Yoshihara Eiji, Fujimoto Shimpei, Inagaki Nobuya, Okawa Katsuya, Masaki So, Yodoi Junji, Masutani Hiroshi
1] Department of Biological Responses, Institute for Virus Research, Kyoto University, Kyoto 606-8507, Japan. [2] Division of Systemic Life Science, Graduate School of Biostudies, Kyoto University, Kyoto 606-8501, Japan.
Nat Commun. 2010 Nov 23;1:127. doi: 10.1038/ncomms1127.
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, Ca(2+) 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.
2型糖尿病（T2DM）的特征在于胰岛素敏感性和葡萄糖刺激的胰岛素分泌（GSIS）均存在缺陷，并且常伴有肥胖。在本研究中，我们发现肥胖小鼠（ob/ob）中硫氧还蛋白结合蛋白-2（TBP-2，也称为Txnip）的缺失可显著改善高血糖症和葡萄糖不耐受，而不影响肥胖或脂肪细胞因子浓度。与ob/ob小鼠相比，TBP-2缺陷型ob/ob小鼠在骨骼肌中表现出增强的胰岛素敏感性，胰岛素受体底物-1/Akt信号通路被激活，胰岛中的GSIS也增强。TBP-2缺陷下调了ob/ob胰岛中解偶联蛋白-2（UCP-2）的表达升高。TBP-2过表达抑制了葡萄糖诱导的三磷酸腺苷生成、Ca(2+)内流和GSIS。在β细胞中，TBP-2通过将过氧化物酶体增殖物激活受体-γ共激活因子-1α募集到UCP-2启动子上，增强了UCP-2的表达水平和转录活性。因此，TBP-2是糖尿病中胰岛素敏感性和GSIS的关键调节分子，这增加了抑制TBP-2可能是T2DM的一种新型治疗方法的可能性。
