The Rab-GTPase-activating protein TBC1D1 regulates skeletal muscle glucose metabolism

Abstract

The Rab-GTPase-activating protein TBC1D1 has emerged as a novel candidate involved in metabolic regulation. Our aim was to determine whether TBC1D1 is involved in insulin as well as energy-sensing signals controlling skeletal muscle metabolism. TBC1D1-deficient congenic B6.SJL-Nob1.10 (Nob1.10(SJL)) and wild-type littermates were studied. Glucose and insulin tolerance, glucose utilization, hepatic glucose production, and tissue-specific insulin-mediated glucose uptake were determined. The effect of insulin, AICAR, or contraction on glucose transport was studied in isolated skeletal muscle. Glucose and insulin tolerance tests were normal in TBC1D1-deficient Nob1.10(SJL) mice, yet the 4-h-fasted insulin concentration was increased. Insulin-stimulated peripheral glucose utilization during a euglycemic hyperinsulinemic clamp was similar between genotypes, whereas the suppression of hepatic glucose production was increased in TBC1D1-deficient mice. In isolated extensor digitorum longus (EDL) but not soleus muscle, glucose transport in response to insulin, AICAR, or contraction was impaired by TBC1D1 deficiency. The reduction in glucose transport in EDL muscle from TBC1D1-deficient Nob1.10(SJL) mice may be explained partly by a 50% reduction in GLUT4 protein, since proximal signaling at the level of Akt, AMPK, and acetyl-CoA carboxylase (ACC) was unaltered. Paradoxically, in vivo insulin-stimulated 2-deoxyglucose uptake was increased in EDL and tibialis anterior muscle from TBC1D1-deficient mice. In conclusion, TBC1D1 plays a role in regulation of glucose metabolism in skeletal muscle. Moreover, functional TBC1D1 is required for AICAR- or contraction-induced metabolic responses, implicating a role in energy-sensing signals.

Deletion of Both Rab-GTPase–Activating Proteins TBC1D1 and TBC1D4 in Mice Eliminates Insulin- and AICAR-Stimulated Glucose Transport

“…Previous studies of isolated L6 muscle cells and 3L3-L1 adipocytes demonstrated that ablation of either Tbc1d1 or Tbc1d4, or overexpression of mutated proteins, resulted in reduced insulin-stimulated translocation of GLUT4 (20)(21)(22). However, knockout mice lacking either Tbc1d1 (15,23) or Tbc1d4 (14,24) displayed only tissue-specific impairments of insulin-stimulated glucose uptake and rather minor alterations in glycemic control, indicating a substantial level of redundant expression and signaling.…”

“…In humans, mutations in TBC1D4 (R3633) and TBC1D1 (R125W) have been linked to severe postprandial hyperinsulinemia and obesity, respectively (11)(12)(13). TBC1D4 is found mainly in the heart, adipose tissue, and oxidative muscle fibers, whereas TBC1D1 is predominantly expressed in glycolytic skeletal muscle and is nearly absent from fat tissue (10,14,15). Both TBC1D1 and TBC1D4 display a similar domain architecture that includes two N-terminal phosphotyrosine-binding domains and a Rab-GTPaseactivating (GAP) domain.…”

The RabGAP TBC1D1 Plays a Central Role in Exercise-Regulated Glucose Metabolism in Skeletal Muscle

“…These mice show no change in body weight or reduced body weight; reduced glucose uptake into isolated white muscle in response to various agonists, including insulin, contraction, or AICAR, an AMPK agonist; and increased fatty acid oxidation at the whole-body level and in muscle. In general, no defect in whole-body insulinmediated glucose metabolism was found (22)(23)(24)(25).…”

“…Several mouse models with reduced TBC1D1 expression have been described, including a congenic model that contains a locus from the Swiss Jim Lambert strain, and a gene trap knockout (22)(23)(24)(25). These mice show no change in body weight or reduced body weight; reduced glucose uptake into isolated white muscle in response to various agonists, including insulin, contraction, or AICAR, an AMPK agonist; and increased fatty acid oxidation at the whole-body level and in muscle.…”

General aspects of muscle glucose uptake

“…TBC1D1 in regulation of glucose metabolism in skeletal muscle in response to contraction and insulin stimuli , Pehmoller et al 2009, Szekeres et al 2012). …”