Hypoglycemic effect of isoleucine involves increased muscle glucose uptake and whole body glucose oxidation and decreased hepatic gluconeogenesis. Am J Physiol Endocrinol Metab 292: E1683-E1693, 2007. First published February 13, 2007; doi:10.1152/ajpendo.00609.2006.-Isoleucine, a branched chain amino acid, plays an important role in the improvement of glucose metabolism as evidenced by the increase of insulin-independent glucose uptake in vitro. This study evaluated the effect of isoleucine on glucose uptake and oxidation in fasted rats and on gluconeogenesis in vivo and in vitro. Oral administration of isoleucine decreased the plasma glucose level by 20% and significantly increased muscle glucose uptake by 71% without significant elevation of the plasma insulin level compared with controls at 60 min after administration. Furthermore, expiratory excretion of 14 CO2 from [U-14 C]glucose in isoleucine-administered rats was increased by 19% compared with controls. Meanwhile, isoleucine decreased AMP levels in the liver but did not affect hepatic glycogen synthesis. Under insulin-free conditions, isoleucine significantly inhibited glucose production when alanine was used as a glucogenic substrate in isolated hepatocytes. This inhibition by isoleucine was also associated with a decline in mRNA levels for phosphoenolpyruvate carboxykinase and glucose-6-phosphatase (G6Pase) and a decreased activity of G6Pase in isolated hepatocytes. These findings suggest that a reduction of gluconeogenesis in liver, along with an increase of glucose uptake in the muscle, is also involved in the hypoglycemic effect of isoleucine. In conclusion, isoleucine administration stimulates both glucose uptake in the muscle and whole body glucose oxidation, in addition to depressing gluconeogenesis in the liver, thereby leading to the hypoglycemic effect in rats.insulin; amino acid; leucine; hepatocyte; glucose production PREVIOUS STUDIES HAVE SHOWN that amino acids decrease insulinstimulated glucose uptake and glucose utilization (7,11,33,34). As an alternative to glucose oxidation, amino acids, including the glucogenic amino acids (alanine, valine, or glutamine), may serve as fuel, and therefore, amino acids are considered to be able to increase glucose production and blood glucose levels. Also, amino acids (especially leucine) stimulate protein synthesis via the mammalian target of rapamycin (mTOR) (1, 37), whereas amino acids can also induce degradation of the insulin receptor substrate-1 (IRS-1) by stimulating mTOR and S6 kinase-1 (S6K1), leading to desensitization of insulin signaling (20,30,34). In addition, leucine reduces the duration of insulin-induced IRS-1-associated phosphatidylinositol 3-kinase (PI3 kinase) in skeletal muscle (3). Given these results, it is to be expected that amino acids will decrease glucose oxidation and cause an amino acidinduced insulin resistance.However, it has been reported that amino acid infusion causes a decrease in blood glucose levels and increases glucose oxidation in humans (31, 32), although there ...