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Disruption of TBP-2 ameliorates insulin sensitivity and secretion without affecting obesity

Author

Listed:
  • Eiji Yoshihara

    (Institute for Virus Research, Kyoto University
    Graduate School of Biostudies, Kyoto University)

  • Shimpei Fujimoto

    (Faculty of Medicine, Kyoto University)

  • Nobuya Inagaki

    (Faculty of Medicine, Kyoto University)

  • Katsuya Okawa

    (Drug Discovery Research Laboratories, Kyowa Hakko Kirin Co. Ltd)

  • So Masaki

    (Institute for Virus Research, Kyoto University)

  • Junji Yodoi

    (Institute for Virus Research, Kyoto University)

  • Hiroshi Masutani

    (Institute for Virus Research, Kyoto University)

Abstract

Type 2 diabetes mellitus (T2DM) is characterized by defects in both insulin sensitivity and glucose-stimulated insulin secretion (GSIS) and is often accompanied by obesity. In this study, we show that disruption of thioredoxin binding protein-2 (TBP-2, also called Txnip) in obese mice (ob/ob) dramatically improves hyperglycaemia and glucose intolerance, without affecting obesity or adipocytokine concentrations. TBP-2-deficient ob/ob mice exhibited enhanced insulin sensitivity with activated insulin receptor substrate-1/Akt signalling in skeletal muscle and GSIS in islets compared with ob/ob mice. The elevation of uncoupling protein-2 (UCP-2) expression in ob/ob islets was downregulated by TBP-2 deficiency. TBP-2 overexpression suppressed glucose-induced adenosine triphosphate production, Ca2+ influx and GSIS. In β-cells, TBP-2 enhanced the expression level and transcriptional activity of UCP-2 by recruitment of peroxisome proliferator-activated receptor-γ co-activator-1α to the UCP-2 promoter. Thus, TBP-2 is a key regulatory molecule of both insulin sensitivity and GSIS in diabetes, raising the possibility that inhibition of TBP-2 may be a novel therapeutic approach for T2DM.

Suggested Citation

  • Eiji Yoshihara & Shimpei Fujimoto & Nobuya Inagaki & Katsuya Okawa & So Masaki & Junji Yodoi & Hiroshi Masutani, 2010. "Disruption of TBP-2 ameliorates insulin sensitivity and secretion without affecting obesity," Nature Communications, Nature, vol. 1(1), pages 1-12, December.
    • Handle: RePEc:nat:natcom:v:1:y:2010:i:1:d:10.1038_ncomms1127
    DOI: 10.1038/ncomms1127
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    Cited by:

    1. Liu Wang & Jie Wu & Madeline Sramek & S. M. Bukola Obayomi & Peidong Gao & Yan Li & Aleksey V. Matveyenko & Zong Wei, 2024. "Heterogeneous enhancer states orchestrate β cell responses to metabolic stress," Nature Communications, Nature, vol. 15(1), pages 1-19, December.

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