The RabGAP TBC1D1 plays a central role in exercise-regulated glucose metabolism in skeletal muscle

TY - JOUR

T1 - The RabGAP TBC1D1 plays a central role in exercise-regulated glucose metabolism in skeletal muscle

AU - Stöckli, Jacqueline

AU - Meoli, Christopher C

AU - Hoffman, Nolan J

AU - Fazakerley, Daniel J

AU - Pant, Himani

AU - Cleasby, Mark E

AU - Ma, Xiuquan

AU - Kleinert, Maximilian

AU - Brandon, Amanda E

AU - Lopez, Jamie A

AU - Cooney, Gregory J

AU - James, David E

N1 - CURIS 2015 NEXS 269

PY - 2015/6

Y1 - 2015/6

N2 - Insulin and exercise stimulate glucose uptake into skeletal muscle via different pathways. Both stimuli converge on the translocation of the glucose transporter GLUT4 from intracellular vesicles to the cell surface. Two Rab guanosine triphosphatases-activating proteins (GAPs) have been implicated in this process: AS160 for insulin stimulation and its homolog, TBC1D1, are suggested to regulate exercise-mediated glucose uptake into muscle. TBC1D1 has also been implicated in obesity in humans and mice. We investigated the role of TBC1D1 in glucose metabolism by generating TBC1D1(-/-) mice and analyzing body weight, insulin action, and exercise. TBC1D1(-/-) mice showed normal glucose and insulin tolerance, with no difference in body weight compared with wild-type littermates. GLUT4 protein levels were reduced by ∼40% in white TBC1D1(-/-) muscle, and TBC1D1(-/-) mice showed impaired exercise endurance together with impaired exercise-mediated 2-deoxyglucose uptake into white but not red muscles. These findings indicate that the RabGAP TBC1D1 plays a key role in regulating GLUT4 protein levels and in exercise-mediated glucose uptake in nonoxidative muscle fibers.

AB - Insulin and exercise stimulate glucose uptake into skeletal muscle via different pathways. Both stimuli converge on the translocation of the glucose transporter GLUT4 from intracellular vesicles to the cell surface. Two Rab guanosine triphosphatases-activating proteins (GAPs) have been implicated in this process: AS160 for insulin stimulation and its homolog, TBC1D1, are suggested to regulate exercise-mediated glucose uptake into muscle. TBC1D1 has also been implicated in obesity in humans and mice. We investigated the role of TBC1D1 in glucose metabolism by generating TBC1D1(-/-) mice and analyzing body weight, insulin action, and exercise. TBC1D1(-/-) mice showed normal glucose and insulin tolerance, with no difference in body weight compared with wild-type littermates. GLUT4 protein levels were reduced by ∼40% in white TBC1D1(-/-) muscle, and TBC1D1(-/-) mice showed impaired exercise endurance together with impaired exercise-mediated 2-deoxyglucose uptake into white but not red muscles. These findings indicate that the RabGAP TBC1D1 plays a key role in regulating GLUT4 protein levels and in exercise-mediated glucose uptake in nonoxidative muscle fibers.

U2 - 10.2337/db13-1489

DO - 10.2337/db13-1489

M3 - Journal article

C2 - 25576050

SN - 0012-1797

VL - 64

SP - 1914

EP - 1922

JO - Diabetes

JF - Diabetes

IS - 6

ER -