期刊
DIABETES
卷 60, 期 3, 页码 746-756出版社
AMER DIABETES ASSOC
DOI: 10.2337/db10-1246
关键词
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资金
- Ministry of Science and Technology of China [2009CB919001, 2010CB912502]
- National Natural Science Foundation [30871208, 30890043]
- Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences [SIBS2008006]
- Science and Technology Commission of Shanghai Municipality [08DJ1400601]
- Clinical Research Center, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences [CRC2010005]
- Key Program of Shanghai Scientific and Technological Innovation Action Plan [10JC1416900]
- CAS-Pfizer [Pfizer-SIBS2 01002]
- Chinese Academy of Sciences
- Shanghai Municipality [08PJ1410700]
OBJECTIVE-We have previously shown that serum insulin levels decrease threefold and blood glucose levels remain normal in mice fed a leucine-deficient diet, suggesting increased insulin sensitivity. The goal of the current study is to investigate this possibility and elucidate the underlying cellular mechanisms. RESEARCH DESIGN AND METHODS-Changes in metabolic parameters and expression of genes and proteins involved in regulation of insulin sensitivity were analyzed in mice, human HepG2 cells, and mouse primary hepatocytes under leucine deprivation. RESULTS-We show that leucine deprivation improves hepatic insulin sensitivity by sequentially activating general control non-derepressible (GCN)2 and decreasing mammalian target of rapamycin/S6K1 signaling. In addition, we show that activation of AMP-activated protein kinase also contributes to leucine deprivation-increased hepatic insulin sensitivity. Finally, we show that leucine deprivation improves insulin sensitivity under insulin-resistant conditions. CONCLUSIONS-This study describes mechanisms underlying increased hepatic insulin sensitivity under leucine deprivation. Furthermore, we demonstrate a novel function for GCN2 in the regulation of insulin sensitivity. These observations provide a rationale for short-term dietary restriction of leucine for the treatment of insulin resistance and associated metabolic diseases. Diabetes 60:746-756, 2011
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