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.

Material/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.

Conclusion: 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.

Keywords: Bile acids; Common bile duct surgery; FXR signaling; Hepatic insulin sensitivity; Type 2 diabetes.