The Rab-GTPase-activating protein TBC1D1 regulates skeletal muscle glucose metabolism
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The Rab-GTPase-activating protein TBC1D1 regulates skeletal muscle glucose metabolism. / Szekeres, Ferenc; Chadt, Alexandra; Tom, Robby Z; Deshmukh, Atul S; Chibalin, Alexander V; Björnholm, Marie; Al-Hasani, Hadi; Zierath, Juleen R.
In: American Journal of Physiology: Endocrinology and Metabolism, Vol. 303, No. 4, 15.08.2012, p. E524-33.Research output: Contribution to journal › Journal article › Research › peer-review
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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
VL - 303
SP - E524-33
JO - American Journal of Physiology - Endocrinology and Metabolism
JF - American Journal of Physiology - Endocrinology and Metabolism
SN - 0193-1849
IS - 4
ER -
ID: 170597492