Orally efficacious novel small molecule 6-chloro-6-deoxy-1,2,3,4- tetra-O-galloyl-a-D-glucopyranose selectively and potently stimulates insulin receptor and alleviates diabetes Yanyan Cao 1,3,4 , Yunsheng Li 3 , Jaekyung Kim 3 , Yulin Ren 3 , Klaus Himmeldirk 2 , Yi Liu 1,3,4 , Yanrong Qian 2,3,4 , Fengming Liu 1,3,4 and Xiaozhuo Chen 1,2,3,4,5 Departments of 1 Biological Science, 2 Chemistry and Biochemistry, 3 Edison Biotechnology Institute, 109 Konneker Research Laboratories, 4 Molecular and Cellular Biology Program, 5 Department of Biomedical Science, Ohio University, Athens, Ohio, USA (Y Cao is now at Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, New York 10461, USA) (Y Ren is now at Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University, 500 West 12th Avenue, Columbus, Ohio 43210, USA) (Y Liu is now at The Methodist Hospital Research Institute, Cancer COE, Houston, Texas 77030, USA) Correspondence should be addressed to X Chen Email chenx@ohio.edu Abstract Type 2 diabetes (T2D) has become an epidemic worldwide while T1D remains a great medical challenge. Insulin receptor (IR) signaling activators could alleviate hyperglycemia, reduce the burden on the pancreas, and contribute to prevention and treatment of both types of diabetes. Previously, we reported the synthesis and identification of a natural antidiabetic compound a-penta-galloyl-glucose (a-PGG). Subsequent studies led to the identification of an a-P6GG derivative, 6-chloro-6-deoxy-1,2,3,4-tetra-O-galloyl- a-D-glucopyranose (6Cl-TGQ). Here, we report that 6Cl-TGQ not only induced rapid and long-lasting glucose uptake comparable to insulin in adipocytes but also reduced high blood glucose levels to near normal and significantly decreased plasma insulin levels and improved glucose tolerance performance in high-fat diet-induced T2D mice when administered orally at 5 mg/kg once every other day. Moreover, a single gavage of 6Cl-TGQ at 10 mg/kg induced rapid and sharp decline of blood glucose in streptozotocin- induced T1D mice. Our studies further indicated that 6Cl-TGQ activated IR signaling in cell models and insulin-responsive tissues of mice. 6Cl-TGQ-induced Akt phosphorylation was completely blocked by IR and PI3K inhibitors, while the induced glucose uptake was blocked by the same compounds and a Glut4 inhibitor. Receptor binding studies indicated that 6Cl-TGQ bound to IR with a higher affinity than a-PGG. Importantly, 6Cl-TGQ, unlike insulin, selectively induced phosphorylation of IR without activating IGF1R or its signaling and did not increase cancer cell proliferation. These results indicate Key Words " polyphenol " 6Cl-TGQ " IR " Akt " Glut4 translocation " IGF1R " diabetes Journal of Molecular Endocrinology Research Y CAO and others TGQ selectively activates IR to alleviate diabetes 51 :1 15–26 http://jme.endocrinology-journals.org Ñ 2013 Society for Endocrinology DOI: 10.1530/JME-12-0171 Printed in Great Britain Published by Bioscientifica Ltd.