George D. Dimitriadis

The effects of insulin on transport and metabolism of glucose in skeletal muscle from hyperthyroid and hypothyroid rats

The effects of insulin on the rates of glucose disposal were studied in soleus muscles isolated from hyper‐ or hypothyroid rats. Treatment with triiodothyronine for 5 or 10 days decreased the sensitivity of glycogen synthesis but increased the sensitivity of lactate formation to insulin. The sensitivity of 3‐O methylglucose to insulin was increased only after 10 days of treatment and was accompanied by an increase in the sensitivity of 2‐deoxyglucose phosphorylation; however, 2‐deoxyglucose and glucose 6‐phosphate in response to insulin remained unaltered. In hypothyroidism, insulin‐stimulated rates of 3‐O‐methylglucose transport and 2‐deoxyglucose phosphorylation were decreased; however, at basal levels of insulin, 3‐O‐methylglucose transport was increased, while 2‐deoxyglucose phosphorylation was normal. In these muscles, the sensitivity of lactate formation to insulin was decreased; this defect was improved after incubation of the muscles with prostaglandin E2. The results suggest: (a) in hyperthyroidism, insulin‐stimulated rates of glucose utilization in muscle to form lactate are increased mainly because of a decrease in glycogen synthesis; when hyperthyroidism progresses in severity, increases in the sensitivity of glucose transport to insulin and in the activity of hexokinase may also be involved; (b) in hypothyroidism, the decrease in insulin‐stimulated rates of glucose utilization is caused by decreased rates of glycolysis; (c) prostaglandins may be involved in the changes in sensitivity of glucose utilization to insulin observed in muscle in altered thyroid states.

Effects of hypothyroidism on the sensitivity of glycolysis and glycogen synthesis to insulin in the soleus muscle of the rat

1. The effects of hypothyroidism on the sensitivity of glycolysis and glycogen synthesis to insulin were investigated in the isolated, incubated soleus muscle of the rat. 2. Hypothyroidism, which was induced by administration of propylthiouracil to the rats, decreased fasting plasma levels of free fatty acids and increased plasma levels of glucose but did not significantly change plasma levels of insulin. 3. The sensitivity of the rates of glycogen synthesis to insulin was increased at physiological, but decreased at supraphysiological, concentrations of insulin. 4. The rates of glycolysis in the hypothyroid muscles were decreased at all insulin concentrations studied and the EC50 for insulin was increased more than 8-fold; the latter indicates decreased sensitivity of this process to insulin. However, at physiological concentrations of insulin, the rates of glucose phosphorylation in the soleus muscles of hypothyroid rats were not different from controls. This suggests that hypothyroidism affects glucose metabolism in muscle not by affecting glucose transport but by decreasing the rate of glucose 6-phosphate conversion to lactate and increasing the rate of conversion of glucose 6-phosphate to glycogen. 5. The rates of glucose oxidation were decreased in the hypothyroid muscles at all insulin concentrations.

Skeletal muscle glutamine metabolism during sepsis in the rat

1. The effect of sepsis, induced by caecal ligation plus puncture (CLP) or endotoxin injection, on glutamine metabolism was studied in rat skeletal muscle. 2. The concentration of glutamine in muscle was decreased by CLP or after 24 or 48 hr after injection of endotoxin. However, the concentration was increased 3 hr after injection of endotoxin. 3. The plasma glutamine concentration was decreased by CLP, but it was unchanged after injection of endotoxin. 4. The rate of glutamine release from incubated stripped soleus muscles was increased in the muscles removed from animals subjected to CLP or from animals injected with endotoxin. 5. It is concluded that sepsis results in marked changes in skeletal muscle glutamine metabolism, which may be used as an early indicator of the septic state. During sepsis there is likely to be an increased demand for glutamine by the immune system, kidney and intestine. 6. This study provides evidence that during sepsis the rate of release of glutamine from the skeletal muscle per se is increased to a sufficient extent to satisfy this increased requirement.

The effect of tumour bearing on skeletal muscle glutamine metabolism

1. The effects of tumour bearing on glutamine metabolism in rat skeletal muscle were examined using the Walker 256 carcinosarcoma. 2. There was a rapid and marked decrease in skeletal muscle glutamine content, which was correlated with the size of the tumour, and a decrease in plasma glutamine concentration. 3. The rate of release of glutamine from EDL muscle in vitro was increased in cachectic, tumour bearing animals, but was unaffected from the soleus muscle of the same animals. 4. It is hypothesized that the increase in the rate of muscle glutamine release during cachexia represents a response of this tissue in order to satisfy the demand for glutamine by the tumour or by cells of the immune system.

Effects of physiological and pathological levels of glucocorticoids on skeletal muscle glutamine metabolism in the rat

The effects of physiological and pathological concentrations of glucocorticoids were investigated using the glucocorticoid antagonist RU486 and the synthetic glucocorticoid dexamethasone, respectively. The effects of these treatments on the concentrations of glutamine and other amino acids in skeletal muscle and plasma and on the rates of release of glutamine and alanine from incubated preparations of skeletal muscle of the rat were investigated. Dexamethasone treatment increased the concentration of glutamine and the rate of release of this amino acid from incubated soleus muscle preparations. This treatment decreased the concentration of glutamine in both gastrocnemius and EDL muscles, but was without effect on the rate of glutamine release from EDL muscles. In contrast, administration of the glucocorticoid antagonist RU486 decreased the rate of glutamine release from muscle. It is concluded that glucocorticoids have marked effects on the metabolism of glutamine by skeletal muscle per se and that these hormones may be important in the control of the rate of glutamine release from muscle in both physiological and pathological conditions.

Studies on the effects of growth hormone administration in vivo on the rates of glucose transport and utilization in rat skeletal muscle

Abstract. The effects of growth hormone (GH) administration to rats in vivo on the sensitivity of the rate of glucose utilization to insulin were studied in soleus muscles isolated from these rats. A single injection of GH did not increase the rate of glucose transport within 1–2 h. However, 12 h after, the rate of glucose transport was increased at 10 mU insulin l‐1 and was accompanied by a similar increase in the rate of lactate formation but no change in the rate of glycogen synthesis. Prolonged treatment with GH decreased the rate of glucose transport and glycogen synthesis and increased the content of glucose 6‐phosphate at physiological levels of insulin but did not affect the rate of lactate formation. These results suggest that: (a) GH does not increase the rate of glucose transport acutely; however, after several hours, the sensitivity of glucose transport and glycolysis to insulin are increased; (b) prolonged elevations of the level of GH in plasma decrease the sensitivity of the rate of glucose transport and glycogen synthesis to insulin. However, redirection of glucose residues away from the pathway of glycogen synthesis towards that of glycolysis and a possible increase in the rate of glycogenolysis maintain a normal rate of lactate formation, although the rate of glucose transport is decreased.

Effects of the diuretic furosemide on the sensitivity of glycolysis and glycogen synthesis to insulin in the soleus muscle of the rat

SummaryThe diuretic furosemide (0.5 mmol/l) impaired glucose uptake in the soleus muscle of the rat by decreasing the sensitivity of glycolysis to insulin. In addition, at higher concentrations (1.0 mmol/l) the drug inhibited the basal rate of glycolysis. It did not, however, inhibit the rate of glycogen synthesis except at a concentration of 6.0 mmol/l. Since furosemide has some structural similarities to adenosine, the above effects on insulin sensitivity may be due to its ability to act as an adenosine receptor agonist in muscle. These effects of furosemide in skeletal muscle may contribute to the glucose intolerance following therapy with this and similar agents in man.

Thyroid hormone analogue SKF L-94901: effects on amino acid and carbohydrate metabolism in rat skeletal muscle in vitro

In summary, hyperthyroidism increased the rate of glycolysis and decreased glycogen synthesis in isolated incubated rat soleus muscle preparations. SKF 901 also increased glycolysis, but the stimulation was 5-fold less than in T3-treated muscles. Hyperthyroidism increased the rate of glutamine release from skeletal muscle, but SKF 901 did not affect glutamine metabolism.