MammalianTribbleshomolog 3 impairs insulin action in skeletal muscle: role in glucose-induced insulin resistance

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. glucose toxicity; type 2 diabetes; insulin signaling THE PREVALENCE OF TYPE 2 DIABETES MELLITUS (T2DM) is rapidly increasing in Westernized nations. Although it likely results from both genetic and environment factors, a key pathogenic characteristic of T2DM is insulin resistance, due to impaired stimulation of glucose uptake in skeletal muscle.To obtain a more comprehensive understanding of insulin resistance, we have performed cDNA microarray studies to systematically assess differential gene expression in skeletal muscle from insulin-sensitive (IS) vs. insulin-resistant (IR) humans (59, 60). These analyses identified Tribbles homolog 3 (TRIB3) as a gene with increased expression in patients with T2DM. Tribbles was first identified by Mata et al. (31) in 2000 as a regulator of germ-cell development in Drosophila (31). Tribbles inhibits mitosis and regulates DNA damage repair by promoting ubiquitination and proteasome-mediated degradation of specific cell cycle regulators early in development (17,31,46,49). Mammals express a family of three genes, TRIB1, TRIB2, and TRIB3, that are homologous to Tribbles. These family members are characterized by a variant kinase domain in the center of molecule with a high homology to serine/ threonine kinases (22). However, they app...

Intensive insulin treatment induces insulin resistance in diabetic rats by impairing glucose metabolism-related mechanisms in muscle and liver

“…High doses of insulin induce insulin resistance (Blondel & Portha 1989), and we now show the same effect in alloxan-treated rats. Some metabolic alterations, as observed here, have already been pointed out to contribute to insulin resistance in hypoinsulinemic diabetic rats, such as deficient GLUT4 expression and translocation in skeletal muscle (Liu et al 2010) and increased hepatic glucose output (Blondel & Portha 1989, Burcelin et al 1995. Now, we show in the liver of diabetic rats that: 1) GSK3 activation decreased, contributing to impaired glycogen synthesis and 2) nuclear content of FOXO1 decreased, which concurs with the increased expression of FOXO1-dependent genes, such as Pepck and G6pase, contributing to enhanced gluconeogenesis and glucose outflow.…”

Trib3 Is Elevated in Parkinson's Disease and Mediates Death in Parkinson's Disease Models

“…␣-Synuclein recruited into intracellular synucleinopathy lesions undergoes extensive phosphorylation at Ser129 (Fujiwara et al, 2002). The intracellular accumulation of aggregated ␣-synuclein leads to synaptic dysfunction, impairments in connectivity and excitability, and, ultimately, neuron death (Volpicelli-Daley et al, 2011;Luk et al, 2012). As expected, we found that fibril-treated cultured dopaminergic neurons were positive for phosphorylated, thus pathogenic, ␣-synuclein (P-S129 ␣SYN) inclusions.…”

“…Converging evidence indicates that Trib3 is a pseudokinase with scaffold-like regulatory functions for a number of signaling pathways (Hegedus et al, 2006(Hegedus et al, , 2007. Trib3 is induced by a wide variety of stresses with potential relevance to PD pathophysiology, including metabolic stress (Du et al, 2003;Bi et al, 2008;Carraro et al, 2010;Liu et al, 2010), endoplasmic reticulum stress (Corcoran et al, 2005;Ord and Ord, 2005;Salazar et al, 2009;Zou et al, 2009), oxidative stress (Lange et al, 2008), mitochondrial stress (Ishikawa et al, 2009), and neurotrophic factor deprivation (Mayumi-Matsuda et al, 1999;Kristiansen et al, 2011;Zareen et al, 2013). Both proapoptotic Shang et al, 2009) and antiapoptotic Zhou et al, 2013) actions have been attributed to Trib3.…”

Developmental roles of tribbles protein family members

“…Under starvation conditions, Trib3 is up-regulated in the liver and binds and blocks insulin stimulation of the activity of Akt (PKB), ERK1/2 and IRS1 kinases to spur glucose production (Du et al, 2003;Liu et al, 2010). Complementarily, Trib3 binds and directs ACC to the proteosome to promote lipolysis (Qi et al, 2006).…”