LAUSR

&NA; Excessive glucocorticoid (GC) in type 2 diabetes mellitus (T2DM) reduces insulin sensitivity, impairs &bgr;‐cell function, increases gluconeogenesis and glycogenolysis, impairs glucose uptake and metabolism, and reduces the insulinotropic effects of glucagon‐like peptide 1. Melatonin, which serves as a physiological regulator of the hypothalamic‐pituitary‐adrenal (HPA) axis, has been suggested to have anti‐diabetic effects. The objective of the present study was to investigate the effect of the MT1/MT2 melatonin agonist Neu‐P11 on glucose and lipid metabolism in T2DM rats induced by a high fat diet combined with low doses of streptozotocin. T2DM rats were intragastrically administered melatonin (20 mg/kg), Neu‐P11 (20, 10, 5 mg/kg), or a vehicle for 4 weeks. The results showed that the increased food intake, water consumption, hyperglycemia, glucose intolerance, and insulin resistance in T2DM rats were all improved by Neu‐P11 treatment. Neu‐P11 increased GC receptor expression and suppressed 11&bgr;‐hydroxysteroid dehydrogenase 1 activity in the hippocampus by enhancing GC sensitivity and HPA feedback, thus decreasing the high GC levels. Transcript levels of the glucose metabolism‐related genes peroxisome proliferator‐activated receptor‐&ggr;, glucose transporter type‐4, and adiponectin in adipose tissue were significantly increased after Neu‐P11 treatment, while leptin mRNA was significantly decreased. Furthermore, MT1 and MT2 protein levels were enhanced by Neu‐P11. These data suggest that normalization of the hyperactivated HPA axis by melatonin and Neu‐P11 in T2DM regulates metabolic profiles and insulin sensitivity, which may attenuate insulin resistance and glucose homeostasis. Because Neu‐P11 has superior pharmacokinetics and a longer half‐life than melatonin, it might be beneficial in treating obesity and T2DM.