Muscle group-specific regulation of GLUT 4 glucose transporters in control, diabetic, and insulin-treated diabetic rats

Abstract

Insulin resistance in diabetic rats involves pretranslational suppression of the GLUT 4 glucose transporter in muscle. Because the capacity for insulin-mediated glucose transport varies as a function of muscle group, we hypothesized that GLUT 4 was differentially expressed and regulated by diabetes in a muscle-specific manner. We studied control (C), streptozocin (STZ)-induced diabetic (D), and insulin-treated diabetic (Tx) rats and examined the following muscles that vary in fiber composition: soleus (type I fibers), gastrocnemius (mixed type IIa > IIb), vastus lateralis and rectus abdominis (type IIb > IIa), and cardiac muscle. In C animals, these muscles exhibited significant differences in the baseline expression of GLUT 4. Relative GLUT 4 content was highest in cardiac muscle, intermediate in soleus, and significantly lower in gastrocnemius, rectus abdominis, and vastus lateralis (1.8:1.0:0.6). The impact of diabetes and insulin therapy on GLUT 4 expression also varied as a function of muscle group. After four weeks of diabetes, GLUT 4 levels were reduced by approximately 50% in cardiac muscle, soleus, and gastrocnemius. In contrast, GLUT 4 content in rectus abdominis and vastus lateralis was similar to that in control rats. Exogenous insulin treatment of diabetic rats increased GLUT 4 content in soleus, cardiac muscle, and gastrocnemius, but had no effect in either vastus lateralis or rectus abdominis. Temporal effects of diabetes and insulin treatment were also examined in different skeletal muscle. Soleus showed a significant decrease in GLUT 4 content as early as 2 days with a further decrease at 4 weeks; rectus abdominis showed little change at either time point. In conclusion, (1) skeletal muscle groups that vary in fiber composition exhibit different levels of GLUT 4 expression in C rats and differential regulation of GLUT 4 content by diabetes and insulin treatment; (2) relative baseline GLUT 4 expression is greatest in cardiac muscle, intermediate in soleus, and lower in gastrocnemius, vastus lateralis, and rectus abdominis; and (3) GLUT 4 depletion in diabetes and the increase in levels following insulin therapy are most profound in cardiac muscle, soleus, and gastrocnemius, whereas effects in vastus lateralis and rectus abdominis are minimal or nonexistent. These results should be considered in evaluating previous studies that have tested for effects in total hindlimb musculature, and have major implications relevant to reported data in non-insulin-dependent diabetes mellitus (NIDDM).