E. A. Gulve

Lithium Increases Susceptibility of Muscle Glucose Transport to Stimulation by Various Agents

Lithium is thought to have an insulin-like effect on glucose transport and metabolism in skeletal muscle and adipocytes. However, we found that lithium had only a minimal effect on basal glucose transport activity in rat epitrochlearis muscles. Instead, lithium markedly increased the sensitivity of glucose transport to insulin, so that the increase in glucose transport activity induced by 300 pM insulin was ∼2.5-fold greater in the presence of lithium than in its absence. Lithium also caused a modest increase in insulin responsiveness. This enhancement of the susceptibility of the glucose transport process to stimulation was not limited to insulin, because lithium induced increases in the susceptibility of glucose transport to stimulation by contractile activity, hypoxia, a phorbol ester, and phospholipase C. Lithium also blunted the activation of glycogen phosphorylase by epinephrine. These effects were not mediated by inhibition of adenylate cyclase, because neither basal- nor epinephrine-stimulated muscle cAMP concentration was affected by lithium treatment. The effects of lithium on glucose transport and metabolism in skeletal muscle are strikingly similar to the persistent effects of exercise. These results support the possibility that lithium might be useful in the treatment of insulin resistance in patients with non-insulin-dependent diabetes mellitus.

Effects of wheel running on glucose transporter (GLUT4) concentration in skeletal muscle of young adult and old rats

We examined the effects of voluntary exercise on glucose transporter concentration in skeletal muscle from young adult and old female Long-Evans rats. Rats had free access to voluntary running wheels beginning at 4 months of age or remained sedentary. Exercising rats ran approximately 7.5, 6.2, 5.6 and 5.3 km/day during their 6th, 8th, 9th and 10th month of age, respectively. During the 23rd, 24th and 25th month of age running distance averaged 3.0, 2.8 and 2.4 km/day, respectively. At 10 and 25 months of age, glucose transporter protein concentration was assessed in epitrochlearis and flexor digitorum brevis muscles with a polyclonal antibody directed against the GLUT4 transporter isoform. GLUT4 protein concentration was not altered by the aging process (i.e., comparing 10- and 25-month-old rats) in either muscle type. Wheel running increased GLUT4 protein concentration by 45% in epitrochlearis muscles of 10-month-old rats relative to age-matched sedentary controls. The training-induced adaptation in GLUT4 protein was no longer present at age 25 months, probably because the running distance had declined by 50%. In the flexor digitorum brevis, exercise did not alter GLUT4 concentration at either 10 or 25 months, presumably due to insufficient recruitment of this muscle during wheel running as assessed by measurement of citrate synthase and hexokinase enzyme activities. Wheel running induced cardiac and soleus muscle hypertrophy in 10- and 25-month-old rats. In summary, voluntary wheel running can induce an increase in skeletal muscle GLUT4 protein concentration in adult rats. Older rats that run less exhibit cardiac and soleus muscle hypertrophy, but do not maintain an elevated GLUT4 protein concentration in the epitrochlearis muscle. Aging does not alter GLUT4 protein concentration in the epitrochlearis or FDB muscles.

Effects of alkaline pH on the stimulation of glucose transport in rat skeletal muscle.

Alkaline pH has been reported to cause release of Ca2+ from skeletal muscle sarcoplasmic reticulum (SR). Elevation of sarcoplasmic Ca2+ concentration is thought to stimulate glucose transport in skeletal muscle. In this context, we examined the effect of alkaline pH (extracellular pH of 8.6) on 3-O-methylglucose transport in skeletal muscle. Incubation of rat epitrochlearis muscles at pH 8.6 for 45 min resulted in an approx. 3-fold increase in glucose transport activity, which was not affected by reducing Ca2+ concentration in the incubation medium and essentially completely blocked by 25 microM dantrolene, an inhibitor of SR Ca2+ release. In addition to stimulating glucose transport by itself, alkaline pH may partially inhibit the stimulation of sugar transport by insulin hypoxia and contractions, as the combined effect of alkaline pH and the maximal effect of insulin, contractions, or hypoxia on glucose transport are not different from the maximal effects of insulin, hypoxia, or contractions alone. The maximal effects of insulin and contractions, and of insulin and hypoxia, on glucose transport are normally additive in muscle. Alkaline pH completely prevented this additivity. In summary, our results show that alkaline pH stimulates glucose transport activity in skeletal muscle and provide evidence suggesting that this effect is mediated by Ca2+. They further show that alkaline pH blocks the additivity of the maximal effects of insulin and contractions or hypoxia suggesting that alkaline pH may partially inhibit the stimulation of glucose transport by insulin, contraction and hypoxia.