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

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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 function1. Although the GLP-1 receptor (GLP-1R) is a validated drug target for diabetes1, the importance of the GIP receptor (GIPR) for the function of beta cells remains uncertain2-4. We demonstrate that mice with selective ablation of GIPR in beta cells (MIP-Cre:GiprFlox/Flox; Gipr./.Cell) 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./.Cell 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./.Cell 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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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. Nature Medicine, 22(1), 84–90. https://doi.org/10.1038/nm.3997

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