title: X-3, a mangiferin derivative, stimulates AMP-activated protein kinase and reduces hyperglycemia and obesity in db/db mice.
abstract: Diabetes mellitus is a major health concern, affecting nearly 10% of the population. Here we describe a potential novel therapeutic agent for this disease, X-3, a derivative of mangiferin. Therapeutic administration of X-3 significantly and dose-dependently reduced plasma glucose and triglycerides in db/db mice following 8 week-treatments. Treatment with X-3 dose-dependently increased the number of insulin-positive β-cell mass. Importantly, X-3 did not cause any death or signs of toxicity in acute toxicity studies. Study of mechanism of action revealed that X-3 increased glucose uptake in parallel with increased phosphorylation of AMP-activated protein kinase (AMPK) in 3T3-L1 cells. It activates AMPK in both LKB1-dependent and -independent manner. Furthermore, administration of X-3 resulted in activation of AMPK and its downstream target, acetyl-CoA carboxylase (ACC) in the hypothalamus, liver, muscle and adipose tissues of C57BL/6 mice. An 80 mg/kg X-3 was more potent than metformin at 500 mg/kg in the hypothalamus, and interscapular fat tissues, potent than MF at the same dose in the liver. Thus, we conclude that X-3 is a promising new class of AMPK activating drug, and can potentially be used in the treatment of type 2 diabetes.
authors: Department of Gastroenterology, Changzheng Hospital, Second Military Medical University, Shanghai, China.
authors: Jun
authors: J
authors: Han
authors: Department of Pharmacy, Changzheng Hospital, Second Military Medical University, Shanghai, China.
authors: Jia
authors: J
authors: Yi
authors: Department of Pharmacy, Changzheng Hospital, Second Military Medical University, Shanghai, China.
authors: Fengying
authors: F
authors: Liang
authors: Department of Pharmacy, Changzheng Hospital, Second Military Medical University, Shanghai, China.
authors: Bo
authors: B
authors: Jiang
authors: Department of Pharmacy, Changzheng Hospital, Second Military Medical University, Shanghai, China.
authors: Ying
authors: Y
authors: Xiao
authors: Department of Pharmacy, Changzheng Hospital, Second Military Medical University, Shanghai, China.
authors: Shouhong
authors: S
authors: Gao
authors: Department of Pharmacy, Changzheng Hospital, Second Military Medical University, Shanghai, China.
authors: Na
authors: N
authors: Yang
authors: Department of Organic Chemistry, School of Pharmacy, Second Military Medical University, Shanghai, China.
authors: Honggang
authors: H
authors: Hu
authors: Department of Gastroenterology, Changzheng Hospital, Second Military Medical University, Shanghai, China.
authors: Wei-Fen
authors: WF
authors: Xie
authors: Department of Pharmacy, Changzheng Hospital, Second Military Medical University, Shanghai, China. Electronic address: wschen126@126.com.
authors: Wansheng
authors: W
authors: Chen
mesh_terms: D041721:3T3-L1 Cells; D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D000818:Animals; D019440:Anti-Obesity Agents / Q000494:pharmacology* / Q000627:therapeutic use; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy / Q000201:enzymology; D004353:Drug Evaluation, Preclinical; D005260:Female; D006943:Hyperglycemia / Q000188:drug therapy* / Q000201:enzymology; D007004:Hypoglycemic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D050417:Insulin-Secreting Cells / Q000187:drug effects; D007928:Lethal Dose 50; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D009765:Obesity / Q000188:drug therapy* / Q000201:enzymology; D009928:Organ Specificity; D011422:Propionates / Q000494:pharmacology* / Q000627:therapeutic use; D044004:Xanthones / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D019440:Anti-Obesity Agents; D007004:Hypoglycemic Agents; D011422:Propionates; C000603589:X-3 xanthone compound; D044004:Xanthones; D055372:AMP-Activated Protein Kinases
keywords: AMP-activated protein kinase; Animal experiment; Anti-diabetic; Compounds