Metabolic interactions of glucagon and cortisol in man--studies with somatostatin.

The metabolic response to pathophysiologic concentrations of glucagon, induced by glucagon infusion, has been examined in normal man before and after 36-60 hr hypercortisolaemia, induced by administration of tetracosactrin-depot. Glucagon alone increased serum insulin levels twofold but blood glucose was unaltered. Plasma NEFA and blood ketone body concentrations were decreased by glucagon infusion. Tetracosactrin produced a threefold rise in serum cortisol levels and caused mild fasting hyperglycemia and hyperinsulinaemia. Subsequent glucagon infusion had no effect on circulating insulin, glucose, NEFA or ketone body concentrations. Simultaneous infusion of somatostatin, to produce partial insulin-deficiency, unmasked a hyperglycemic action of glucagon (+ 3.8 +/- 0.2 mmol/l at 90 min, p less than 0.02). This glucagon-induced rise in blood glucose was diminished by prior tetracosactrin administration. Tetracosactrin revealed a mild lipolytic action of glucagon in partial insulin deficiency, not apparent in the euadrenal state. Glucagon was equally hyperketonemic during somatostatin infusion before and after tetracosactrin. Thus the hyperglycemic and hyperketonemic actions of glucagon at pathophysiologic levels are restricted to insulin deficiency. Hypercortisolaemia reveals a lipolytic action of glucagon in insulin-deficient man but does not potentiate the hyperglycemic or hyperketonemic effects.

Metabolic effects of cortisol in man--studies with somatostatin.

The metabolic effects of chronic hypercortisolaemia were studied by administration of tetracosactrin-depot, 1 mg I.M. daily for 36-60 hr to normal subjects. Partial insulin and glucagon deficiency were induced at the end of the period by infusion of somatostatin, 100 micrograms/h for 210 min. Tetracosactrin alone induced a three fold rise in basal serum cortisol levels and fasting blood glucose concentration rose from 5.2 +/- 0.2 to 7.2 +/- 0.2 mmole/l (p less than 0.01) with a rise in fasting serum insulin from 5.2 +/- 1.2 to 13.1 +/- 1.9 mU/l (p less than 0.02). Concentrations of the gluconeogenic precursors lactate, pyruvate and alanine were also raised, but non-esterified fatty acid, glycerol and ketone body levels were unchanged. Somatostatin infusion caused a 30%-50% decrease in serum insulin and a 20%-60% decrease in plasma glucagon concentrations both before and after tetracosactrin administration. A similar rise in blood glucose concentration, relative to the saline control, occurred over the period of somatostatin infusion both with and without elevated cortisol levels. However, prior tetracosactrin administration caused a 100% greater rise in blood ketone body concentrations during infusion of somatostatin than was seen in the euadrenal state, despite similar plasma NEFA concentrations. Hypercortisolaemia causes hyperglycaemia and elevated gluconeogenic precursor concentrations but the associated rise in serum insulin concentrations limits lipolysis and ketosis. In insulin deficiency, a ketotic effort of glucocorticoid excess is evident which may be independent of lipolysis and occurs despite concurrent glucagon deficiency. These catabolic actions of cortisol are likely to be of major importance in the metabolic response to stress.

Improved discrimination in the detection of neural tube defects: five biochemical tests compared.

Five biochemical tests, which have been proposed as possible adjuncts to the measurement of amniotic fluid alphafetoprotein for the identification of neural tube defects, have been measured in 49 normal and 46 neural tube defect affected pregnancies. One test, the alphafetoprotein component non-reactive with concanavalin A, was ineffective in differentiating normal and abnormal. The remaining four procedures, the activity of acetyl and total cholinesterase, the concentration of alpha 2 macroglobulin and the electrophoretic identification of acetyl cholinesterase effectively separated the normal and abnormal populations. The relative merits of these four latter tests in the evaluation of false positive and false negative amniotic fluid alphafetoprotein results, as well as in liquor samples with high alphafetoprotein levels associated with abnormalities not of neural origin, are discussed.

Urine proteins after burn injury.

Two-dimensional immunoelectrophoresis was used to examine the proteins present in urine during the first week following burn injury. Of the "serum" proteins present in the urine some glycoproteins were found to be in different relative proportions from those observed in serum. In patients sustaining severe burns the amount of protein excreted was increased compared to patients with mild burns and to controls. alpha 1-Antichymotrypsin detected in the urine of patients with severe burns was at times seen as a twin peak. This altered peak was of slower electrophoretic mobility and may represent a polymer of the protein or a complex of the protein with some other, possibly tissue-derived, protein.

Observations on serum and urine alkaline ribonuclease activity and urate after burn injury in man.

In an investigation into the disturbances of body function associated with burn injury we have measured the activity of alkaline ribonuclease (EC 3.1.4.22) and the level of urate in the serum and urine of patients sustaining burn injury. Ribonuclease activity was elevated in all patients. The degree of elevation can be related to the percentage of the body surface area burned and to a predictive index of burn mortality. Increased serum ribonuclease activity was accompanied by increased urine ribonuclease output. The relationship between serum urea and ribonuclease activity has been investigated. A significant correlation between these two parameters was observed during the first week post burn. We suggest that this correlation shows as a result of increased protein catabolism and renal dysfunction. After the first week a significant correlation between serum urea and ribonuclease activity was not observed. It is possible that, at this stage, increased ribonuclease activity is perhaps a result of tissue repair. Serum urate was found to be decreased in all patients after burn injury. Serum urate decrease expressed as a percentage of initial value, correlated very strongly with the predictive index of burn mortality. In severely burned patients the decrease in serum urate was accompanied by increased urine urate output and may indicate a change in renal handling of urate after burn injury.

The validation of a fluoroimmunoassay for the determination of theophylline concentration in dried blood spots suitable for domiciliary therapeutic drug monitoring.

A commercially available substrate-labelled fluorescent immunoassay procedure has been modified to create a simple rapid method for the determination of capillary theophylline concentration in the dried filter paper blood spots of patients on theophylline therapy. The specimens are collected and dispatched to the laboratory by the patient; thus domiciliary monitoring of theophylline therapy can take place. The technique offers a convenient method for overcoming many of the practical problems that arise during theophylline therapy in asthmatic patients.

The effects of septic complications upon the serum protein changes associated with thermal injury.

The levels of 12 serum proteins including 'acute-phase reactants', immunoglobulins and albumin were measured in 20 patients suffering from thermal burns. The acute-phase reactants: C-reactive protein, alpha-l antitrypsin, alpha-l antichymotrypsin, haptoglobin and orosomucoid, all increased in concentration. Highest levels, which showed significant correlations with injury severity, occurred at 6-8 days post-burn. The levels of albumin, alpha-l lipoprotein and transferrin were decreased. The immunoglobulins IgG, IgA and IgM showed an initial decrease followed by a steady return to normal levels. Four patients, of whom three died, developed serious sepsis. The levels of alpha-l antichymotrypsin and C-reactive protein were much higher in patients with sepsis than in those without sepsis. The highest levels occurred during and often before the episode of sepsis was clinically evident. The immunoglobulins especially IgG and IgA were lower in those patients who developed sepsis than in those who did not. The results suggest that the serum levels of either C-reactive protein or alpha-l antichymotrypsin could be used both as an aid to diagnosis of sepsis and also to monitor the effect of therapy.

A phenytoin assay using dried blood spot samples suitable for domiciliary therapeutic drug monitoring.

A commercially available substrate-labelled fluorescent immunoassay procedure has been modified to create a simple rapid method for the determination of capillary phenytoin concentration in dried filter paper blood spots of patients on phenytoin therapy. The specimens are collected and dispatched to the laboratory by the patient, thus domiciliary monitoring of phenytoin therapy can take place. The technique was validated by comparing the phenytoin results of simultaneously collected capillary dried blood spots and conventional plasma samples. The technique offers a convenient method for overcoming many of the practical problems of monitoring phenytoin therapy in epilepsy.

Urine cortisol levels after burn injury.

The urinary level of cortisol has been assayed in 19 patients with burn injuries of varying severity over a 10-day period. Urine cortisol was increased in all patients over the initial days post burn when compared to normal health volunteers. In patients with the more severe burns mean cortisol levels correlated with the percentage body surface area of the burn. The overall pattern of cortisol excretion was similar in extent and duration to the changes in the levels of serum cortisol described in a previous study (Batstone et al., 1976). Further, urine cortisol excretion correlated with the levels of urine creatinine, magnesium, potassium and the sodium: potassium ratio lending further evidence to an important role of cortisol in peripheral tissue (particularly muscle). Cortisol output was still significantly raised at the end of the study period emphasizing the duration of the cortisol-induced catabolic drive after burn injury.

Lipoprotein changes after burn injury in man.

Lipoprotein changes have been investigated in 16 patients with burn injury. Serum, urine, and blister fluid were examined for apoprotein content. In the group of patients with moderate burns serum High Density Lipoprotein (HDL) fell drastically, and Low Density Lipoprotein (LDL) decreased slightly, whilst Very Low Density Lipoprotein (VLDL) rose. In blister fluid there was a greater loss of HDL apoprotein than LDL apoprotein or apoprotein C, whilst in concentrated urine a small quantity of HDL apoprotein could be detected. The loss of HDL, which is necessary as an apoprotein C receptor in the conversion of VLDL leads to LDL, may lead to a block in the conversion of VLDL to LDL. This may in part contribute to the hypertriglyceridemia, hypocholesterolemia, and hypophospholipidemia noted after burn injury.