Mark Parry-Billings

Does glutamine contribute to immunosuppression after major burns

The effects of glutamine concentration on the rates of lymphocyte proliferation after mitogenic stimulation and of phagocytosis by macrophages were investigated in vitro. A decrease in the glutamine concentration in culture medium from 0.6 to 0.05 mmol/l greatly decreased the rate of proliferation of human lymphocytes and of phagocytosis by mouse macrophages. In patients with major burn injury plasma glutamine concentration was 58% lower than that in normal controls and it remained low for at least 21 days after the injury. The findings indicate that the decrease in plasma glutamine concentration may contribute to the injury-induced impairment of immune function occurring after major burn injury.

Plasma amino acid concentrations in the overtraining syndrome: possible effects on the immune system.

Overtraining and long-term exercise are associated with an impairment of immune function. We provide evidence in support of the hypothesis that the supply of glutamine, a key fuel for cells of the immune system, is impaired in these conditions and that this may contribute to immunosuppression. Plasma glutamine concentration was decreased in overtrained athletes and after long-term exercise (marathon race) and was increased after short-term, high intensity exercise (sprinting). Branched chain amino acid supplementation during long-term exercise was shown to prevent this decrease in the plasma glutamine level. Overtraining was without effect on the rate of T-lymphocyte proliferation in vitro or on the plasma levels of interleukin-1 and -6, suggesting that immune function is not impaired in this condition. Given the proposed importance of glutamine for cells of the immune system, it is concluded that the decrease in plasma glutamine concentration in overtraining and following long-term exercise, and not an intrinsic defect in T lymphocyte function, may contribute to the immune deficiency reported in these conditions.

Dieting reduces plasma tryptophan and alters brain 5-HT function in women

A three week low calorie diet significantly reduced both total plasma tryptophan and the ratio of tryptophan to competing amino acids in a group of 15 healthy volunteers. Despite a similar percentage weight loss the reduction in plasma tryptophan was greater in women than men. In addition, only in women was dieting associated with increased prolactin secretion following intravenous tryptophan, a measure of brain 5-hydroxytryptamine (5-HT) function. These results suggest that dieting reduces the availability of circulating tryptophan for brain 5-HT synthesis. Women appear more vulnerable than men both to this effect and to its consequences for brain 5-HT function. Altered brain 5-HT function may play a part in some of the psychological consequences of dieting, including the development of clinical eating disorders.

Decreased plasma tryptophan levels in major depression

Total plasma tryptophan was significantly lower in 12 depressed patients than in 12 normal controls. The ratio of total tryptophan to neutral amino acids was also decreased in the depressed patients suggesting that tryptophan availability to the brain might be reduced. There was no correlation between basal tryptophan concentrations in the depressed subjects and the subsequent neuroendocrine response to intravenous tryptophan.

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.

Decreased plasma tryptophan concentration in major depression: relationship to melancholia and weight loss.

Plasma total tryptophan (TRP) concentration was significantly lower in 31 patients with major depression compared to a healthy control group. The ratio of plasma TRP concentration to that of other branch chain amino acids (the TRP:BCAA ratio) was also decreased. Further analysis revealed that the decrease in plasma TRP and TRP:BCAA ratio was most apparent in patients with major depression and melancholia. Overall, women but not men had significantly decreased plasma tryptophan concentrations, perhaps because of a contributory effect of weight loss; this latter effect, however, could not be distinguished clearly from a diagnosis of melancholia. Our data suggest that in some depressed patients, reductions in plasma tryptophan availability may contribute to abnormalities in brain 5-hydroxytryptamine function.

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.