Irisin Gene Delivery Elicits Sustained Amelioration of Diabetes in Akita Mice via Insulin-Independent Regulation of Hepatic Glucose Metabolism.

Lu, Wen-Bin; Huang, Yi-Shan; Wu, Jian-Ching; Chen, Lee-Wei; Lin, I-Wen; Chen, Pei-Chin; Chen, Po-Han; Huang, Cheng-Yi et al. · Diabetes · 2026

basic_science · Level V

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Abstract

The exercise-induced hormone irisin plays an important role in the regulation of glucose homeostasis; however, its underlying mechanisms under insulin-deficient conditions remain unclear. We investigated whether irisin can directly regulate hepatic glucose metabolism and manage diabetic phenotypes in insulin-deficient Akita mice. Irisin improved diabetic phenotypes and was associated with enhanced glucose uptake (peroxisome proliferator-activated receptor-γ/GLUT2/GCK axis), increased glycogen storage (GSK-3β-dependent and GSK-3β-independent pathways), and reduced gluconeogenic activity, accompanied by increased AMPK phosphorylation independently of increases in insulin levels. These findings identify irisin as an insulin-independent regulator in hepatic glucose metabolism and suggest a potential therapeutic strategy for insulin-deficient diabetes.