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Chinese Researchers Made a Series of Progress in Nutritional Intervention for Diabetes Mellitus

Calorie restriction (CR) has been commonly recognized as the best means to improve metabolic health and extend lifespan. However, it is difficult to carry on continuous CR in practice. Therefore, the concept of intermittent CR has been proposed in recent years, that is, to reduce calorie intake for a short period of time and then restore normal diet.

To investigate whether intermittent CR can effectively prevent the progression of diabetes, Prof. CHEN Yan’s group from Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences, conducted a series of studies and published the articles entitled “Intermittent administration of a fasting-mimicking diet intervenes in diabetes progression, restores β cells and reconstructs gut microbiota in mice”, “Intermittent administration of a leucine-deprived diet is able to intervene in type 2 diabetes in db/db mice” and “Gut microbiota mediates the anti-obesity effect of calorie restriction in mice” in Nutrition & Metabolism, Heliyon, and Scientific Reports, respectively.

Under the guidance of Prof. CHEN Yan, PhD students WEI Siying et al. used db/db mice as a model of type 2 diabetes mellitus to analyze the effect of intermittent CR on prevention of diabetes. This study used a "fasting-mimicking diet" (FMD) to intermittently limit calorie intake in mice. FMD is a low-carbohydrate, low-protein, and high-fiber food rich in a variety of plant ingredients. The mice were fed low-calorie FMD for one week (30% of the calorie intake of the control group), and then resumed normal chow for one week. The program was lasted for eight weeks. It was found that intermittent administration of the FMD significantly reduced fasting blood glucose, improved glucose tolerance and insulin sensitivity, increased the number of insulin-secreting beta cells in islets, and increased the expression of Ngn3, a marker of stem cells in beta cells, suggesting that FMD can effectively interfere with the progression of type 2 diabetes. The study also found that the gut microbiota of the mice changed significantly after FMD treatment, and some of the changes were associated with the interventional effect of diabetes.

On the basis of this study, PhD students WEI Siying et al. studied another novel strategy of nutritional intervention, i.e., intermittent administration with leucine deficiency diet in mice and normal chow every other day for 8 weeks. It was found that the diabetic progression of db/db mice with intermittent use of leucine-deprived diet was partially improved. Also, the fasting blood glucose was significantly reduced. The number of islet beta cells was increased. In addition, the gut microbiota was greatly changed. These data suggested that intermittent use of leucine-deficient diet also has an effect on the prevention of type 2 diabetes.

PhD students HAN Ruomei et al. in Prof. CHEN Yan’s lab analyzed the interventional effect of the FMD on type 1 diabetes mellitus. Firstly, this study established type 1 diabetes model in mice by injecting a drug (STZ) to destroy islet beta cells. It was found that intermittent use of the FMD could significantly reduce fasting blood glucose and increase the number of islet beta cells, suggesting that intermittent caloric restriction also functioned in preventing type 1 diabetes mellitus.

Gut microbiota has been reported to be associated with the beneficial effects of CR. To investigate the functional role of gut microbiota in CR-mediated metabolic improvement, PhD students WANG Shuo et al. in Prof. CHEN Yan’s lab constructed an antibiotic-induced microbiota-depleted (AIMD) mouse model. Depletion of gut microbiota rendered mice resistant to CR-induced loss of body weight, accompanied by the increase in fasting blood glucose. In addition, CR altered the composition of gut microbiota with significant increases in major probiotic genera such as Lactobacillus and Bifidobacterium, together with the decrease of Helicobacter. To further investigate whether gut microbiota alteration during CR is causally associated with metabolic improvement of the mice, they performed fecal microbiota transplantation (FMT) in diet-induced obesity (DIO) mice. Mice with transferred microbiota from calorie-restricted mice resisted high fat diet-induced obesity and exhibited metabolic improvement such as alleviated hepatic lipid accumulation. This study indicated that CR-induced metabolic improvement especially in body weight reduction is mediated by intestinal microbiota to a certain extent.

This series of work suggests that caloric restriction, especially intermittent caloric restriction or intermittent amino acid restriction, is an effective nutritional intervention for diabetes, and that gut microbiota partially mediates the effect of caloric restriction on the metabolic improvement. These projects were supported by the National Natural Science Foundation, the Ministry of Science and Technology, and the Chinese Academy of Sciences.

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