| First Author | Han B | Year | 2014 |
| Journal | Hum Mol Genet | Volume | 23 |
| Issue | 17 | Pages | 4597-611 |
| PubMed ID | 24728038 | Mgi Jnum | J:213611 |
| Mgi Id | MGI:5585382 | Doi | 10.1093/hmg/ddu173 |
| Citation | Han B, et al. (2014) TGFBI (betaIG-H3) is a diabetes-risk gene based on mouse and human genetic studies. Hum Mol Genet 23(17):4597-611 |
| abstractText | Transforming growth factor beta-induced (TGFBI/betaIG-H3), also known as betaig-H3, is a protein inducible by TGFbeta1 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. |
