Title | Mammalian Tribbles homolog 3 impairs insulin action in skeletal muscle: role in glucose-induced insulin resistance. |
Publication Type | Journal Article |
Year of Publication | 2010 |
Authors | Liu J, Wu X, Franklin JL, Messina JL, Hill HS, Moellering DR, R Walton G, Martin M, W Garvey T |
Journal | Am J Physiol Endocrinol Metab |
Volume | 298 |
Issue | 3 |
Pagination | E565-76 |
Date Published | 2010 Mar |
ISSN | 1522-1555 |
Keywords | Adult, Animals, Diabetes Mellitus, Type 2, Female, Glucose, Humans, Insulin, Insulin Resistance, Male, Mice, Muscle, Skeletal, Protein Kinases, Protein-Serine-Threonine Kinases, Rats, Rats, Zucker |
Abstract | Tribbles homolog 3 (TRIB3) was found to inhibit insulin-stimulated Akt phosphorylation and modulate gluconeogenesis in rodent liver. Currently, we examined a role for TRIB3 in skeletal muscle insulin resistance. Ten insulin-sensitive, ten insulin-resistant, and ten untreated type 2 diabetic (T2DM) patients were metabolically characterized by hyperinsulinemic euglycemic glucose clamps, and biopsies of vastus lateralis were obtained. Skeletal muscle samples were also collected from rodent models including streptozotocin (STZ)-induced diabetic rats, db/db mice, and Zucker fatty rats. Finally, L6 muscle cells were used to examine regulation of TRIB3 by glucose, and stable cell lines hyperexpressing TRIB3 were generated to identify mechanisms underlying TRIB3-induced insulin resistance. We found that 1) skeletal muscle TRIB3 protein levels are significantly elevated in T2DM patients; 2) muscle TRIB3 protein content is inversely correlated with glucose disposal rates and positively correlated with fasting glucose; 3) skeletal muscle TRIB3 protein levels are increased in STZ-diabetic rats, db/db mice, and Zucker fatty rats; 4) stable TRIB3 hyperexpression in muscle cells blocks insulin-stimulated glucose transport and glucose transporter 4 (GLUT4) translocation and impairs phosphorylation of Akt, ERK, and insulin receptor substrate-1 in insulin signal transduction; and 5) TRIB3 mRNA and protein levels are increased by high glucose concentrations, as well as by glucose deprivation in muscle cells. These data identify TRIB3 induction as a novel molecular mechanism in human insulin resistance and diabetes. TRIB3 acts as a nutrient sensor and could mediate the component of insulin resistance attributable to hyperglycemia (i.e., glucose toxicity) in diabetes. |
DOI | 10.1152/ajpendo.00467.2009 |
Alternate Journal | Am. J. Physiol. Endocrinol. Metab. |
PubMed ID | 19996382 |
PubMed Central ID | PMC2838520 |
Grant List | UL1 RR025777 / RR / NCRR NIH HHS / United States DK-62071 / DK / NIDDK NIH HHS / United States HL-055782 / HL / NHLBI NIH HHS / United States P30-DK56336 / DK / NIDDK NIH HHS / United States DK-083562 / DK / NIDDK NIH HHS / United States P60-DK079626 / DK / NIDDK NIH HHS / United States DK-038764 / DK / NIDDK NIH HHS / United States |