d -Allulose, a C-3 epimer of d -fructose, is a rare sugar that has no calories. Although d- allulose has been reported to have several health benefits, such as anti-obesity and anti-diabetic effects, there have been no reports evaluating the effects of d- allulose on insulin resistance using a hyperinsulinemic-euglycemic clamp (HE-clamp). Therefore, we investigated the effects of d- allulose on a high-sucrose diet (HSD)-induced insulin resistance model. Wistar rats were randomly divided into three dietary groups: HSD containing 5% cellulose (HSC), 5% d- allulose (HSA), and a commercial diet. The insulin tolerance test (ITT) and HE-clamp were performed after administration of the diets for 4 and 7 weeks. After 7 weeks, the muscle and adipose tissues of rats were obtained to analyze Akt signaling via western blotting, and plasma adipocytokine levels were measured. ITT revealed that d- allulose ameliorated systemic insulin resistance. Furthermore, the results of the 2-step HE-clamp procedure indicated that d- allulose reversed systemic and muscular insulin resistance. d- Allulose reversed the insulin-induced suppression of Akt phosphorylation in the soleus muscle and epididymal fat tissues and reduced plasma TNF-α levels. This study is the first to show that d- allulose improves systemic and muscle insulin sensitivity in conscious rats.

Background: d-Allulose is a rare sugar with antiobesity and antidiabetic activities. However, its direct effect on insulin sensitivity and the underlying mechanism involved are unknown. Objective: This study aimed to investigate the effect of d-allulose on high-fat diet (HFD)-induced insulin resistance using the hyperinsulinemic–euglycemic (HE)-clamp method and intramuscular signaling analysis. Methods: Wistar rats were randomly divided into three dietary groups: chow diet, HFD with 5% cellulose (HFC), and HFD with 5% d-allulose (HFA). After four weeks of feeding, the insulin tolerance test (ITT), intraperitoneal glucose tolerance test (IPGTT), and HE-clamp study were performed. The levels of plasma leptin, adiponectin, and tumor necrosis factor (TNF)-α were measured using the enzyme-linked immunosorbent assay. We analyzed the levels of cell signaling pathway components in the skeletal muscle using Western blotting. Results: d-allulose alleviated the increase in HFD-induced body weight and visceral fat and reduced the area under the curve as per ITT and IPGTT. d-Allulose increased the glucose infusion rate in the two-step HE-clamp test. Consistently, the insulin-induced phosphorylation of serine 307 in the insulin receptor substrate-1 and Akt and expression of glucose transporter 4 (Glut-4) in the muscle were higher in the HFA group than HFC group. Furthermore, d-allulose decreased plasma TNF-α concentration and insulin-induced phosphorylation of stress-activated protein kinase/Jun N-terminal kinase in the muscle and inhibited adiponectin secretion in HFD-fed rats. Conclusions: d-allulose improved HFD-induced insulin resistance in Wistar rats. The reduction of the proinflammatory cytokine production, amelioration of adiponectin secretion, and increase in insulin signaling and Glut-4 expression in the muscle contributed to this effect.

d-Allulose, a rare sugar, improves glucose metabolism and has been proposed as a candidate calorie restriction mimetic. This study aimed to investigate the effects of d-allulose on aerobic performance and recovery from exhaustion and compared them with the effects of exercise training. Male C57BL/6J mice were subjected to exercise and allowed to run freely on a wheel. Aerobic performance was evaluated using a treadmill. Glucose metabolism was analyzed by an intraperitoneal glucose tolerance test (ipGTT). Skeletal muscle intracellular signaling was analyzed by Western blotting. Four weeks of daily oral administration of 3% d-allulose increased running distance and shortened recovery time as assessed by an endurance test. d-Allulose administration also increased the maximal aerobic speed (MAS), which was observed following treatment for >3 or 7 days. The improved performance was associated with lower blood lactate levels and increased liver glycogen levels. Although d-allulose did not change the overall glucose levels as determined by ipGTT, it decreased plasma insulin levels, indicating enhanced insulin sensitivity. Finally, d-allulose enhanced the phosphorylation of AMP-activated protein kinase and acetyl-CoA carboxylase and the expression of peroxisome proliferator-activated receptor γ coactivator 1α. Our results indicate that d-allulose administration enhances endurance ability, reduces fatigue, and improves insulin sensitivity similarly to exercise training. d-Allulose administration may be a potential treatment option to alleviate obesity and enhance aerobic exercise performance.

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