title: Glucose Uptake Activities of Bis (2, 3-Dibromo-4, 5-Dihydroxybenzyl) Ether, a Novel Marine Natural Product from Red Alga Odonthaliacorymbifera with Protein Tyrosine Phosphatase 1B Inhibition, In Vitro and In Vivo.
abstract: OBJECTIVE
  Protein tyrosine phosphatase 1B (PTP1B) is a novel therapeutic target for type-2 diabetes, which negatively regulates the insulin signaling transduction. Bis (2, 3-dibromo-4, 5-dihydroxybenzyl) ether (BDDE), a novel bromophenol isolated from the Red Alga, is a novel PTP1B inhibitor. But the anti-diabetic effects are not clear. In the present study, we evaluated the in vitro and in vivo antidiabetic effects of BDDE.
  
  
  METHODS
  The insulin-resistant HepG2 cells were used to evaluate the in vitro antidiabetic effects of BDDE. MTT assay was used to determine the safety concentrations in HepG2 cells. Glucose assay kit was used to check glucose uptake after treated with BDDE. Western blotting assay was used to explore the potent mechanisms. The db/db mice were used to evaluate the in vivo antidiabetic effects of BDDE. Body weight, blood glucose, Glycated hemoglobin (HbA1c), lipid profile, and insulin level were checked at the respective time points. Gastrocnemii were dissected and used to analyze the PTP1B and insulin receptor β (IRβ) expression.
  
  
  RESULTS
  BDDE increased the insulin-resisted glucose uptake in HepG2 cells. BDDE also decreased the expression of PTP1B and activated the substrates and downstream signals in insulin signal pathway, such as IRβ, insulin receptor substrate-1/2 (IRS1/2), phosphoinositide 3-kinase (PI3K), and protein kinase B (PKB/Akt). In the db/db mice model, BDDE significantly decreased the blood glucose, HbA1c and triglyceride (TG) levels. BDDE also decreased the expression of PTP1B and activated the phosphorylation of IRβ in gastrocnemii. Moreover, BDDE at high doses downregulated the body weight without affecting food and water intake.
  
  
  CONCLUSIONS
  Our results suggest that BDDE as a new PTP1B inhibitor improves glucose metabolism by stimulating the insulin signaling and could be used in the treatment of type-2 diabetes mellitus.
authors.affiliation: Research and Education Department, The Affiliated Hospital of Qingdao University, Qingdao, China.
authors.forename: Feng
authors.initials: F
authors.lastname: Xu
authors.affiliation: Department of Endocrinology, The Affiliated Hospital of Qingdao University, Qingdao, China.
authors.forename: Fang
authors.initials: F
authors.lastname: Wang
authors.affiliation: Department of Continued Education, The Affiliated Hospital of Qingdao University, Qingdao, China.
authors.forename: Zhenhong
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Department of Endocrinology, The Affiliated Hospital of Qingdao University, Qingdao, China.
authors.forename: Wenshan
authors.initials: W
authors.lastname: Lv
authors.affiliation: Department of Hematology, The Affiliated Hospital of Qingdao University, Qingdao, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Wang
authors.affiliation: Department of Endocrinology, The Affiliated Hospital of Qingdao University, Qingdao, China.
authors.forename: Yangang
authors.initials: Y
authors.lastname: Wang
mesh_terms: D000818:Animals; D002396:Catechols / Q000494:pharmacology*; D004987:Ethers / Q000494:pharmacology*; D005947:Glucose / Q000378:metabolism*; D056945:Hep G2 Cells; D006801:Humans; D066298:In Vitro Techniques; D055504:Insulin Receptor Substrate Proteins / Q000378:metabolism; D007333:Insulin Resistance; D051379:Mice; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D017027:Protein Tyrosine Phosphatases / Q000037:antagonists & inhibitors*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011972:Receptor, Insulin / Q000378:metabolism; D000461:Rhodophyta / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D002396:Catechols; D004987:Ethers; D055504:Insulin Receptor Substrate Proteins; C526295:Irs1 protein, mouse; C000601939:bis(2,3-dibromo-4,5-dihydroxybenzyl) ether; D019869:Phosphatidylinositol 3-Kinases; D011972:Receptor, Insulin; D051057:Proto-Oncogene Proteins c-akt; D017027:Protein Tyrosine Phosphatases; D005947:Glucose