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

Abstract

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 alpha1 activity in skeletal muscle was not affected by leucine or isoleucine administration. However, isoleucine, but not leucine, significantly decreased AMPK alpha2 activity. The decrease in AMPK alpha2 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.

New Therapeutic Strategy for Amino Acid Medicine: Notable Functions of Branched Chain Amino Acids as Biological Regulators

“…Valine was excluded from the scope of this research, as valine caused an increase in plasma glucose levels. Oral administration of isoleucine, but not leucine, significantly decreased plasma glucose concentration in food-deprived rats (9). 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 that in food-deprived controls, thus suggesting that isoleucine increases skeletal muscle glucose uptake in vivo.…”

“…However, the pharmacological effects of the other BCAAs, isoleucine and valine, have not been well clarified. We recently found that among the BCAAs, isoleucine acts as a nutrient regulator of glucose metabolism (9,10).…”

Content of selected amino acids in the gastrocnemius muscle during experimental hypothyroidism in rats

“…However, it plays a slightly different role; in particular it is a factor in carbohydrate metabolism. It stimulates the capture and, independently from insulin and mTOR, transport of glucose in skeletal muscles (5). In contrast to leucine, it does not exhibit anabolic properties by increasing protein synthesis in skeletal muscles: it does not increase the activation of translation initiation factors (7).…”

Branched chain amino acids in feeding pigs: Review

“…Resultados similares foram encontrados por Doi et al (2005), quando administraram via oral uma concentração de 1,35 g de L-leucina/kg de peso em ratos, sem encontrar diferença na concentração de insulina plasmática no músculo gastrocnêmio uma hora após a administração.…”