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 uncertain2,3,4. We demonstrate that mice with selective ablation of GIPR in beta cells (MIP-Cre:GiprFlox/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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Acknowledgements
The authors thank H. Bates for excellent technical assistance and B. Yusta for thoughtful discussions and critical reading of the manuscript; H. Clevers for Tcf7−/− mice; and R. DiMarchi for critical reagents. This work in Toronto was supported by the Canada Research Chairs Program, the Banting and Best Diabetes Centre Novo Nordisk Chair in Incretin Biology, and Canadian Institute for Health Research (CIHR) grants 82700 and 123391 (DJD). We thank the Human Organ Procurement and Exchange (HOPE) program and the Trillium Gift of Life Network (TGLN) for their assistance in obtaining pancreases and islets from human organ donors for research, and we thank J. Lyon (Alberta Diabetes Institute; http://www.bcell.org/isletcore.html) and T. Kin and A.M.J. Shapiro (University of Alberta, Clinical Islet Isolation Facility) for human islet isolation. The Alberta Diabetes Foundation funded the human islet isolations. Work at the University of Alberta was funded by a grant from the Canadian Diabetes Association (to P.E.M.). P.E.M. holds a Canada Research Chair in Islet Biology. Postdoctoral fellowship funding was provided by the Canadian Institute for Health Research (J.E.C., J.R.U., and E.E.M.), Banting and Best Diabetes Centre (J.E.C.), the Canadian Diabetes Association (E.E.M.) and Alberta Innovates Health Solutions (J.R.U.). D.J.D. is the main guarantor of this work and takes responsibility for all content.
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J.E.C. and D.J.D. designed and directed the study, analyzed data and wrote the manuscript. J.R.U., E.E.M., L.L.B. and P.E.M. contributed to the study design and the preparation of the manuscript. J.E.C., J.R.U., E.E.M., J.K., L.L.B., X.C., B.J.L. and T.M. performed experiments. J.K. and P.E.M. carried out experiments on human islets. Y.L. and J.L.W. provided assistance with the RNA-seq data. N.T. and L.H.P. provided MIP-Cre mice. C.J.S. performed the electron microscopy. All authors reviewed the manuscript and provided final approval for submission.
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D.J.D. has been a consultant to Novo Nordisk Inc. and other companies that develop and/or sell incretin-based therapies, including Arisaph Pharmaceuticals Inc., Intarcia Therapeutics, Merck Research Laboratories, MedImmune, Receptos, Sanofi, Takeda and Transition Pharmaceuticals Inc. Neither D.J.D. nor his family members hold stock directly or indirectly in any of these companies.
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Campbell, J., Ussher, J., Mulvihill, E. et al. TCF1 links GIPR signaling to the control of beta cell function and survival. Nat Med 22, 84–90 (2016). https://doi.org/10.1038/nm.3997
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DOI: https://doi.org/10.1038/nm.3997
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