A new glycotoxin inhibitor mitigates diabetes in genetic mice model

Background: Pathotical implications of glycotoxins are well reported in the diseases such as renal faliure, cardiovascular diseases and diabetes. A variety of organs and tissues are damaged due to abnormal accumulation of advanced glycation end products (AGEs). Existing AGEs inhibitors are not in clinical use and there is a need for development of novel inhibitors. Objectives: The present investigation aimed at identifying the novel AGEs inhibitors and assessing their mechanism of action for treating diabetes in mice. Methods: We synthesized new derivatives of benzylidene of indane 1,3-dione. For in vitro investigations, were performed in human hepatocyts and murine adipocytes. In vivo experiments were carried out in mice model of diabetes. ROS production was assessed by dihydroethidium fluorescence assay. AGEs level in the serum was observed by ELISA. Gene expression was evaluated by RT-PCR. Glucose uptake was measured by fluorescent method. Microscopy was used to analyze function of insulin responsive tissues. Results: Among several derivatives of indanedione, PYIDD-25, demonstrated highest inhibition of AGESs. PYIDD-25 significantly reduced AGEs formation and expression of receptor for advanced glycation end products (RAGE) in fat, liver and muscle tissue of mice. We also observed suppression of AGEs mediated ROS production in human hepatocytes and murine fat cell, after treatment with PYIDD-25. Glycogen synthesis was also increased in muscle tissue of mice treated with PYIDD-25. In adipocytes, PYIDD-25 prevented AGEs induced reduced glucose uptake. Mice treated with PYIDD-25 exhibited increased glucose tolerance, and decreased insulin resistance. Conclusion: We conclude that PYIDD-25 can be a possible treatment target to address glycotoxins induced insulin resistance.