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The Rab-GTPase-activating protein TBC1D1 regulates skeletal muscle glucose metabolism
Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
German Institute of Human Nutrition, Potsdam-Rehbruecke, Department of Pharmacology, Nuthetal, Germany.
Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.ORCID iD: 0000-0002-2278-1843
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2012 (English)In: American Journal of Physiology. Endocrinology and Metabolism, ISSN 0193-1849, E-ISSN 1522-1555, Vol. 303, no 4, E524-E533 p.Article in journal (Refereed) Published
Abstract [en]

Szekeres F, Chadt A, Tom RZ, Deshmukh AS, Chibalin AV, Bjornholm M, Al-Hasani H, Zierath JR. The Rab-GTPase-activating protein TBC1D1 regulates skeletal muscle glucose metabolism. Am J Physiol Endocrinol Metab 303: E524-E533, 2012. First published June 12, 2012; doi:10.1152/ajpendo.00605.2011.-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.

Place, publisher, year, edition, pages
2012. Vol. 303, no 4, E524-E533 p.
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Physiology
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URN: urn:nbn:se:his:diva-13783DOI: 10.1152/ajpendo.00605.2011ISI: 000307804200010PubMedID: 22693207Scopus ID: 2-s2.0-84865152468OAI: oai:DiVA.org:his-13783DiVA: diva2:1112174
Available from: 2017-06-20 Created: 2017-06-20 Last updated: 2017-11-27Bibliographically approved

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Szekeres, FerencDeshmukh, Atul S.Chibalin, Alexander V.Zierath, Juleen R.

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Szekeres, FerencDeshmukh, Atul S.Chibalin, Alexander V.Zierath, Juleen R.
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