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

Abstract

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.