The pathological feature of type 2 diabetes is insulin resistance. In addition to hereditary factor, environmental factors are closely related to the development of insulin resistance. Amino acids are widely known as the basic materials of protein. Recent studies have showed that they are also important signal molecules which can regulate many key signaling pathways in life processes and affect many important physiological activities. Cohort studies have showed the positive correlation between the incidence of obesity and diabetes and the levels of essential amino acids. This correlation was also found by the previous work of Dr. GUO's group which discovered that removing an essential amino acid leucine from the diet can significantly enhance insulin sensitivity.  

These findings provide theoretical basis and novel ideas for understanding the pathogenesis and intervention strategies of diabetes. However, whether the improvement effect of leucine deprivation on insulin resistance can be maintained for long term and the related mechanisms remain unclear. Therefore, Dr. GUO's group developed a novel amino acid (intermittent leucine deprivation) intervention pattern that can improve insulin sensitivity in the long term.          

The researchers found that a short-term (one day) leucine deprivation improved the insulin sensitivity in mice for up to three days. Inspired by the beneficial effects of intermittent fasting on metabolism, they gave mice intermittent leucine deprivation diet for further study. They found that seven cycles of intermittent leucine deprivation (one cycle=one day leucine deprivation+ three days of control diet), enhanced insulin sensitivity on mice at least nearly three months even return to normal diet, by forming metabolic memory.   

Besides, the researchers found that intermittent leucine treatment also significantly improved insulin sensitivity in different insulin resistance models. Further studies showed that the beneficial effects of intermittent leucine deprivation depended on the increase of hepatic GCN2 expression, and the expression of GCN2 relied on the up-regulation of the demethylase Gadd45b to affect the CpG sites of its promoter and then regulate the methylation level of GCN2.     

This study found that intermittent leucine deprivation can improve insulin sensitivity in the long term in an epigenetic manner. It provides important evidence of the formation of the liver metabolic memory and the regulation of amino acid deficient sensor GCN2 at the epigenetic level. It also provides an important theoretical basis for understanding the pathogenesis and treatment of diabetes.