Chronic effects of beta-guanidinopropionic acid on skeletal muscle fatty acid and glucose metabolism
Administration of ?-guanidinopropionic acid (?-GPA), a synthetic creatine analogue used to decrease tissue high-energy phosphagens, results in enhanced oxidative capacity in rodent skeletal muscle. Limited evidence also points to a possible improvement in whole body glucose tolerance. However, the effect of ?-GPA administration on muscle insulin sensitivity has been relatively unexamined. Furthermore, the effect of ?-GPA on muscle lipid metabolism, which is known to influence insulin sensitivity, has also been virtually unexamined. The purpose of this study was to examine the effect of chronic ?-GPA feeding on muscle fatty acid (FA) metabolism and insulin stimulated glucose uptake in rodent skeletal muscle. Rats were fed a diet containing 1% ?-GPA for 8 weeks, resulting in significantly decreased muscle phosphagen stores and increased oxidative capacity as previously reported. Furthermore, insulin-stimulated glucose transport was increased in the soleus of ?-GPA fed rats when compared to Controls, and was associated with an increase in total muscle and plasma GLUT4 protein content in red and white muscle, indicating that ?-GPA can improve insulin sensitivity at the level of skeletal muscle. Although basal (unchallenged) rates of palmitate oxidation in soleus were not altered with ?-GPA, the increase from basal to AICAR-stimulated conditions was significantly greater in ?-GPA fed rats. The increase in palmitate oxidation was associated with increases in total muscle and plasma membrane FAT/CD36 in red and white muscle. FABPpm content was not increased, implying a more important physiological role for FAT/CD36 as a FA transporter. It is likely that the increases in glucose and FA metabolism of ?-GPA fed rats were mediated in part by the observed increased in phosphorylated AMPK content. The results of the present study indicate that compromising the cellular energy charge in skeletal muscle results in compensatory increases in glucose and FA transport proteins, oxidative capacity, FA oxidation and insulin-stimulated glucose transport. Thus, the administration of agents such as ?-GPA, which reduce muscle phosphagens, may have value as an anti-diabetic treatment.