近几年临床研究发现支链氨基酸代谢紊乱与糖尿病的发生发展紧密相关，血清支链氨基酸水平甚至可以预测糖尿病的发生及治疗手段的预后。基础研究则报道了高支链氨基酸具有促进或抑制糖代谢的两种截然不同的效果，原因尚不清楚，据推测与研究对象的肥胖程度有关，对该问题的探索是现在相关领域的热点之一。我们的前期工作显示高支链氨基酸在正常体重小鼠中增强了糖耐受、糖酵解及胰岛素敏感度，并且发现支链氨基酸代谢产物BCKA在这一过程中行使特殊功能。本课题拟在这些研究的基础上，充分利用我们独特的代谢紊乱小鼠模型，探索支链氨基酸在不同营养状态下（肥胖与正常体重）对糖代谢的影响，深入探讨支链氨基酸代谢异常在糖尿病发生发展中的功能及机制，并探索通过改变支链氨基酸摄入和代谢影响糖尿病发生发展的可行性。这些研究不但会丰富支链氨基酸及糖脂代谢的生物学知识，阐明代谢调控的新机制，并且有望为临床预防和治疗糖尿病提供新的理论基础及应用手段

Diabetes is a major public health threat in China and worldwide. Lipid and carbohydrates have been recognized as major players in diabetes and thus studied extensively. However, little is known about the role of amino acids in this disease process. Recently, several clinical studies reported that high plasma level of Branched-Chain Amino Acid (BCAA) was tightly associated with type 2 diabetes and predictive to future insulin resistance. On the other hand, in animals, some studies showed that high level BCAA promoted diabetes while the others showed the opposite effect. The underlying mechanism of this discrepancy remains unclear while the adiposity has been indicated to play a role. Branched chain amino acid (BCAA), including leucine, isoleucine, and valine, are essential amino acids. BCAA’s abundance is tightly controlled by a degradation system consisting of dozens of enzymes. We have identified a protein phosphatase, named PP2Cm, as a key regulator of BCAA catabolism. Genetically ablation of PP2Cm in mice led to defect in BCAA disposal, resulting in elevated level of BCAA and their metabolites branched-chain keto acids (BCKA). Therefore, PP2Cm deficient animal offers us a unique opportunity to investigate the specific role of BCAA/BCKA in insulin resistance. In lean mice, our preliminary study demonstrated an improved glucose tolerance and higher glucose utilization in PP2Cm knockout mice. High BCAA diet also promoted glucose tolerance in lean wildtype mice. Insulin signaling was enhanced in PP2Cm knockout mice with a lower basal mTOR activity which likely released the feedback regulation on insulin signaling. Interestingly, we found that high level BCKA treatment suppressed the respiration in isolated mitochondria but enhanced the glucose utilization in cultured cell. BCKA also could suppress mTOR activity. These data suggested a unique role of BCKA in the metabolic regulation. The hypothesis of this project is that BCAA exerts opposite effect on glucose metabolism in lean and obese animals. The main objective is to elucidate the functional impact of BCAA/BCKA on glucose tolerance and utilization in lean and obese mice and to unravel the underlying mechanism of BCAA/BCKA mediated signaling and impact on energy metabolism. Finally, the potential approaches to treat diabetes by targeting BCAA will be explored. This proposal may clarify certain confusion in this field and uncover a novel and potentially important role for BCAA/BCKA in metabolic regulation. Understanding the mechanisms will help to identify novel therapeutic targets for this major disease.