Inhibition of Intestinal Bile Acid Transporter Slc10a2 Improves Triglyceride Metabolism and Normalizes Elevated Plasma Glucose Levels in Mice

Interruption of the enterohepatic circulation of bile acids increases cholesterol catabolism, thereby stimulating hepatic cholesterol synthesis from acetate. We hypothesized that such treatment should lower the hepatic acetate pool which may alter triglyceride and glucose metabolism. We explored this using mice deficient of the ileal sodium-dependent BA transporter (Slc10a2) and ob/ob mice treated with a specific inhibitor of Slc10a2. Plasma TG levels were reduced in Slc10a2-deficient mice, and when challenged with a sucrose-rich diet, they displayed a reduced response in hepatic TG production as observed from the mRNA levels of several key enzymes in fatty acid synthesis. This effect was paralleled by a diminished induction of mature sterol regulatory element-binding protein 1c (Srebp1c). Unexpectedly, the SR-diet induced intestinal fibroblast growth factor (FGF) 15 mRNA and normalized bile acid synthesis in Slc10a2−/− mice. Pharmacologic inhibition of Slc10a2 in diabetic ob/ob mice reduced serum glucose, insulin and TGs, as well as hepatic mRNA levels of Srebp1c and its target genes. These responses are contrary to those reported following treatment of mice with a bile acid binding resin. Moreover, when key metabolic signal transduction pathways in the liver were investigated, those of Mek1/2 - Erk1/2 and Akt were blunted after treatment of ob/ob mice with the Slc10a2 inhibitor. It is concluded that abrogation of Slc10a2 reduces hepatic Srebp1c activity and serum TGs, and in the diabetic ob/ob model it also reduces glucose and insulin levels. Hence, targeting of Slc10a2 may be a promising strategy to treat hypertriglyceridemia and diabetes

Complications to thyroid surgery: results as reported in a database from a multicenter audit comprising 3,660 patients

BACKGROUND AND AIM: During recent years, more radical surgery for thyroid disease, i.e., total instead of subtotal resection, has been evident. Results following this strategy on national levels are scarce. MATERIALS AND METHODS: From 2004 to 2006, 26 Scandinavian Departments registered 3,660 thyroid operations in a database. Risk factors for complications were analyzed with multiple logistic regression. RESULTS: After thyroidectomy, re-bleeding occurred in 2.1% and was associated with older age (OR 1.04; p < 0.0001) and male gender (OR 1.90; p = 0.014). Postoperative infection occurred in 1.6% and associated with lymph node operation (OR 8.18; p < 0.0001). Postoperative unilateral paresis of the recurrent laryngeal nerve was diagnosed 3.9% and bilateral paresis in 0.2%. Unilateral paresis was associated with older age, intrathoracic goiter, thyreotoxicosis, and if routine laryngoscopy was practiced (OR 1.92; p = 0.0002). After 6 months, the incidence of nerve paresis was 0.97%. After bilateral thyroid surgery (n = 1,648), hypocalcaemia treated with vitamin D analogue occurred in 9.9% of the patients at the first follow-up and in 4.4% after 6 months. CONCLUSION: Complications to thyroid surgery are not uncommon. The high frequency of hypocalcaemia treated with vitamin D after 6 months is a cause of concern