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

• Published in: Nature medicine Vol. 22; no. 1; pp. 84 - 90
• Main Authors: Campbell, Jonathan E, Ussher, John R, Mulvihill, Erin E, Kolic, Jelena, Baggio, Laurie L, Cao, Xiemen, Liu, Yu, Lamont, Benjamin J, Morii, Tsukasa, Streutker, Catherine J, Tamarina, Natalia, Philipson, Louis H, Wrana, Jeffrey L, MacDonald, Patrick E, Drucker, Daniel J
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.01.2016; Nature Publishing Group
• Subjects: 631/443/319/1642; 64; 64/110; 692/163/2743/137/773; Adipose tissue; Animals; Apoptosis - genetics; Biomedicine; Blotting, Western; Cancer Research; Cell receptors; Cellular biology; Comparative analysis; Diabetes; Diabetes Mellitus, Experimental - genetics; Diabetes Mellitus, Experimental - metabolism; Diabetes Mellitus, Type 2 - genetics; Diabetes Mellitus, Type 2 - metabolism; Gene Knockout Techniques; Genetic aspects; Glucose; Glucose Tolerance Test; Hepatocyte Nuclear Factor 1-alpha - genetics; Hepatocyte Nuclear Factor 1-alpha - metabolism; Humans; Infectious Diseases; Insulin - metabolism; Insulin Resistance - genetics; Insulin Secretion; Insulin-Secreting Cells - metabolism; Islets of Langerhans - metabolism; letter; Male; Metabolic Diseases; Mice; Molecular Medicine; Neurosciences; Nutrients; Pancreatic beta cells; Physiological aspects; Real-Time Polymerase Chain Reaction; Receptors, Gastrointestinal Hormone - genetics; Receptors, Gastrointestinal Hormone - metabolism; RNA, Messenger - metabolism; Sequence Analysis, RNA; Signal Transduction; Survival; T Cell Transcription Factor 1 - genetics; T Cell Transcription Factor 1 - metabolism; Transcription factors; Canada
• ISSN: 1078-8956; 1546-170X; 1546-170X
• DOI: 10.1038/nm.3997

The details of the GIP signaling pathway are murky, but new data identify a downstream pathway involving Tcf7 that regulates beta cell survival and activity. 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 1 . Although the GLP-1 receptor (GLP-1R) is a validated drug target for diabetes 1 , the importance of the GIP receptor (GIPR) for the function of beta cells remains uncertain 2 , 3 , 4 . We demonstrate that mice with selective ablation of GIPR in beta cells ( MIP-Cre:Gipr Flox/Flox ; Gipr −/− β 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 −/− β 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 −/− β 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.