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

Eiji Yoshihara, Shimpei Fujimoto, Nobuya Inagaki, Katsuya Okawa, So Masaki, Junji Yodoi and Hiroshi Masutani ()
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Eiji Yoshihara: Institute for Virus Research, 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

Nature Communications, 2010, vol. 1, issue 1, 1-12

Abstract: 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.

Date: 2010
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DOI: 10.1038/ncomms1127

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