d-Allulose Ameliorates Hyperglycemia Through IRE1α Sulfonation-RIDD- Sirt1 Decay Axis in the Skeletal Muscle

The skeletal muscle maintains glucose disposal insulin signaling and glucose transport. The progression of diabetes and insulin resistance is critically influenced by endoplasmic reticulum (ER) stress. d-Allulose, a low-calorie sugar substitute, has shown crucial physiological activities under conditions involving hyperglycemia and insulin resistance. However, the molecular mechanisms of d-allulose in the progression of diabetes have not been fully elucidated. Here, we evaluated the effect of d-allulose on hyperglycemia-associated ER stress responses in human skeletal myoblasts (HSkM) and diabetic and high-fat diet-fed mice. d-allulose effectively controlled glycemic markers such as insulin and hemoglobin A1c (HbA1c), showing anti-diabetic effects by inhibiting the disruption of insulin receptor substrate (IRS)-1 tyrosine phosphorylation and glucose transporter 4 (GLUT4) expression, in which the phosphatidylinositol-3 kinase (PI3K)/protein kinase B (Akt) pathway is involved. The levels of glucose dysmetabolism-based NADPH oxidase, such as NADPH-dependent oxidoreductase (Nox) 4, were highly increased, and their interaction with IRE1α and the resultant sulfonation-regulated IRE1-dependent decay (RIDD)- decay were also highly increased under diabetic conditions, which were controlled with d-allulose treatment. Skeletal muscle cells grown with a high glucose medium supplemented with d-allulose showed controlled IRE1α sulfonation-RIDD- decay, in which Nox4 was involved. The study observations indicate that d-allulose contributes to the muscular glucose disposal in the diabetic state where ER-localized Nox4-induced IRE1α sulfonation results in the decay of , a core factor for controlling glucose metabolism.