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Intermittent Fasting for Long-Lasting Insulin Sensitivity

A pattern of intermittent leucine deprivation can produce long-lasting insulin sensitivity, offering a promising strategy against diabetes.

With Type 2 Diabetes, one’s body is said to have developed insulin resistance and are not able to respond effectively to insulin, the hormone that facilitates the uptake of glucose into our cells. Leucine, an essential amino acid, is found in high levels in obese individuals and have been associated with an increased risk of Type 2 Diabetes and insulin resistance. While past research has shown that leucine deprivation improves insulin sensitivity, the extent of this effect remains to be known.

A recent study led by Dr. Guo Feifan from the Shanghai Institute of Nutrition and Health of the Chinese Academy of Sciences identified a new dietary pattern that a diet with intermittent leucine deprivation could improve insulin sensitivity in the long term by forming a metabolic memory in the liver.

Metabolic memory describes a phenomenon in which the effects of metabolic stimulation are maintained for a prolonged period after stimulation. This is regulated by multiple nutritional status factors. As intermittent fasting, a diet that alternates between fasting and non-fasting, has been shown to improve insulin sensitivity in mammals for an extended period through the formation of metabolic memory, Dr. Guo and colleagues hypothesised that intermittent leucine deprivation might also trigger extended insulin sensitivity through metabolic memory.

With the use of mouse models, the researchers found that a short-term (one day) leucine deprivation improved insulin sensitivity for up to three days. Then, the team carried out a diet-switch experiment consisting of various cycles of intermittent leucine deprivation treatment in wild-type mice, with one cycle comprising of one-day leucine deprivation and three-day control diet. After seven cycles, glucose metabolism (i.e. insulin sensitivity) improved and the effects were observed to remain for nearly three months.

Additionally, the research team found that intermittent leucine treatment also markedly improved insulin sensitivity in different insulin resistance models. Further studies showed that the beneficial effects of intermittent leucine deprivation relied on the increase of hepatic GCN2 expression and this increased expression of GCN2 was facilitated by reducing DNA methylation through the intermittent leucine treatment.

The results of this study had provided valuable insight into understanding the link between leucine deprivation and insulin sensitivity, and provided evidence for liver-specific metabolic memory after treatment and novel epigenetic mechanisms for GCN2 regulation. The team’s work offers potential nutritional intervention strategies that can be used to treat insulin resistance and related diseases. [APBN]

Source: Hanrui et al. (2021). Intermittent leucine deprivation produces long-lasting improvement in insulin sensitivity by increasing hepatic Gcn2 expression. Diabetes.