Intermittent leucine deprivation produces long-lasting improvement in insulin sensitivity by regulating hepatic Gadd45b/GCN2 signals. [Image: Dr. Guo Feifan’s group]

The incidence of type 2 diabetes in China currently exceeds 100 million. The pathological feature of type 2 diabetes is insulin resistance, which, if not controlled in time, will cause a variety of serious complications, including atherosclerosis, neuropathy, retinopathy and so on. Therefore, it is urgent to elucidate its pathogenesis and explore effective intervention methods.

In a study published in Diabetes on November 5, 2021, researchers of Dr. Guo Feifan’s group from the Shanghai Institute of Nutrition and Health (SINH) of the Chinese Academy of Sciences (CAS) found a new dietary pattern — an intermittent leucine deprivation diet was shown to improve insulin sensitivity in the long term by forming the liver’s metabolic memory in an epigenetic pattern.

In addition to hereditary factors, environmental factors, especially nutrition, are closely related to the development of insulin resistance. Amino acids are widely known as the basic materials of protein, but recently more and more studies have found 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 found a positive correlation between the incidence of obesity and diabetes and levels of essential amino acids such as branched amino acids. The previous work of Dr. Guo’s group also found the above correlation in a Shanghai population study. In particular, they discovered that removing the essential amino acid leucine from the diet can significantly enhance insulin sensitivity, and outlined a series of mechanisms.

This research provides an important theoretical basis and novel ideas for understanding the pathogenesis and intervention strategies of diabetes. However, whether the improvement brought about by leucine deprivation on insulin resistance can be maintained over the long term and the related mechanisms remain unclear. Dr. Guo’s group therefore developed a novel amino acid (intermittent leucine deprivation) intervention pattern that can improve insulin sensitivity for long periods.

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, researchers gave mice an 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), formed metabolic memory in mice and enhanced their insulin sensitivity for at least nearly three months even after a return to normal diet.

More importantly, intermittent leucine treatment also significantly improved insulin sensitivity in different insulin resistance models. Further studies showed that the beneficial effects of intermittent leucine deprivation depend on the increase of hepatic GCN2 expression. The expression of GCN2 relies on the up-regulation of the demethylase Gadd45b to affect the CpG sites of its promoter followed by regulation of the methylation level of GCN2.

In conclusion, this study found that intermittent leucine deprivation can improve insulin sensitivity in the long term in an epigenetic manner. In addition, this work also provides important evidence of the formation of the liver metabolic memory and the regulation of amino acid deficient sensor GCN2 at the epigenetic level. The study provides an important theoretical basis for understanding the pathogenesis and treatment of diabetes, and also provides a new idea for nutrition intervention for diabetes.

Professor Guo Feifan from CAS’s SINH, Professor Li Yiming from Huashan Hospital of Fudan University, and Professor Hu Cheng from Shanghai Jiao Tong University Affiliated Sixth People’s Hospital are the corresponding authors of this paper. Yin Hanrui, PhD at CAS’s SINH, is the first author of the paper. This research was funded by the National Key R&D Program of China, the National Natural Science Foundation of China, the Shanghai Leading Talent Program, and the Novo Nordisk-Chinese Academy of Sciences Research Fund.

For more information, please contact:

Ms. Wang Jin

E-mail: sibssc@sibs.ac.cn

Shanghai Institute of Nutrition and Health (SINH),

Chinese Academy of Sciences

Source: Shanghai Institute of Nutrition and Health (SINH),

Chinese Academy of Sciences