title: TRIB3 mediates glucose-induced insulin resistance via a mechanism that requires the hexosamine biosynthetic pathway.
abstract: In the current study, we investigated the role of tribbles homolog 3 (TRIB3) in glucose-induced insulin resistance and whether the induction of TRIB3 by glucose is dependent on the nutrient-sensing hexosamine biosynthetic pathway (HBP) known to mediate glucose toxicity in diabetes. In diabetic rats, TRIB3 expression in skeletal muscle was increased after 10 days of hyperglycemia, and glycemia and muscle TRIB3 were both restored toward normal by insulin therapy. In L6 myocytes, the induction of TRIB3 by high glucose or glucosamine was reversible upon removal of these substrates. To assess the role of HBP in the induction of TRIB3, we demonstrated that the ability of high glucose to augment TRIB3 expression was prevented by azaserine, an inhibitor of glutamine: fructose-6-phosphate amidotransferase (GFAT), which is the rate-limiting enzyme in the HBP pathway. TRIB3 expression was also substantially stimulated by glucosamine, which bypasses GFAT, accompanied by a decrease in the insulin-stimulated glucose transport rate, and neither response was affected by azaserine. Further, knockdown of TRIB3 inhibited, and TRIB3 overexpression enhanced, the ability of both high glucose and glucosamine to induce insulin resistance. These data provide the mechanistic link between the HBP flux and insulin resistance and point to TRIB3 as a novel target for treatment of glucose-induced insulin resistance.
authors.affiliation: Department of Nutrition Sciences, University of Alabama at Birmingham, Birmingham, Alabama.
authors.forename: Wei
authors.initials: W
authors.lastname: Zhang
authors.forename: Jiarong
authors.initials: J
authors.lastname: Liu
authors.forename: Ling
authors.initials: L
authors.lastname: Tian
authors.forename: Qinglan
authors.initials: Q
authors.lastname: Liu
authors.forename: Yuchang
authors.initials: Y
authors.lastname: Fu
authors.forename: W Timothy
authors.initials: WT
authors.lastname: Garvey
mesh_terms: D000818:Animals; D053898:Biosynthetic Pathways / Q000502:physiology*; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism; D005947:Glucose / Q000378:metabolism*; D006595:Hexosamines / Q000096:biosynthesis*; D006943:Hyperglycemia / Q000378:metabolism*; D007328:Insulin / Q000378:metabolism; D007333:Insulin Resistance / Q000502:physiology*; D008297:Male; D018482:Muscle, Skeletal / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D015854:Up-Regulation / Q000502:physiology
chemical_list: D006595:Hexosamines; D007328:Insulin; C502443:Trib3 protein, rat; D017346:Protein Serine-Threonine Kinases; D005947:Glucose