A potent high-titre glucagon antibody pool was used to induce a state of acute glucagon deficiency in order to investigate the importance of glucagon in maintaining euglycaemia in the fed and fasted anaesthetised rat. Binding characteristics of the antiserum and evidence of its neutralisation of the biological effects of exogenous glucagon are described. The amount of antibody administered was capable of neutralising up to 12 times the total content of glucagon (approximately 1nmol) in the rat pancreas. The hyperglycaemic response to 1.43 nmol exogenous glucagon was significantly inhibited in the rat by glucagon antibodies given intravenously or intraperitoneally (p < 0.001). However, no changes in plasma glucose occurred in rats fasted 16 h (4.35±0.1 mmol/l or 24 h (4.0±0.05 mmol/l) after antibody administration. The same dose of glucagon antibodies produced no change in plasma glucose (6.1±0.2 mmol/l), immunoreactive insulin (1.85±0.05 μg/l) or immunoreactive somatostatin (110±30 ng/l) in rats after antibody administration. Antibody excess, equivalent to a binding capacity for glucagon of 40 nmol/l in the plasma of recipient animals, was demonstrable at all times after passive immunisation. The absence of any affect on glucose concentrations following immunoneutralisation of glucagon suggests that glucagon secretion may not be a major factor in the maintenance of euglycaemia in the rat.

L-tryptophan was given to fasted rats intragastrically or intravenously at a dose of 500 of 166 mg/kg b.w., respectively. Mean (+/- SEM) plasma insulin levels rose after both stimuli and at 10, 30 and 45 min were 63 +/- 26, 86 +/- 25, 48 +/- 7 mU/l after oral, and 28 +/- 4, 25 +/- 6, 19 +/- 6 mU/l after intravenous administration, respectively; plasma tryptophan levels at the above intervals during the oral study were 27%, 60% and 128%, respectively of those during the intravenous study. Plasma GIP levels rose only after intragastric tryptophan administration, and plasma GLI levels did not change in response to either intragastric or intravenous tryptophan. Intragastric tryptophan consistently raised plasma pancreatic glucagon levels which were significantly higher than those observed in control rats given saline, 5, 10, 30 and 45 min after administration. The rise in plasma glucagon was attributed to the glucagonotropic effect of GIP.

Little is currently known about the factors controlling somatostatin secretion. A radioimmunoassay has been developed that is sufficiently specific and sensitive to be used for physiological studies of circulating levels in man. During insulin-induced hypoglycaemia a rise in plasma somatostatin was seen in each of ten subjects studies. Although this paralleled the rise in circulating glucagon and growth hormone, no individual relationships were found either between these variables or to any change in cortisol or insulin C-peptide. In contrast no rise in somatostatin was seen during surgical stress. Thus, contrary to expectation, circulating somatostatin levels can be altered by metabolic stimuli. It seems likely that this peptide may serve an endocrine as well as a paracrine role since its modulating effects may occur not only near to but also at a distance from the site of secretion. It is not yet clear whether the somatostatin measured comes from the hypothalamus, any other part of the central nervous system or the gastrointestinal tract.

SUMMARY Using a recently validated radioimmunoassay, changes in circulating somatostatin have been measured in normal subjects after food (a standard breakfast), and oral and intravenous glucose. After the standard breakfast, a clear and sustained rise in plasma somatostatin was seen in all subjects from a mean value (± 1 SE) of 28 ± 7 pg/ml to a mean peak value, at 60 min of 57 ± 11 pg/ml. When glucose was taken by mouth a significant but smaller rise was seen, but intravenous glucose caused no significant change in plasma somatostatin. A rise in circulating somatostatin after feeding has not previously been demonstrated in normal man and it is suggested that somatostatin may have an important endocrine role in the gut.

Five healthy volunteers and 6 diabetics were given a mixed test meal on two occasions — once with and once without 10 g guar flour. Addition of guar caused a 47% decrease in maximum post-prandial GIP levels, a 48% decrease in blood glucose and a 48% decrease in plasma insulin in normal subjects. In diabetics, addition of guar caused a 30% reduction in maximum post-prandial GIP and 58% decrease in blood glucose. Four normal and 6 diabetic subjects were given a predominantly carbohydrate meal, again with and without 10 g guar. Addition of guar caused a 78% decrease in blood glucose and a 59% decrease in plasma insulin in normal subjects. In diabetics addition of guar caused a 71% decrease in maximum post-prandial plasma GIP and a 68% decrease in blood glucose. Lowering of post-prandial blood glucose, plasma insulin and GIP levels by guar was statistically significant in every case. Addition of guar to the predominantly carbohydrate meal caused a decrease in total plasma GLI in both normal and diabetic subjects but reached statistical significance only in the normal subjects. There was a highly significant correlation (r=0.83; p<0.0005) between peak post-prandial insulin levels in normal subjects and the corresponding plasma GIP concentration. The reduction in GIP or GLI secretion may, therefore, be partly responsible for the smaller rise in plasma insulin observed in normal volunteers when guar is added to meals.