Oral Administration of the Adiponectin Receptor 1 Agonistic Dipeptide Tyr-Pro Prevents Hyperglycemia in Spontaneously Diabetic Torii Rats

The dipeptide Tyr-Pro, a novel natural agonist of adiponectin receptor 1 (AdipoR1), promotes glucose uptake in skeletal muscle cells. This study investigated the antidiabetic effect of orally administered Tyr-Pro in spontaneously diabetic Torii (SDT) rats. Oral administration of Tyr-Pro (1 mg/kg/day) improved glucose intolerance in SDT rats at 22 weeks of prediabetic age. By 29 weeks of age, fasting blood glucose levels (BGLs) increased to 142 ± 14 mg/dL in the control group, whereas those in the Tyr-Pro group remained within the normal range (80-99 mg/dL), demonstrating a novel antidiabetic effect <i>in vivo</i>. Substantially increased levels of AdipoR1 and <i>p</i>-AMPK/AMPK were observed in the skeletal muscle of Tyr-Pro-administrated SDT rats. The intake of Tyr-Pro also enhanced insulin secretion and inhibited <i>p</i>-IRS-1(Ser) in skeletal muscle. These findings demonstrate that Tyr-Pro prevented the onset of diabetes and improved impaired insulin signaling pathways in SDT rats by inducing AdipoR1-mediated AMPK activation.