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

Insulin has been regarded as the central regulator of systemic glucose homeostasis through regulation of hepatic glucose metabolism. Loss of insulin leads to dysregulation of glucose homeostasis in diabetes. Physical activity improves glycemic control in insulin-resistant and insulin-deficient states. However, it remains unclear whether exercise regulates hepatic glucose metabolism independently of insulin signaling. Irisin, an exercise-induced myokine cleaved from fibronectin type III domain-containing 5 (FNDC5), has been implicated in systemic metabolic regulation; however, its role in hepatic glucose metabolism plasticity under insulin-deficient conditions remains unknown. To address this question, we used persistent insulin-deficient Akita mice and found that circulating and hepatic irisin levels were reduced in Akita mice, accompanied by impaired hepatic glucose metabolism. To restore irisin level, adenoviral vectors encoding full-length FNDC5 and secreted form irisin were generated and administered. Notably, the secreted form of irisin was more effective in restoring circulating irisin levels and contributed to improving diabetic phenotypes. Dose- and time-dependent analyses further demonstrated that, upon reaching an effective dose, irisin gene delivery improved diabetic phenotypes for up to 10–12 weeks. Mechanistically, irisin was associated with coordinated changes in hepatic glucose metabolism, including increased expression of glucose uptake–related genes (peroxisome proliferator–activated receptor-γ/GLUT2/GCK), enhanced glycogen synthesis–related signaling (GSK-dependent and GSK-independent pathways), and reduced gluconeogenic activity, accompanied by reduced phosphoenolpyruvate carboxykinase expression and increased AMPK phosphorylation, despite no changes in circulating insulin or glucagon levels. In summary, our findings suggest that irisin may contribute to the regulation of hepatic glucose metabolism under insulin-deficient conditions and represent a potential insulin-independent pathway for improving systemic glucose homeostasis. Article Highlights 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.