title: Orally efficacious novel small molecule 6-chloro-6-deoxy-1,2,3,4-tetra-O-galloyl-α-D-glucopyranose selectively and potently stimulates insulin receptor and alleviates diabetes.
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 α-penta-galloyl-glucose (α-PGG). Subsequent studies led to the identification of an α-P6GG derivative, 6-chloro-6-deoxy-1,2,3,4-tetra-O-galloyl-α-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 α-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 that 6Cl-TGQ is a potent orally efficacious compound with low carcinogenic potential and may contribute to the prevention and treatment of T1D and T2D.
authors.affiliation: Department of Biological Science, Ohio University, Athens, Ohio, USA.
authors.forename: Yanyan
authors.initials: Y
authors.lastname: Cao
authors.forename: Yunsheng
authors.initials: Y
authors.lastname: Li
authors.forename: Jaekyung
authors.initials: J
authors.lastname: Kim
authors.forename: Yulin
authors.initials: Y
authors.lastname: Ren
authors.forename: Klaus
authors.initials: K
authors.lastname: Himmeldirk
authors.forename: Yi
authors.initials: Y
authors.lastname: Liu
authors.forename: Yanrong
authors.initials: Y
authors.lastname: Qian
authors.forename: Fengming
authors.initials: F
authors.lastname: Liu
authors.forename: Xiaozhuo
authors.initials: X
authors.lastname: Chen
mesh_terms: D017667:Adipocytes / Q000378:metabolism; D000284:Administration, Oral; D000818:Animals; D001786:Blood Glucose; D001835:Body Weight / Q000187:drug effects; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D003847:Deoxyglucose / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy / Q000378:metabolism*; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy / Q000378:metabolism*; D059305:Diet, High-Fat; D004195:Disease Models, Animal; D005947:Glucose / Q000378:metabolism; D018149:Glucose Intolerance / Q000188:drug therapy / Q000378:metabolism; D006801:Humans; D006943:Hyperglycemia / Q000188:drug therapy / Q000378:metabolism; D007004:Hypoglycemic Agents / Q000008:administration & dosage* / Q000737:chemistry / Q000378:metabolism; D007328:Insulin / Q000378:metabolism / Q000494:pharmacology; D008024:Ligands; D008297:Male; D051379:Mice; D011485:Protein Binding; D011972:Receptor, Insulin / Q000819:agonists / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors
chemical_list: C585459:6-chloro-6-deoxy-1,2,3,4-tetra-O-galloylglucopyranose; D001786:Blood Glucose; D007004:Hypoglycemic Agents; D007328:Insulin; D008024:Ligands; D003847:Deoxyglucose; D011972:Receptor, Insulin; D005947:Glucose
keywords: 6Cl-TGQ; Akt; Glut4 translocation; IGF1R; IR; diabetes; polyphenol