Aims: The skeletal muscle maintains glucose disposal via 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 db/db diabetic and high-fat diet-fed mice. Results: 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)-Sirt1 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-Sirt1 decay, in which Nox4 was involved. Innovation and Conclusion: 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 Sirt1, a core factor for controlling glucose metabolism. Antioxid. Redox Signal. 37, 229-245.

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