d-Allulose Ameliorates Skeletal Muscle Insulin Resistance in High-Fat Diet-Fed Rats

Molecules. 2021 Oct 19;26(20):6310. doi: 10.3390/molecules26206310.


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.

Keywords: d-allulose; glucose uptake; hyperinsulinemic–euglycemic clamp; inflammation; insulin resistance; skeletal muscle; white adipose tissue.

MeSH terms

  • Animals
  • Cytokines / metabolism
  • Diet, High-Fat
  • Fructose / pharmacology*
  • Glucose / metabolism
  • Glucose Tolerance Test / methods
  • Hypoglycemic Agents / pharmacology
  • Inflammation / drug therapy
  • Inflammation / metabolism
  • Insulin / metabolism
  • Insulin Resistance / physiology*
  • Male
  • Muscle, Skeletal / drug effects*
  • Muscle, Skeletal / metabolism
  • Phosphorylation / drug effects
  • Rats
  • Rats, Wistar
  • Signal Transduction / drug effects


  • Cytokines
  • Hypoglycemic Agents
  • Insulin
  • psicose
  • Fructose
  • Glucose