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

TY - JOUR

T1 - The Rab-GTPase-activating protein TBC1D1 regulates skeletal muscle glucose metabolism

AU - Szekeres, Ferenc

AU - Chadt, Alexandra

AU - Tom, Robby Z

AU - Deshmukh, Atul S

AU - Chibalin, Alexander V

AU - Björnholm, Marie

AU - Al-Hasani, Hadi

AU - Zierath, Juleen R

PY - 2012/8/15

Y1 - 2012/8/15

N2 - 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.

AB - 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.

KW - Aminoimidazole Carboxamide

KW - Animals

KW - Biological Transport

KW - Deoxyglucose

KW - Fasting

KW - GTPase-Activating Proteins

KW - Gluconeogenesis

KW - Glucose

KW - Glucose Tolerance Test

KW - Glucose Transporter Type 4

KW - Hypoglycemic Agents

KW - Insulin

KW - Liver

KW - Male

KW - Mice

KW - Muscle Contraction

KW - Muscle, Skeletal

KW - Nuclear Proteins

KW - Ribonucleotides

KW - Signal Transduction

KW - Journal Article

KW - Research Support, Non-U.S. Gov't

U2 - 10.1152/ajpendo.00605.2011

DO - 10.1152/ajpendo.00605.2011

M3 - Journal article

C2 - 22693207

SN - 0193-1849

VL - 303

SP - E524-33

JO - American Journal of Physiology - Endocrinology and Metabolism

JF - American Journal of Physiology - Endocrinology and Metabolism

IS - 4

ER -