title: Andrographolide derivative AL-1 improves insulin resistance through down-regulation of NF-κB signalling pathway.
abstract: OBJECTIVE
  Andrographolide is the most active constituent of the medicinal plant Andrographis paniculata. Previously, we synthesized a novel andrographolide derivative AL-1, conjugating andrographolide with lipoic acid. Although the antioxidative and/or anti-inflammatory activity of AL-1 contributes to its cytoprotective effects, whether AL-1 can improve insulin resistance and the mechanisms responsible for its action have not been elucidated.
  
  
  METHODS
  We investigated the anti-hyperlipidaemic and anti-hyperglycaemic effects of AL-1 in a high-fat diet/streptozocin-induced animal diabetic model. In addition, we investigated the effect of AL-1 on the NF-κB signalling pathway in rat islet derived insulinoma cells (RIN-m cells) with a focus on the link between reactive oxygen species-associated inflammation and insulin resistance.
  
  
  RESULTS
  AL-1, at doses of 40 and 80 mg · kg(-1), had a significant hypoglycaemic effect; it significantly reduced the level of cholesterol and increased HDL. AL-1 also reduced the homeostasis model assessment of insulin resistance and enhanced insulin sensitivity. In addition, AL-1 improved the morphology of pancreatic islets and their function. Furthermore, AL-1 suppressed high glucose-induced phosphorylation of p65 and IκBα in RIN-m cells.
  
  
  CONCLUSIONS
  AL-1 has a hypoglycaemic effect and improves insulin resistance in type 2 diabetic rats. It protected islet from high glucose-induced oxidative damage by down-regulating the NF-κB signalling pathway. Further investigations of AL-1 as a promising new agent for treatment and/or prevention of diabetes are warranted.
authors.affiliation: Institute of New Drug Research and Guangdong Province Key Laboratory of Pharmacodynamic Constituents of Traditional Chinese Medicine, College of Pharmacy, Jinan University, Guangzhou, China.
authors.forename: Yongmei
authors.initials: Y
authors.lastname: Li
authors.affiliation: Institute of New Drug Research and Guangdong Province Key Laboratory of Pharmacodynamic Constituents of Traditional Chinese Medicine, College of Pharmacy, Jinan University, Guangzhou, China.
authors.forename: Hui
authors.initials: H
authors.lastname: Yan
authors.affiliation: Institute of New Drug Research and Guangdong Province Key Laboratory of Pharmacodynamic Constituents of Traditional Chinese Medicine, College of Pharmacy, Jinan University, Guangzhou, China.
authors.forename: Zaijun
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Institute of New Drug Research and Guangdong Province Key Laboratory of Pharmacodynamic Constituents of Traditional Chinese Medicine, College of Pharmacy, Jinan University, Guangzhou, China.
authors.forename: Gaoxiao
authors.initials: G
authors.lastname: Zhang
authors.affiliation: Institute of New Drug Research and Guangdong Province Key Laboratory of Pharmacodynamic Constituents of Traditional Chinese Medicine, College of Pharmacy, Jinan University, Guangzhou, China.
authors.forename: Yewei
authors.initials: Y
authors.lastname: Sun
authors.affiliation: Institute of New Drug Research and Guangdong Province Key Laboratory of Pharmacodynamic Constituents of Traditional Chinese Medicine, College of Pharmacy, Jinan University, Guangzhou, China.
authors.forename: Pei
authors.initials: P
authors.lastname: Yu
authors.affiliation: Institute of New Drug Research and Guangdong Province Key Laboratory of Pharmacodynamic Constituents of Traditional Chinese Medicine, College of Pharmacy, Jinan University, Guangzhou, China.
authors.forename: Yuqiang
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Institute of New Drug Research and Guangdong Province Key Laboratory of Pharmacodynamic Constituents of Traditional Chinese Medicine, College of Pharmacy, Jinan University, Guangzhou, China.
authors.forename: Lipeng
authors.initials: L
authors.lastname: Xu
mesh_terms: D035685:Andrographis / Q000737:chemistry; D000818:Animals; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy / Q000473:pathology; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy / Q000473:pathology; D004224:Diterpenes / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation / Q000187:drug effects*; D007004:Hypoglycemic Agents / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology; D007249:Inflammation / Q000188:drug therapy; D007333:Insulin Resistance; D007340:Insulinoma / Q000378:metabolism; D007515:Islets of Langerhans / Q000378:metabolism; D008297:Male; D016328:NF-kappa B / Q000378:metabolism*; D010190:Pancreatic Neoplasms / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013311:Streptozocin; D008063:Thioctic Acid / Q000737:chemistry
chemical_list: D004224:Diterpenes; D007004:Hypoglycemic Agents; D016328:NF-kappa B; D017382:Reactive Oxygen Species; C030419:andrographolide; D013311:Streptozocin; D008063:Thioctic Acid