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Biochemical and Molecular Actions of Nutrients

Isoleucine, a Blood Glucose-Lowering Amino Acid, Increases Glucose Uptake in Rat Skeletal Muscle in the Absence of Increases in AMP-Activated Protein Kinase Activity

Division of Pharmacology, Drug Safety and Metabolism, Otsuka Pharmaceutical Factory Incorporated, Naruto, Tokushima 772-8601 and ^* Department of Animal Science, Utsunomiya University, Utsunomiya, Tochigi 321-8505, Japan

¹To whom correspondence should be addressed. E-mail: doims{at}otsukakj.co.jp.

Leucine and isoleucine were shown to stimulate insulin-independent glucose uptake in skeletal muscle cells in vitro. In this study, we examined the effects of leucine and isoleucine on blood glucose in food-deprived rats and on glucose metabolism in skeletal muscle in vivo. Furthermore, we investigated the possible involvement of the energy sensor, 5'-AMP-activated protein kinase (AMPK), in the modulation of glucose uptake in skeletal muscle, which is independent of insulin, and also in leucine- or isoleucine-stimulated glucose uptake. Oral administration of isoleucine, but not leucine, significantly decreased the plasma glucose concentration. An i.v. bolus of 2-[1,2-³H]-deoxyglucose (2-[³H]DG) was administered to calculate glucose uptake. Glucose uptake in the skeletal muscle did not differ after leucine administration, but glucose uptake in the muscles of rats administered isoleucine was 73% greater than in controls, suggesting that isoleucine increases skeletal muscle glucose uptake in vivo. On the contrary, in the skeletal muscles, administration of leucine but not isoleucine significantly increased [U-¹⁴C]-glucose incorporation into glycogen compared with controls. AMPK 1 activity in skeletal muscle was not affected by leucine or isoleucine administration. However, isoleucine, but not leucine, significantly decreased AMPK 2 activity. The decrease in AMPK 2 activity was thought to be due to decreases in AMP content and the AMP:ATP ratio, which were related to the isoleucine administration. This is the first report of isoleucine stimulating glucose uptake in rat skeletal muscle in vivo, and these results indicate that there might be a relation between the reduction in blood glucose and the increase in skeletal muscle glucose uptake that occur with isoleucine administration in rats. The alterations in glucose metabolism caused by isoleucine may result in an improvement of the availability of ATP in the absence of increases in AMP-activated protein kinase activity in skeletal muscle.

KEY WORDS: • isoleucine • leucine • glucose • muscle • AMP-activated protein kinase

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				P. She, C. Van Horn, T. Reid, S. M. Hutson, R. N. Cooney, and C. J. Lynch Obesity-related elevations in plasma leucine are associated with alterations in enzymes involved in branched-chain amino acid metabolism Am J Physiol Endocrinol Metab, December 1, 2007; 293(6): E1552 - E1563. [Abstract] [Full Text] [PDF]

				M. Doi, I. Yamaoka, M. Nakayama, K. Sugahara, and F. Yoshizawa Hypoglycemic effect of isoleucine involves increased muscle glucose uptake and whole body glucose oxidation and decreased hepatic gluconeogenesis Am J Physiol Endocrinol Metab, June 1, 2007; 292(6): E1683 - E1693. [Abstract] [Full Text] [PDF]