title: Novel anti-diabetic effect of SCM-198 via inhibiting the hepatic NF-κB pathway in db/db mice.
abstract: There are reports of early evidence that suggest the involvement of chronic low-grade inflammation in the pathogenesis of Type 2 diabetes. Thus, substances that have effects in reducing inflammation could be potential drugs for Type 2 diabetes. Leonurine (4-guanidino-n-butyl syringate; SCM-198) is an alkaloid in HL (Herba leonuri), which was reported to possess anti-inflammatory properties. We hypothesize that SCM-198 may have beneficial effects on Type 2 diabetes. In the present study, we attempted to test this hypothesis by evaluating the anti-diabetic effect of SCM-198 and the possible underlying mechanisms of its effects in db/db mice. SCM-198 (50, 100 and 200 mg/kg of body weight), pioglitazone (50 mg/kg of body weight, as a positive control) or 1% CMC-Na (sodium carboxymethylcellulose) were administered to the db/db or db/m mice once daily for 3 weeks. After 3 weeks, SCM-198 (200 mg/kg of body weight) treatment significantly reduced the fasting blood glucose level and increased the plasma insulin concentration in the db/db mice, meanwhile it significantly lowered the plasma TAG (triacylglycerol) concentration and increased the HDL (high-density lipoprotein)-cholesterol concentration. Moreover, the dysregulated transcription of the hepatic glucose metabolic enzymes, including GK (glucokinase), G6Pase (glucose-6-phosphatase) and PEPCK (phosphoenolpyruvate carboxykinase), was recovered by an Akt-dependent pathway. The pro-inflammatory mediators {such as TNFα (tumour necrosis factor α), IL (interleukin)-6, IL-1β, degradation of IκB [inhibitor of NF-κB (nuclear factor-κB)] α and thereafter activation of NF-κB} were reversed by SCM-198 treatment in the db/db mice. The present study provides first evidence that SCM-198 exhibits anti-inflammatory activity and has an ameliorating effect on diabetic symptoms via inhibiting of NF-κB/IKK (IκB kinase) pathway. Consequently, we suggest that SCM-198 may be a prospective agent for prevention and/or moderation of the progress of Type 2 diabetes.
authors.affiliation: Department of Pharmacology, School of Pharmacy and Institute of Biomedical Sciences, Fudan University, Shanghai Chempartner Co. Ltd, Shanghai 201203, People's Republic of China.
authors.forename: Hui
authors.initials: H
authors.lastname: Huang
authors.forename: Hong
authors.initials: H
authors.lastname: Xin
authors.forename: Xinhua
authors.initials: X
authors.lastname: Liu
authors.forename: Yajun
authors.initials: Y
authors.lastname: Xu
authors.forename: Danyi
authors.initials: D
authors.lastname: Wen
authors.forename: Yahua
authors.initials: Y
authors.lastname: Zhang
authors.forename: Yi Zhun
authors.initials: YZ
authors.lastname: Zhu
mesh_terms: D052436:Adipose Tissue, White / Q000187:drug effects; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D001786:Blood Glucose / Q000378:metabolism; D001835:Body Weight / Q000187:drug effects; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism; D005707:Gallic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D018836:Inflammation Mediators / Q000276:immunology; D031332:Leonurus / Q000737:chemistry*; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000276:immunology
chemical_list: D000893:Anti-Inflammatory Agents; D001786:Blood Glucose; D007004:Hypoglycemic Agents; D018836:Inflammation Mediators; D016328:NF-kappa B; C013587:leonurine; D005707:Gallic Acid