title: TGFBI (βIG-H3) is a diabetes-risk gene based on mouse and human genetic studies.
abstract: Transforming growth factor beta-induced (TGFBI/βIG-H3), also known as βig-H3, is a protein inducible by TGFβ1 and secreted by many cell types. It binds to collagen, forms part of the extracellular matrix and interacts with integrins on the cell surface. Recombinant TGFBI and transgenic TGFBI overexpression can promote both islet survival and function. In this study, we generated TGFBI KO mice and further assessed TGFBI function and signaling pathways in islets. Islets from KO mice were of normal size and quantity, and these animals were normoglycemic. However, KO islet survival and function was compromised in vitro. In vivo, KO donor islets became inferior to wild-type donor islets in achieving normoglycemia when transplanted into KO diabetic recipients. TGFBI KO mice were more prone to straptozotocin-induced diabetes than the wild-type counterpart. Phosphoprotein array analysis established that AKT1S1, a molecule linking the AKT and mTORC1 signaling pathways, was modulated by TGFBI in islets. Phosphorylation of four molecules in the AKT and mTORC1 signaling pathway, i.e. AKT, AKT1S1, RPS6 and EIF4EBP1, was upregulated in islets upon TGFBI stimulation. Suppression of AKT activity by a chemical inhibitor, or knockdown of AKT1S1, RPS6 and EIF4EBP1 expression by small interfering RNA, modulated islet survival, proving the relevance of these molecules in TGFBI-triggered signaling. Human genetic studies revealed that in the TGFBI gene and its vicinity, three single-nucleotide polymorphisms were significantly associated with type 1 diabetes risks, and one with type 2 diabetes risks. Our study suggests that TGFBI is a potential risk gene for human diabetes.
authors.affiliation: Centre de Recherche and.
authors.forename: Bing
authors.initials: B
authors.lastname: Han
authors.affiliation: Centre de Recherche and.
authors.forename: Hongyu
authors.initials: H
authors.lastname: Luo
authors.affiliation: PGX-Services, Montreal, QC, Canada.
authors.forename: John
authors.initials: J
authors.lastname: Raelson
authors.affiliation: Department of Genetics and Biostatistics, University of North Carolina Chapel Hill, Chapel Hill, NC, USA and.
authors.forename: Jie
authors.initials: J
authors.lastname: Huang
authors.affiliation: Department of Genetics and Biostatistics, University of North Carolina Chapel Hill, Chapel Hill, NC, USA and.
authors.forename: Yun
authors.initials: Y
authors.lastname: Li
authors.affiliation: Centre de Recherche and.
authors.forename: Johanne
authors.initials: J
authors.lastname: Tremblay
authors.affiliation: AmeriPath, Orlando, FL, USA.
authors.forename: Bing
authors.initials: B
authors.lastname: Hu
authors.affiliation: Centre de Recherche and.
authors.forename: Shijie
authors.initials: S
authors.lastname: Qi
authors.affiliation: Centre de Recherche and Service de Néphrologie, Centre Hospitalier de L'Université de Montréal (CRCHUM), Montréal, QC, Canada, jianping.wu@umontreal.ca.
authors.forename: Jiangping
authors.initials: J
authors.lastname: Wu
mesh_terms: D000818:Animals; D003920:Diabetes Mellitus / Q000235:genetics*; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics; D016326:Extracellular Matrix Proteins / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D006801:Humans; D007515:Islets of Langerhans / Q000473:pathology; D016381:Islets of Langerhans Transplantation; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D012307:Risk Factors; D015398:Signal Transduction / Q000187:drug effects; D014022:Tissue Survival; D016212:Transforming Growth Factor beta / Q000235:genetics*; D053773:Transforming Growth Factor beta1 / Q000494:pharmacology; D000099222:betaIG-H3 Protein
chemical_list: D016326:Extracellular Matrix Proteins; D010750:Phosphoproteins; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D000099222:betaIG-H3 Protein
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