Mechanisms of Abnormal Glucose Metabolism During the Treatment of Acute Severe Asthma

Twenty-five patients with acute severe asthma were treated withoxygen, corticosteroids and either salbutamol or aminophyllineby intravenous infusion. Blood glucose, plasma insulin and glucagonwere measured during the first 24 hours of treatment. Salbutamoland aminophylline rapidly caused hyperglycaemia, accompaniedby a rise in insulin and a fall in plasma glucagon. At firstthe increase in plasma insulin was insufficient to restore normoglycaemia,but by 24 hours homeostasis was restored. The early submaximalinsulin response was attributed to the fasting caused by breathlessness.There was no evidence of an increase in hormone secretion causedby direct ß₂-adrenergic stimulation of the pancreaticislets. The effect of corticosteroids on blood glucose overthe period of study was considerably less than the contributionof either salbutamol, or aminophylline.     

Glucagon-induced insulin secretion in normal diabetic subjects.

Eight normal subjects and ten diabetic patients were studied to compare the response of plasma insulin to glucagon with that to glucose and tolbutamide. Oral glucose tolerance test, glucagon test and tolbutamide-glucagon test were performed at intervals of several days. In glucose tolerance test, insulin response was reduced in the patients with severe diabetes. Plasma insulin increased and reached the peak 3 min after glucagon injection (glucagon I) in the normal controls, while plasma insulin response was reduced in diabetic patients, especially in the severe diabetics. In the normal controls plasma insulin rose and reached the peak 6 min after the tolbutamide injection and thereafter fell to the initial level. Glucagon injection following tolbutamide (glucagon II) caused the rise in insulin in the control subjects. In diabetics insulin response to either tolbutamide or glucagon I was reduced. Tolbutamide or glucagon II caused a significant difference in plasma insulin response in all the diabetic groups compared with the normal subjects, while glucose or glucagon I showed a significant increment of plasma insulin between the normal subjects and the severe diabetics. These results suggest that injection of tolbutamide as well as glucagon II provides a definite discrimination of insulin response in diabetics from the normal controls. The usefulness of the tolbutamide-glucagon test in the diagnosis of diabetes mellitus was discussed. -- glucose tolerance test; glucagon test; tolbutamide-glucagon test; plasma insulin.     

The effect of insulin on adenosine 3':5'-monophosphate and guanosine 3':5'-monophosphate concentrations in human plasma.

1. The action of insulin on plasma cyclic nucleotide concentrations in normal human subjects has been studied after intravenous injection, alone and in combination with glucagon. 2. After injection of insulin alone there was an initial small, though not significant, decrease in plasma cyclic AMP at 15 min followed by an increase to more than twice the initial concentration at 30 min. The increase was absent when hypoglycaemia was lessened by infusion of glucose after insulin injection. 3. Injection of insulin caused no significant change in plasma cyclic GMP concentration, whether or not glucose was infused after the hormone. 4. Glucagon (3-300 nmol, 10-1000 mug), caused a dose-dependent increase in plasma cyclic AMP concentration. The rise in plasma cyclic AMP produced by 3 or 30 nmol of glucagon was not significantly modified by simultaneous injection of insulin (44 nmol; 6 units).     

Somatostatin-Induced Changes in Insulin and Glucagon Secretion in Normal and Diabetic Dogs

In conscious dogs intravenously infused somatostatin (3.3 mug per min for 1 h) caused prompt and sustained declines in mean plasma insulin and glucagon, even during alanine infusion and intraduodenal casein hydrolysate feeding; plasma glucose declined, but not significantly. 6.7 mug per min of somatostatin significantly lowered pancreatoduodenal vein glucagon and insulin within 2.5 min and profoundly suppressed their secretion throughout the infusion. Consistent bihormonal suppression occurred at rates as low as 24 ng per kg per min, but was variable at 12 and 2.4 ng per kg per min. When somatostatin-induced (3.3 mug per min) hypoglucagonemia was corrected by exogenous glucagon, hyperglycemia occurred. In dogs with long-standing insulin-requiring alloxan diabetes 3.3 mug per min of somatostatin suppressed glucagon to 55 pg per ml throughout the 30-min infusion and lowered glucose by 36.4+/-6.1 mg per dl, about 1 mg per dl per min. Glucagon suppression was maintained despite alanine infusion, and glucose, which rose 29 mg per dl during alanine infusion without somatostatin, declined 58 mg per dl in the somatostatin-treated diabetic dogs despite alanine. Continuous infusion of somatostatin for 24 h in five insulin-requiring alloxan-diabetic dogs suppressed glucagon and lowered glucose significantly, usually to below normal.It is concluded that in normal dogs pharmacologic doses of somatostatin virtually abolish insulin and glucagon secretion in the basal state and during hyperaminoacidemia. Hyperglycemia occurs during somatostatin-induced insulin lack only if hypoglucagonemia is corrected. Somatostatin suppresses glucagon in diabetic dogs and lowers their plasma glucose approximately 1 mg per dl per min, even when the gluconeogenic substrate alanine is abundant. Glucagon suppression can be maintained for several hours in such dogs and hyperglycemia is thereby reduced.     

Effects of the new somatostatin analogue (BIM 23014) on blood glucose homeostasis in normal men

Changes in blood glucose homeostasis induced by the new somatostatin analogue BIM 23014 (BIM) were studied. Eight normal men (study 1) received either vehicle or 1000, 2000 and 3000 micrograms BIM as a 24 h s.c. infusion. Blood glucose, plasma insulin, C-peptide, glucagon and growth hormone (GH) were measured before treatment and then hourly for 24 h. In five normal men (study 2) an oral glucose tolerance test (OGTT) was performed during vehicle infusion and then on days 1 and 7 of a continuous s.c. infusion of 2000 micrograms BIM daily for 7 days. The same biological parameters as in study 1 were measured before OGTT and then twice-hourly for 5 h. Dose-dependent and transient glucose intolerance was observed in the first half of study 1. Except for glucagon, BIM significantly (P < 0.01) reduced plasma insulin, C-peptide and GH levels. In study 2 BIM infusion induced glucose intolerance and a drop in plasma insulin and C-peptide on day 1 which disappeared on day 7 of infusion. Higher on day 7 than on day 1, plasma GH secretion was significantly (P < 0.01) reduced throughout BIM infusion. In contrast plasma glucagon levels were not modified at any time. Side-effects were abdominal cramps and diarrhoea which were observed in most subjects when increasing BIM daily dose. In conclusion, BIM infusion induced transient changes in glucose homeostasis and insulin secretion in normal men. By contrast, plasma GH levels remained reduced throughout the treatment. BIM appears to be a useful tool to selectively inhibit GH secretion.     

Metabolic effects of norepinephrine and dobutamine in healthy volunteers

The objective of the present study was to evaluate the effects of norepinephrine (n = 9) and dobutamine (n = 7) on carbohydrate and protein metabolism in healthy volunteers in comparison with a control group (n = 9). Norepinephrine (0.1 microg/kg min), dobutamine (5 microg/kg min), or placebo was infused for 240 min. The plasma concentration of glucose, lactate, epinephrine, norepinephrine, insulin, and glucagon were determined. Glucose and urea production and leucine flux were measured using a tracer technique. Norepinephrine caused a persisting rise in plasma glucose concentration, whereas the increase in glucose production was only transient. A minor increase in plasma lactate concentration was observed, but it did not exceed the physiological range. No change in leucine flux, urea production, or plasma concentration of insulin, glucagon, or epinephrine was found. Dobutamine slightly decreased glucose production, whereas the plasma concentration of glucose and lactate did not change. The reduction in leucine flux was paralleled by a decrease in urea production. No change in the plasma concentration of insulin, glucagon, or the catecholamines was observed. In conclusion, both norepinephrine and dobutamine have only minor metabolic effects. Because glucose production is enhanced by alpha1- and beta2-adrenoceptor stimulation, we conclude that dobutamine is only a weak agonist at these adrenoceptors. These minor metabolic actions may make both compounds suitable for critically ill patients because no further increase in metabolic rate should be caused.     

Diagnostic value of intravenous glucagon test in insulinoma.

The intravenous glucagon test was performed in 11 patients with insulinoma and the diagnostic significance of the test was studied in comparison with the glucose test, the tolbutamide test and the arginine test. The curves of plasma insulin following the intravenous administration of glucagon were markedly different and strange in those patients with insulinoma compared with the normal controls. The maximal levels of plasma insulin ranged from 85 to 400 muU/ml, exceeding the normal range in 10 out of 11 patients, or 91%. Increased levels in the maximal plasma insulin were observed in 63%, 100% and 56% through the glucose test, the tolbutamide test and the arginine test, respectively. The distribution of the insulin areas, calculated from the insulin curves during these tests, was shown to be similar to that of the maximal levels of plasma insulin. There was no significant correlations between the maximal levels of plasma insulin in the glucagon test and the glucose test, the tolbutamide test or the arginine test. The present experiment demonstrated that the intravenous glucagon test, next to the tolbutamide test, caused a large increase in plasma insulin, and therefore, that this test is one of the most useful tools among the provocation tests, for the diagnosis of insulinoma.     

Effects of racemic, dextro-laevo-propranolol and isoxuprine on the metabolic and endocrine response to cold in the newborn rabbit

Abstract. The effect of racemic, dextro-, laevo-propranol or isoxuprine on the plasma glucose, free fatty acid (FFA), insulin, glucagon and glucocorticoid concentration was studied in rabbits aged 3–5 days at 35°C and after exposure to 25°C for 3 h. Cold exposure alone caused a large rise in plasma FFA and a significant rise in plasma insulin and glucocorticoids. At 35°C laevo-propranolol depressed both plasma FFA and glucose where-as dextro-propranolol caused a significant rise in plasma glucose, FFA, insulin and glucagon and a fall in plasma glucocorticoid concentration. Racemic propranolol resembled the laevo-isomer in depressing plasma FFA and the dextro-isomer in stimulating plasma insulin and glucagon but had no effect on the mean plasma glucose concentration. Isoxuprine caused a rise in plasma FFA and insulin levels. At 25°C laevo-propranolol blocked the cold-induced rise in plasma FFA, caused a rise in plasma insulin and an insignificant drop in plasma glucose. The effects of dextro-propranolol seen at 35°C were abolished by exposure to 25°C. Racemic propranolol resembled the laevo-isomer in partially blocking the rise in plasma FFA. Isoxuprine exaggerated the rise in plasma FFA and caused a significant fall in plasma glucagon concentration. Incubation of pieces of pancreas in vitro from rabbits aged 3–5 days or 5–7 weeks with the three types of propranolol at concentrations of 0.2, 2.0 and 20.0 μg/ml had no effect on basal or glucose stimulated insulin secretion. Racemic propranolol at concentrations of 40 and 60 μg/ml and laevo-propranolol at 80 μg/ml inhibited insulin release stimulated by glucose from pancreas of 5–7 week rabbits in vitro .     

Pharmacokinetics and bioavailability of injected glucagon: differences between intramuscular, subcutaneous, and intravenous administration

Pharmacokinetics and bioavailability of 1 mg glucagon injected intramuscularly (i.m.), subcutaneously (s.c.), or intravenously (i.v.) were studied in 6 nondiabetic men rendered hypoglycemic by s.c. injection of 10 U regular insulin. At 90 min after the insulin injection, when blood glucose levels had fallen to a mean of 49 mg/dl, glucagon was administered. Ten minutes later plasma glucagon levels had risen from a mean of 246 to 3233 pg/ml (s.c. experiment) and from 250 to 2638 pg/ml (i.m. experiment). Accordingly, there was no difference in blood glucose behavior whether glucagon was injected s.c. or i.m. In the i.v. experiment, plasma glucagon levels were significantly higher during the first 15 min after the glucagon injection when compared with the other experiments. The initially high levels of plasma glucagon after i.v. administration were associated with a steeper rise of glycemia during the first 5 min after glucagon injection; the maximal increase of blood glucose was, however, not different when compared with the s.c. or i.m. route of glucagon administration. Thus, in case of severe hypoglycemia, therapeutically administered glucagon will be most efficient when injected i.v., but there is no difference between the i.m. and s.c. routes of administration with regard to the efficacy to increase blood glucose levels.     

Responses of plasma adenosine 3',5'-monophosphate, blood glucose and plasma insulin to glucagon in humans

The effect of glucagon on plasma cyclic AMP (cAMP), insulin and blood glucose was examined in normal adult subjects. After an i.v. injection of glucagon there was a rapid, dose-dependent increase of plasma cAMP as well as insulin and blood glucose. Multiple injection of glucagon to the same subject with 60 min intervals gave almost identical responses of plasma cAMP and blood glucose, whereas the insulin response tended to decrease with time. Dose-dependent increases of plasma cAMP, insulin and blood glucose were also seen during a continuous i.v. infusion of glucagon. With the lowest doses of glucagon the blood glucose and plasma insulin concentrations were increased without any change of plasma cAMP. Plasma cAMP, insulin and blood glucose declined prior to the termination of glucagon infusion. During an endogenous hyperglucagonaemia, induced by alanine injection, there was no discernible change of plasma cAMP. We conclude that the early events of glucagon action may be studied in vivo by monitoring plasma cAMP. However, variations of plasma glucagon within the physiological range are not accompanied by measurable changes of cAMP in the peripheral circulation.     

Epinephrine supports the postabsorptive plasma glucose concentration and prevents hypoglycemia when glucagon secretion is deficient in man.

We hypothesized that adrenergic mechanisms support the postabsorptive plasma glucose concentration, and prevent hypoglycemia when glucagon secretion is deficient. Accordingly, we assessed the impact of glucagon deficiency, produced by infusion of somatostatin with insulin, without and with pharmacologic alpha- and beta-adrenergic blockade on the postabsorptive plasma glucose concentration and glucose kinetics in normal human subjects. During somatostatin with insulin alone mean glucose production fell from 1.5 +/- 0.05 to 0.7 +/- 0.2 mg/kg per min and mean plasma glucose declined from 93 +/- 3 to 67 +/- 4 mg/dl over 1 h; glucose production then increased to base-line rates and plasma glucose plateaued at 64-67 mg/dl over 2 h. This plateau was associated with, and is best attributed to, an eightfold increase in mean plasma epinephrine. It did not occur when adrenergic blockade was added; glucose production remained low and mean plasma glucose declined progressively to a hypoglycemic level of 45 +/- 4 mg/dl, significantly (P less than 0.001) lower than the final value during somatostatin with insulin alone. These data provide further support for the concept that maintenance of the postabsorptive plasma glucose concentration is a function of insulin and glucagon, not of insulin alone, and that adrenergic mechanisms do not normally play a critical role. They indicate, however, that an endogenous adrenergic agonist, likely adrenomedullary epinephrine, compensates for deficient glucagon secretion and prevents hypoglycemia in the postabsorptive state in humans. Thus, postabsorptive hypoglycemia occurs when both glucagon and epinephrine are deficient, but not when either glucagon or epinephrine alone is deficient, and insulin is present.     

Insulin releasing action of N-terminal peptides of glucagon in dogs.

The relationship between the molecular structure and insulin releasing action of glucagon remains unknown. In order to investigate the direct action of N-terminal peptides of glucagon, glucagon (1-14), and glucagon (1-21) were studied using an in situ local circulation of the canine pancreas. These glucagon fragments as well as glucagon (1-29) were infused into the superior pancreaticoduodenal artery in a dose of 400 pmol for 10 min during the glucose or arginine infusion, and plasma insulin and glucagon in the superior pancreaticoduodenal vein were determined by radioimmunoassay. During the glucose infusion, glucagon (1-14) elicited a slight increase in plasma insulin, whereas glucagon (1-21) and (1-29) revealed significant changes in plasma insulin. In these experiments plasma glucagon did not change significantly following the administration of glucagon (1-14) or (1-21). During the arginine infusion all of the glucagon fragments studied enhanced insulin secretion markedly, whereas glucagon secretion was not affected. Furthermore, graded doses of glucagon (1-14) (50, 150, and 400 pmol) elicited an increase in plasma insulin in a dose-related manner. It is concluded from the present study that the N-terminal peptides of glucagon stimulate insulin release especially during the arginine infusion.     

The effect of gastrin on basal and aminoacid-stimulated insulin and glucagon secretion in man

Abstract. The effect of gastrin on basal and aminoacid-stimulated glucagon and insulin secretion was studied in eleven normal young subjects. The concentrations of glucagon, insulin and gastrin in plasma or serum were measured radioimmunochemically. The results of amino-acid-stimulation were compared to those obtained during a protein-rich meal.
Intravenous injection of synthetic human gastrin-17 in doses from 15.6 ng to 1 μg/kg increased the concentration of glucagon and insulin in peripheral venous blood to a maximum within 5 min. In spite of the enhanced concentrations of insulin induced by gastrin, corresponding concentrations of glucose were either unchanged or increased. Infusion of a mixture of fifteen aminoacids increased the concentrations of glucose, glucagon and insulin. While the increases in glucose and insulin concentrations were similar to those obtained after a protein-rich meal, the glucagon response was much larger after the infusion. Injection of gastrin-17 after 30 min of infusion of aminoacids did not potentiate either the glucagon or the insulin response.
The results indicate that gastrin, besides stimulating insulin secretion, can also stimulate glucagon secretion in a dose-dependent manner. The concentrations of gastrin necessary to stimulate glucagon secretion significantly correspond to the concentrations found in diseases with endogenous hypergastrinaemia (achlorhydria and Zollinger-Ellison syndrome). While gastrin potentiates the glucose-induced insulin secretion, it does not potentiate neither the aminoacid-induced insulin nor glucagon secretion.     

The effect of experimental insulin deficiency on glucagon secretion

Suppression of pancreatic glucagon secretion by hyperglycemia is a characteristic of normal alpha cell function. However, in diabetic subjects, plasma glucagon is normal or high despite hyperglycemia. It seemed possible that the presence of glucose or its metabolites within the alpha cell might be essential for suppression of glucagon secretion, and that in diabetes an intracellular deficiency of glucose secondary to insulin lack might be responsible for the nonsuppressibility. The present study was designed to determine the effect upon glucagon secretion of blockade of glucose metabolism and of experimental insulin deficiency.Blockade of glucose metabolism was induced in dogs by administration of 2-deoxyglucose or mannoheptulose. A striking rise in glucagon was observed despite accompanying hyperglycemia and hyperinsulinemia, which, in the case of mannoheptulose, was induced by infusing crystalline insulin.To determine if insulin lack also causes paradoxical hyperglucagonemia, dogs were made severely diabetic by alloxan. Fasting glucagon levels ranged from 3 to 22 times normal despite severe hyperglycemia, and were quickly restored to normal by infusing insulin. Diabetes induced in rats by anti-insulin serum was also associated with significant elevation in plasma glucagon. However, diazoxide-induced insulin lack did not increase glucagon in dogs.It is concluded that normal suppression of glucagon secretion by hyperglycemia does not occur when glucose metabolism is blocked or when severe insulin deficiency is produced. It is suggested that normal glucose metabolism within the alpha cell may be an insulin-requiring process without which hyperglycemic suppression of glucagon release cannot occur.     

Role of changes in insulin and glucagon in glucose homeostasis in exercise.

This experiment was performed to determine if plasma glucose homeostasis is maintained in normal human volunteers during light exercise (40% maximal oxygen consumption [VO2 max]) when changes in insulin and glucagon are prevented. Hormonal control was achieved by the infusion of somatostatin, insulin, and glucagon. Glucose kinetics and oxidation rates were determined with stable isotopic tracers of glucose, and by indirect calorimetry. Two different rates of replacement of insulin and glucagon were used; in one group, insulin was clamped at 19.8 +/- 2.6 microU/ml (high-insulin group), and in the other group insulin was clamped at 9.2 +/- 1.3 microU/ml (low-insulin group). Glucagon was maintained at 261 +/- 16.2 and 124 +/- 6.4 pg/ml, respectively, in the high-insulin and low-insulin groups. Without hormonal control, plasma glucose homeostasis was maintained during exercise because the increase in glucose uptake was balanced by a corresponding increase in glucose production. When changes in insulin and glucagon were prevented, plasma glucose concentration fell, particularly in the high-insulin group. Glucose uptake increased to a greater extent than when hormones were not controlled, and glucose production did not increase sufficiently to compensate. The increase in glucose uptake in the hormonal control groups was associated with an increased rate of glucose oxidation. When euglycemia was maintained by glucose infusion in the hormonal control subjects, the modest increase in glucose production that otherwise occurred was prevented. It is concluded that during light exercise there must be a reduction in insulin concentration and/or an increase in glucagon concentration if plasma glucose homeostasis is to be maintained. If such changes do not occur, hypoglycemia, and hence exhaustion, may occur.     

Practical aspects in performing the glucagon test in the measurement of C-peptide secretion in diabetic patients

The secretion of plasma C-peptide after intravenous glucagon stimulation was studied in 15 insulin-treated diabetic patients with onset of diabetes after the age of 30. The mean stimulation of C-peptide secretion caused by glucagon given in the fasting state and by a standardized breakfast were similar. Low blood glucose values (less than 3.5 mmol/l) were found to suppress the stimulating action of glucagon on the pancreas almost completely. When the glucagon test was performed 1.5 hours after a standardized breakfast, the mean concentration of plasma C-peptide was 62% higher than in the test in the fasting state, showing that the stimulating actions of glucagon and breakfast on the secretion of insulin are additive. The results indicate that when determining the level of plasma C-peptide after stimulation with glucagon, in order to distinguish between insulin-dependent and non-insulin-dependent diabetic patients, it is critical to take into account the consequence of low blood glucose values and to standardize the test conditions in regard to pre-test meals.     

Effect of galanin on plasma glucose,insulin and pancreatic glucagon in dogs

The effect of synthetic galanin on plasma glucose, insulin and pancreatic glucagon levels in dogs was studied. Infusion of galanin caused a rapid, reversible and dose-dependent reduction in basal insulin level. A maximal increase in blood glucose level accompanying the insulin decrease was observed when galanin was administered at a dose of 4 micrograms/kg per h. Pancreatic glucagon levels showed little change compared with basal secretion. These results indicate that galanin is involved in the regulation of glucose through control of insulin secretion.     

Adrenergic control of plasma magnesium in man

Regulation of magnesium balance is poorly understood. However, hypomagnesaemia has been reported in patients in clinical situations where circulating catecholamines are raised including myocardial infarction, cardiac surgery and insulin-induced hypoglycaemia stress tests. The effects of L-adrenaline infusions, sufficient to achieve pathophysiological levels of adrenaline, and of therapeutic intravenous infusions of salbutamol, a beta 2-agonist, on plasma magnesium, plasma potassium, plasma glucose and plasma insulin levels were studied in a placebo-controlled design in eight normal subjects. Plasma magnesium levels fell significantly during the adrenaline infusion and also during the salbutamol infusion, though more slowly. In a 1 h period of observation after cessation of the infusions no recovery of plasma magnesium levels was seen. Significant falls in plasma potassium levels were also observed during both infusions with spontaneous recovery within 30 min after the infusions. No significant changes in plasma insulin levels occurred with either salbutamol or L-adrenaline compared with control. Plasma glucose levels rose significantly during the adrenaline infusion. The study suggests that both L-adrenaline and salbutamol cause shifts in plasma magnesium which are not mediated by insulin. We propose that intracellular shifts of magnesium occur as a result of beta-adrenergic stimulation.     

The role of insulin and glucagon in the regulation of basal glucose production in the postabsorptive dog.

The aim of the present experiments was to determine the role of insulin and glucagon in the regulation of basal glucose production in dogs fasted overnight. A deficiency of either or both pancreatic hormones was achieved by infusin somatostatin (1 mug/kg per min), a potent inhibitor of both insulin and glucagon secretion, alone or in combination with intraportal replacement infusions of either pancreatic hormone. Infusion of somatostatin alone caused the arterial levels of insulin and glucagon to drop rapidly by 72+/-6 and 81+/-8%, respectively. Intraportal infusion of insulin and glucagon at rates of 400 muU/kg per min and 1 ng/kg per min, respectively, resulted in the maintenance of the basal levels of each hormone. Glucose production was measured using tracer (primed constant infusion of [3-3H]glucose) and arteriovenous difference techniques. Isolated glucagon deficiency resulted in a 35+/-5% (P less than 0.05) rapid and sustained decrease in glucose production which was abolished upon restoration of the plasma glucagon level. Isolated insulin deficiency resulted in a 52+/-16% (P less than 0.01) increase in the rate of glucose production which was abolished when the insulin level was restored. Somatostatin had no effect on glucose production when the changes in the pancreatic hormone levels which it normally induces were prevented by simultaneous intraportal infusion of both insulin and glucagon. In conclusion, in the anesthetized dog fasted overnight; (a) basal glucagon is responsible for at least one-third of basal glucose production, (b) basal insulin prevents the increased glucose production which would result from the unrestrained action of glucagon, and (c) somatostatin has no acute effects on glucose turnover other than those it induces through perturbation of pancreatic hormone secretion. This study indicates that the opposing actions of the two pancreatic hormones are important in the regulation of basal glucose production in the postabsorptive state.     

Metabolic responses to plasma concentrations of theophylline.

We investigated the effect of intravenous infusions of aminophylline on plasma glucose, insulin (IRI), glucagon (IRG), growth hormone (HGH), cortisol, and free fatty acid (FFA) levels in healthy young subjects. Six received an intravenous loading dose of aminophylline (6.0 mg/kg over 20 min) followed by a maintenance dose (0.9 mg/kg/hr) for 100 min. Another 7 subjects initially received smaller loading (3.0 mg/kg) and maintenance (0.45 mg/kg/hr) doses, and after 60 min they received a second loading dose (3.0 mg/kg) followed by a larger maintenance dose (0.9 mg/kg/hr) over 120 min. In these fasting volunteers, infusion of aminophylline, which produced theophylline levels in the usual therapeutic range (10 to 20 microgram/ml) caused small increases in plasma glucose levels without changing IRI, IRG, HGH, or cortisol. There were rapid, pronounced, and prolonged rises in FFA associated with the aminophylline infusion. Increases in FFA paralleled the rise in theophylline levels. It is concluded that routine therapeutic doses of theophylline, i.e., doses that achieve serum levels normally encountered in treatment for bronchial asthma, cause a marked rise in FFA and a slight rise in glucose (8 +/- 3 mg/dl) without changing levels of IRI, IRG, HGH, or cortisol.