title: Type 2 diabetes mitigation in the diabetic Goto-Kakizaki rat by elevated bile acids following a common-bile-duct surgery.
abstract: OBJECTIVE
  Elevated plasma bile acids after bariatric surgery are thought to explain type 2 diabetes mellitus (T2DM) remission. Bile acids can bind to and activate the nuclear receptor farnesoid-X receptor (FXR) by regulating lipid and glucose metabolism. We performed a surgical procedure (ligation of the common bile duct and external biliary drainage [LBD]) in the diabetic Goto-Kakizaki (GK) rat in order to investigate its effect on bile acids metabolism and T2DM mitigation.
  
  
  METHODS
  LBD surgery and sham control surgery were performed on diabetic GK rats. The concentrations of total bile acids and blood glucose were analyzed by an automatic analyzer. Intraperitoneal glucose tolerance test (IPGTT) and insulin tolerance test (ITT) were used to monitor blood glucose level. Expression of genes involved in bile acid metabolism (FXR, CYP7A, et al.) and glycolipid metabolism (G6Pase, PEPCK, et al) was analyzed using qRT-PCR. The protein levels of pAKT, AKT and pGSK3β were tested by western blot. The morphological alterations of the liver and epididymal fat were monitored by H&E staining.
  
  
  RESULTS
  LBD increased plasma total bile acids, improved hepatic insulin sensitivity, and eventually mitigated T2DM, whereas food intake and body weight were unaltered. Post-LBD, the levels of total bile acids were elevated from 24.80±7.12 to 61.44±6.40 and the concentration of fast blood glucose was decreased from 204.7±11.06mg/dL to 109.3±5.4mg/dL. IPGTT and ITT showed that LBD operation improved insulin sensitivity in GK rats. Clusters of FXR signaling target genes were altered in the liver, such as FXR, CYP7A, G6Pase and PEPCK. These contributed to sustained bile acid homeostasis, and they ameliorated hepatic endoplasmic reticulum (ER) stress, increased energy expenditure, and reduced gluconeogenesis, resulting in a substantial improvement in hepatic insulin sensitivity. LBD also significantly reduced epididymal fat tissue and decreased the size of adipocytes.
  
  
  CONCLUSIONS
  These results demonstrate that the elevated bile acids observed in LBD-operated GK rats link insulin sensitivity improvement to T2DM mitigation, recapitulating the metabolic effects of bariatric surgery. Our investigation establishes a model for a focused study of bile acids in the context of bariatric surgery that may contribute to the identification of therapeutics for T2DM.
authors.affiliation: Department of Orthopedic Surgery, the First Affiliated Hospital, Nanjing Medical University, Nanjing, Jiangsu, China.
authors.forename: Feng
authors.initials: F
authors.lastname: Gao
authors.affiliation: Key Laboratory of Human Functional Genomics of Jiangsu Province, Jiangsu Diabetes Center, Nanjing Medical University, Nanjing, Jiangsu, China.
authors.forename: Xu
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Department of rheumatism, the First Affiliated Hospital, Nanjing Medical University, Nanjing, Jiangsu, China.
authors.forename: Lanlan
authors.initials: L
authors.lastname: Zhou
authors.affiliation: Department of Orthopedic Surgery, the First Affiliated Hospital, Nanjing Medical University, Nanjing, Jiangsu, China.
authors.forename: Shixiang
authors.initials: S
authors.lastname: Zhou
authors.affiliation: Key Laboratory of Human Functional Genomics of Jiangsu Province, Jiangsu Diabetes Center, Nanjing Medical University, Nanjing, Jiangsu, China.
authors.forename: Yue
authors.initials: Y
authors.lastname: Zheng
authors.affiliation: Key Laboratory of Human Functional Genomics of Jiangsu Province, Jiangsu Diabetes Center, Nanjing Medical University, Nanjing, Jiangsu, China.
authors.forename: Jiani
authors.initials: J
authors.lastname: Yu
authors.affiliation: Department of Orthopedic Surgery, the First Affiliated Hospital, Nanjing Medical University, Nanjing, Jiangsu, China.
authors.forename: Weimin
authors.initials: W
authors.lastname: Fan
authors.affiliation: Key Laboratory of Human Functional Genomics of Jiangsu Province, Jiangsu Diabetes Center, Nanjing Medical University, Nanjing, Jiangsu, China. Electronic address: zhuyx@njmu.edu.cn.
authors.forename: Yunxia
authors.initials: Y
authors.lastname: Zhu
authors.affiliation: Key Laboratory of Human Functional Genomics of Jiangsu Province, Jiangsu Diabetes Center, Nanjing Medical University, Nanjing, Jiangsu, China. Electronic address: hanxiao@njmu.edu.cn.
authors.forename: Xiao
authors.initials: X
authors.lastname: Han
mesh_terms: D017667:Adipocytes / Q000473:pathology; D000818:Animals; D001647:Bile Acids and Salts / Q000097:blood*; D001835:Body Weight; D003135:Common Bile Duct / Q000601:surgery*; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000601:surgery*; D007333:Insulin Resistance; D008026:Ligation; D008297:Male; D051381:Rats
chemical_list: D001647:Bile Acids and Salts
keywords: Bile acids; Common bile duct surgery; FXR signaling; Hepatic insulin sensitivity; Type 2 diabetes