

1546-170X

Publication Date

January 2016

Volume

22

Issue

1

Start / End Page

84 / 90

Location

United States

Related Subject Headings

  • T Cell Transcription Factor 1
  • Signal Transduction
  • Sequence Analysis, RNA
  • Receptors, Gastrointestinal Hormone
  • Real-Time Polymerase Chain Reaction
  • RNA, Messenger
  • Mice
  • Male
  • Islets of Langerhans
  • Insulin-Secreting Cells
 

Citation

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Campbell, J. E., Ussher, J. R., Mulvihill, E. E., Kolic, J., Baggio, L. L., Cao, X., … Drucker, D. J. (2016). TCF1 links GIPR signaling to the control of beta cell function and survival. Nat Med, 22(1), 84–90. https://doi.org/10.1038/nm.3997
Campbell, Jonathan E., John R. Ussher, Erin E. Mulvihill, Jelena Kolic, Laurie L. Baggio, Xiemen Cao, Yu Liu, et al. “TCF1 links GIPR signaling to the control of beta cell function and survival.Nat Med 22, no. 1 (January 2016): 84–90. https://doi.org/10.1038/nm.3997.
Campbell JE, Ussher JR, Mulvihill EE, Kolic J, Baggio LL, Cao X, et al. TCF1 links GIPR signaling to the control of beta cell function and survival. Nat Med. 2016 Jan;22(1):84–90.
Campbell, Jonathan E., et al. “TCF1 links GIPR signaling to the control of beta cell function and survival.Nat Med, vol. 22, no. 1, Jan. 2016, pp. 84–90. Pubmed, doi:10.1038/nm.3997.
Campbell JE, Ussher JR, Mulvihill EE, Kolic J, Baggio LL, Cao X, Liu Y, Lamont BJ, Morii T, Streutker CJ, Tamarina N, Philipson LH, Wrana JL, MacDonald PE, Drucker DJ. TCF1 links GIPR signaling to the control of beta cell function and survival. Nat Med. 2016 Jan;22(1):84–90.

Published In

Nat Med

DOI

EISSN

1546-170X

Publication Date

January 2016

Volume

22

Issue

1

Start / End Page

84 / 90

Location

United States

Related Subject Headings

  • T Cell Transcription Factor 1
  • Signal Transduction
  • Sequence Analysis, RNA
  • Receptors, Gastrointestinal Hormone
  • Real-Time Polymerase Chain Reaction
  • RNA, Messenger
  • Mice
  • Male
  • Islets of Langerhans
  • Insulin-Secreting Cells