Obstructive Jaundice Results in Increased Liver Expression of Uncoupling Protein 2 and Intact Skeletal Muscle Glucose Metabolism in the Rat B. Isaksson, C. Rippe, R. Simonoska, J.-E. Holm, H. Glaumann, R. Segersva¨rd, J. Larsson, C. Erlanson-Albertsson & J. Permert Arvid Wretlind Laboratory for Metabolic and Nutritional Research, Dept. of Surgery, Karolinska Institutet at Huddinge University Hospital, Stockholm, Sweden; Dept. of Cell and Molecular Biology, Biomedical Center (BMC), University of Lund, Lund, Sweden; Dept. of Pathology, Karolinska Institutet at Huddinge University Hospital, Stockholm, Sweden Isaksson B, Rippe C, Simonoska R, Holm J-E, Glaumann H, Segersva¨rd R, Larsson J, Erlanson- Albertsson C, Permert J. Obstructive jaundice results in increased liver expressio n of uncouplin g protein 2 and intact skeletal muscle glucose metabolism in the rat. Scand J Gastroentero l 2002;37:104–111. Background: A majority of patients with pancreatic cancer have obstructiv e jaundice and diabetes with skeletal muscle insulin resistance. Surgery for these patients is associated with signicant morbidity. Uncoupling protein 2 (UCP2) has been proposed to regulate energy expenditur e and promote liver vulnerability. The effects of obstructive jaundice on muscle glucose metabolism and expression of UCP2 in liver and muscle are unknown. Methods: Rats were operated with bile duct ligation (BDL). After 7 days, UCP2 mRNA levels were determined in liver and muscle. Simultaneously, insulin-stimulate d glucose transport and glycogen synthesis in skeletal muscle were analyzed in vitro. Results: The jaundiced rats lost more weight than pair-fed controls. UCP2 mRNA levels were increased 5-fold in liver but not in muscle in jaundiced rats compared to pair-fed controls. The jaundiced rats were hypoglycemi c and hypoinsulinemi c but demonstrated intact or enhanced insulin action on skeletal muscle glucose transport and glycogen synthesis in vitro. Muscle glycogen content was increased in the jaundiced rats. Conclusions: Experimental obstructive jaundice in the rat is associate d with increase d liver expression of UCP2, rapid weight loss, and intact insulin action on skeletal muscle glucose metabolism. Obstructive jaundice, by upregulate d liver UCP2, may contribute to the cachexia and high surgical morbidity observed in these patients, but not to skeletal muscle insulin resistance in pancreati c cancer patients. Key words: Glucose metabolism; glucose transport; glycogen ; obstructiv e jaundice; uncouplin g protein 2 Bengt Isaksson, M.D., Dept. of Surgery, Huddinge University Hospital, SE-141 86 Stockholm, Sweden (fax. ‡46 8 585 83850, e-mail. bengt.isaksson@gastro.hs.sll.se ) A t time of diagnosis, obstructive jaundice occurs in 70% of patients with pancreatic cancer (1). Metabolic complications, such as glucose intolerance (2), and marked weight loss are also present in a majority of these patients. The glucose intolerance observed in a majority of pancreatic cancer patients is characterized by profound skeletal muscle insulin resistance, demonstrated in vivo with hyperinsuliemic clamp (3) and in vitro with skeletal muscle glucose transport (Isaksson, unpublished observa- tion). Impaired glucose tolerance has also been observed in patients with both benign and malignant obstructive jaundice (4, 5), and in experimental animal models of obstructive jaundice (6). It is unclear if obstructive jaundice contributes to insulin resistance in skeletal muscle, which is the primary site of insulin-stimulated glucose disposal and constitute the major tissue responsible for postprandial hyperglycemia in insulin-resistant subjects (7). Surgery in pancreatic cancer patients is associated with high morbidity (8), and it is unclear to what extent and by which mechanism the state of obstructive jaundice per se may contribute to the surgical morbidity. Preoperative weight loss is known to adversely affect surgical outcome in general (9, 10). Experimental obstructive jaundice has been shown to cause weight loss (11), but it remains unclear if this is caused by reduced food intake alone or metabolic alterations. Furthermore, the high morbidity associated with surgery in patients with obstructive jaundice has been proposed to be attributed to increased liver susceptibility to stress (12, 13). This increased liver vulnerability seems to correlate to decreased mitochondrial function (14–16) and ATP produc- tion (12), suggesting uncoupling of oxidative phosphoryla- tion. Uncoupling protein (UCP) homologue s (UCP1-5), a new family of proteins which uncouple mitochondrial respiration from oxidative phosphorylation , increase thermogenesis while reducing the efciency of ATP synthesis (17). Of the ve proteins known at the present time, UCP2 is the most interesting, since it is expressed in several tissues, including the gastrointestinal tract (18). Thus, normal liver has been ORIGINAL ARTICLE Ó 2002 Taylor & Francis