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

Alexandra Chadt, Anja Immisch, Christian De Wendt, Christian Springer, Zhou Zhou, Torben Stermann, Geoffrey D. Holman, Dominique Loffing-cueni, Johannes Loffing, Hans-georg Joost, Hadi Al-hasani

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Abstract

The Rab-GTPase–activating proteins TBC1D1 and TBC1D4 (AS160) were previously shown to regulate GLUT4 translocation in response to activation of AKT and AMP-dependent kinase. However, knockout mice lacking either Tbc1d1 or Tbc1d4 displayed only partially impaired insulin-stimulated glucose uptake in fat and muscle tissue. The aim of this study was to determine the impact of the combined inactivation of Tbc1d1 and Tbc1d4 on glucose metabolism in double-deficient (D1/4KO) mice. D1/4KO mice displayed normal fasting glucose concentrations but had reduced tolerance to intraperitoneally administered glucose, insulin, and AICAR. D1/4KO mice showed reduced respiratory quotient, indicating increased use of lipids as fuel. These mice also consistently showed elevated fatty acid oxidation in isolated skeletal muscle, whereas insulin-stimulated glucose uptake in muscle and adipose cells was almost completely abolished. In skeletal muscle and white adipose tissue, the abundance of GLUT4 protein, but not GLUT4 mRNA, was substantially reduced. Cell surface labeling of GLUTs indicated that RabGAP deficiency impairs retention of GLUT4 in intracellular vesicles in the basal state. Our results show that TBC1D1 and TBC1D4 together play essential roles in insulin-stimulated glucose uptake and substrate preference in skeletal muscle and adipose cells.
Original languageEnglish
Pages (from-to)746-759
Number of pages14
JournalDiabetes
Volume64
Issue number3
Early online date23 Sep 2014
DOIs
Publication statusPublished - Mar 2015

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rab GTP-Binding Proteins
GTPase-Activating Proteins
Insulin
Glucose
Skeletal Muscle
Muscle Cells
Glucose Transporter Type 4
Adenylate Kinase
White Adipose Tissue
Knockout Mice
AICA ribonucleotide
Fasting
Fatty Acids
Fats
Lipids
Muscles
Messenger RNA

Cite this

Chadt, A., Immisch, A., De Wendt, C., Springer, C., Zhou, Z., Stermann, T., ... Al-hasani, H. (2015). Deletion of Both Rab-GTPase–Activating Proteins TBC1D1 and TBC1D4 in Mice Eliminates Insulin- and AICAR-Stimulated Glucose Transport. Diabetes, 64(3), 746-759. https://doi.org/10.2337/db14-0368

Deletion of Both Rab-GTPase–Activating Proteins TBC1D1 and TBC1D4 in Mice Eliminates Insulin- and AICAR-Stimulated Glucose Transport. / Chadt, Alexandra; Immisch, Anja; De Wendt, Christian; Springer, Christian; Zhou, Zhou; Stermann, Torben; Holman, Geoffrey D.; Loffing-cueni, Dominique; Loffing, Johannes; Joost, Hans-georg; Al-hasani, Hadi.

In: Diabetes, Vol. 64, No. 3, 03.2015, p. 746-759.

Research output: Contribution to journalArticle

Chadt, A, Immisch, A, De Wendt, C, Springer, C, Zhou, Z, Stermann, T, Holman, GD, Loffing-cueni, D, Loffing, J, Joost, H & Al-hasani, H 2015, 'Deletion of Both Rab-GTPase–Activating Proteins TBC1D1 and TBC1D4 in Mice Eliminates Insulin- and AICAR-Stimulated Glucose Transport', Diabetes, vol. 64, no. 3, pp. 746-759. https://doi.org/10.2337/db14-0368
Chadt, Alexandra ; Immisch, Anja ; De Wendt, Christian ; Springer, Christian ; Zhou, Zhou ; Stermann, Torben ; Holman, Geoffrey D. ; Loffing-cueni, Dominique ; Loffing, Johannes ; Joost, Hans-georg ; Al-hasani, Hadi. / Deletion of Both Rab-GTPase–Activating Proteins TBC1D1 and TBC1D4 in Mice Eliminates Insulin- and AICAR-Stimulated Glucose Transport. In: Diabetes. 2015 ; Vol. 64, No. 3. pp. 746-759.
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abstract = "The Rab-GTPase–activating proteins TBC1D1 and TBC1D4 (AS160) were previously shown to regulate GLUT4 translocation in response to activation of AKT and AMP-dependent kinase. However, knockout mice lacking either Tbc1d1 or Tbc1d4 displayed only partially impaired insulin-stimulated glucose uptake in fat and muscle tissue. The aim of this study was to determine the impact of the combined inactivation of Tbc1d1 and Tbc1d4 on glucose metabolism in double-deficient (D1/4KO) mice. D1/4KO mice displayed normal fasting glucose concentrations but had reduced tolerance to intraperitoneally administered glucose, insulin, and AICAR. D1/4KO mice showed reduced respiratory quotient, indicating increased use of lipids as fuel. These mice also consistently showed elevated fatty acid oxidation in isolated skeletal muscle, whereas insulin-stimulated glucose uptake in muscle and adipose cells was almost completely abolished. In skeletal muscle and white adipose tissue, the abundance of GLUT4 protein, but not GLUT4 mRNA, was substantially reduced. Cell surface labeling of GLUTs indicated that RabGAP deficiency impairs retention of GLUT4 in intracellular vesicles in the basal state. Our results show that TBC1D1 and TBC1D4 together play essential roles in insulin-stimulated glucose uptake and substrate preference in skeletal muscle and adipose cells.",
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