The Induction of TRIB3 Causing Glucose Toxicity in Muscle Requires the O-GlcNAcylation of SP1

Background: Glucose-induced insulin resistance is mediated by induction of the pseudokinase TRIB3, which requires glucose metabolism via the hexosamine biosynthetic pathway (HBP). We have also shown that the SP1 binding site in the TRIB3 promoter region is essential for glucose’s ability to induce TRIB3 in skeletal muscle. However, the mechanism by which glucose regulates TRIB3 gene expression remains unknown. Hypothesis: Since the HBP provides the substrate for O-GlcNAcylation, we hypothesize that glucose results in O-GlcNAcylation of SP1 and this modulates induction of TRIB3 causing insulin resistance. Results: When treated with 5mM or 25mM glucose, the induction of TRIB3 gene expression (P Conclusion: (1) Increased TRIB3 mRNA expression parallels with upregulated SP1 expression; (2) Glucose induction of TRIB3 mRNA and protein is eliminated when HBP flux and O-GlcNAcylation is disrupted by the inhibition of OGT; (3) SP1 sites are critical in the regulatory action of glucose on the TRIB3 promoter and can be modulated by SP1 O-GlcNAcylation. While further studies are underway, these data provide new insights regarding mechanisms causing glucose-induced insulin resistance, and TRIB3 and TRIB3 promoter regulation are attractive targets for prevention of glucose toxicity in diabetes. Disclosure X. Liu: None. M. Kang: None. W. Garvey: Advisory Panel; Self; Novo Nordisk Inc., Merck & Co., Inc.. Research Support; Self; Sanofi, Pfizer Inc., Novo Nordisk Inc., AstraZeneca, Merck & Co., Inc., Elcelyx Therapeutics, Inc., Lexicon Pharmaceuticals, Inc., Eisai Inc..