title: Antidiabetic Effect of Salvianolic Acid A on Diabetic Animal Models via AMPK Activation and Mitochondrial Regulation.
abstract: OBJECTIVE
  Diabetes mellitus (DM) characterized by hyperglycemia contributes to macrovascular and microvascular complications. Salvianolic acid A (SalA) is a polyphenolic compound isolated from the root of Salvia miltiorrhiza Bunge, which is a traditional Chinese medicine widely used to treat cardiovascular diseases. However, little is known about its antidiabetic effect. Our study aimed to investigate the in vivo and in vitro antidiabetic effect of SalA and the underlying mechanisms.
  
  
  METHODS
  Alloxan-induced type 1 diabetic mice and high-fat diet (HFD) and low-dose streptozotocin (STZ)-induced type 2 diabetic rats received SalA treatment. Blood glucose, oral glucose tolerance test (OGTT), 24-h food and water intake were monitored. In vitro, glucose consumption and uptake were measured in HepG2 cells and L6 myotubes. Mitochondrial function was detected in hepatic and skeletal muscle mitochondria. AMP-activated protein kinase (AMPK) and Akt were analyzed by western blot.
  
  
  RESULTS
  In both type 1 and type 2 diabetic animals, SalA lowered fasting blood glucose (FBG) and fed blood glucose in dose-dependent manner, as well as reduced 24-h food and water intake. In vitro, SalA caused dose-dependent increase in glucose consumption and enhanced glucose uptake. SalA significantly increased ATP production from 10 min to 12 h in HepG2 cells and L6 myotubes. Interestingly, SalA decreased mitochondrial membrane potential (MMP) in HepG2 cells. Furthermore, SalA improved hepatic and skeletal muscle mitochondrial function, increased ATP production, and concurrently decreased MMP. In particularly, SalA activated AMPK phosphorylation through Ca(2+)/calmodulin-dependent protein kinase kinase β (CaMKKβ)/AMPK signaling pathway, independent of liver kinase 1 (LKB1)/AMPK pathway. However, SalA didn't show any effect on insulin secretagogue and activation of PI3K/Akt signaling pathway.
  
  
  CONCLUSIONS
  SalA exhibits the antidiabetic effects in diabetic animal models through improving mitochondrial function, increasing ATP production, and decreasing MMP via CaMKKβ/AMPK signaling pathway.
authors.affiliation: Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
authors.forename: Guifen
authors.initials: G
authors.lastname: Qiang
authors.forename: Xiuying
authors.initials: X
authors.lastname: Yang
authors.forename: Lili
authors.initials: L
authors.lastname: Shi
authors.forename: Hengai
authors.initials: H
authors.lastname: Zhang
authors.forename: Bainian
authors.initials: B
authors.lastname: Chen
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhao
authors.forename: Mian
authors.initials: M
authors.lastname: Zu
authors.forename: Dan
authors.initials: D
authors.lastname: Zhou
authors.forename: Jing
authors.initials: J
authors.lastname: Guo
authors.forename: Haiguang
authors.initials: H
authors.lastname: Yang
authors.forename: Li
authors.initials: L
authors.lastname: Zhang
authors.forename: Guanhua
authors.initials: G
authors.lastname: Du
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000475:Alkenes / Q000008:administration & dosage* / Q000494:pharmacology; D000496:Alloxan; D000818:Animals; D001786:Blood Glucose / Q000187:drug effects; D002460:Cell Line; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy* / Q000378:metabolism; D059305:Diet, High-Fat; D004435:Eating / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects; D056945:Hep G2 Cells; D006801:Humans; D007004:Hypoglycemic Agents / Q000008:administration & dosage* / Q000494:pharmacology; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D051379:Mice; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D059808:Polyphenols / Q000008:administration & dosage* / Q000494:pharmacology; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects; D013311:Streptozocin
chemical_list: D000475:Alkenes; D001786:Blood Glucose; D007004:Hypoglycemic Agents; D059808:Polyphenols; C568740:salvianolic acid; D013311:Streptozocin; D000496:Alloxan; D055372:AMP-Activated Protein Kinases