Insulin antagonistic effects of epinephrine and glucagon in the dog

The effect of glucagon and/or epinephrine on the response to physiologic insulin infusion was evaluated in dogs. Insulin alone produced a transient fall (50%) in glucose output, a threefold rise in glucose clearance, and a decline in plasma glucose, which then stabilized (40--45 mg/dl) afer 1 h. Glucagon infusion prevented the fall in glucose output, but had no effect on insulin-induced elevations in glucose clearance. The fall in plasma glucose was delayed (20 min), but late hypoglycemia was unaltered. Epinephrine infusion blocked the fall in glucose output as well as the insulin-induced rise in glucose clearance and uptake. Thus, while epinephrine and glucagon were equally effective in preventing the fall in glucose output induced by insulin, epinephrine was more effective in preventing insulin-induced hypoglycemia by virtue of its direct inhibitory action on insulin-stimulated glucose utilization. Simultaneous addition of glucagon and epinephrine increased glucose output twofold, suppressed glucose clearance, and caused a 15--30 mg/dl increase in plasma glucose despite ongoing hyperinsulinemia. Our data thus indicate that synergistic hormone interactions may play a role in the counterregulation of insulin hypoglycemia.     

Effects of metoprolol on the counter-regulation and recognition of prolonged hypoglycemia in insulin-dependent diabetics

The effect of metoprolol on the counter-regulation of prolonged hypoglycemia was studied in eight insulin-dependent diabetics. Insulin was given as an i.v. infusion of 2.4 U/h over 180 min alone, or together with metoprolol (3.0 mg i.v. bolus followed by an i.v. infusion of 4.8 mg/h) in random order. Blood glucose, counter-regulatory hormones, hypoglycemic symptoms and the cardiovascular responses were assayed over 240 min. Metoprolol did not significantly modify the blood glucose levels. The plasma levels of free insulin, however, were elevated by approximately 20% (p less than 0.01) by metoprolol during hypoglycemia and the plasma concentrations of epinephrine, norepinephrine, growth hormone and cortisol were enhanced by the drug. Sweating was increased by metoprolol, while other symptoms were unaltered. We conclude that metoprolol administered acutely does not aggravate prolonged hypoglycemia in diabetics with blunted response of glucagon. Moreover, exaggerated responses of counter-regulatory hormones, provoked by metoprolol, may compensate for the inhibitory effect of this drug on insulin clearance.     

Effect of improved glycemic control by continuous subcutaneous insulin infusion on hormonal responses to insulin-induced hypoglycemia in type 1 diabetics

Glucose counter-regulatory capacity and the hormonal responses to insulin-induced hypoglycemia were studied in eight type 1 diabetics before and after improvement of metabolic control by continuous subcutaneous insulin infusion (CSII). The intensified treatment resulted in a decrease in mean glycosylated hemoglobin from 11.6 +/- 0.5 to 9.3 +/- 0.4% within a mean period of 14 weeks. During a constant rate infusion of insulin (2.4 U/h), steady state levels of glucose appeared in all subjects. The steady state glucose level was identical before and after CSII. The counter-regulatory hormonal responses showed significantly higher epinephrine levels, while glucagon, growth hormone, and cortisol were not influenced. In parallel with the heightened epinephrine response the pulse rate response was significantly enhanced. The restitution of blood glucose after insulin hypoglycemia was not modified. It is concluded that a more vigorous catecholaminergic response to hypoglycemia is achieved after improved metabolic control by CSII.     

Differential effects of epinephrine on glucose production and disposal in man.

Normal subjects were infused 1) with epinephrine (50 ng/(kg.min)) for 180 min followed by epinephrine plus glucagon (3 ng/(kg.min)) for 60 min after which the epinephrine infusion rate was increased (125 ng/(kg.min)) or 2) with epinephrine plus somatostatin (500 microgram/h) for 180 min. Epinephrine increased glucose production and plasma glucagon transiently but caused persistent suppression of glucose clearance and sustained hyperglycemia (despite increased plasma insulin and gluconeogenic substrates); glucose production increased again on addition of glucagon and on increasing the epinephrine infusion rate. During epinephrine plus somatostatin, glucose production still increased transiently, but further suppression of glucose clearance caused more marked hyperglycemia. In conclusion, 1) in man hyperepinephrinemia within the physiological range caused sustained suppression of glucose clearance but only a transient increase in glucose production; 2) this transient hepatic response a) was not due to glycogen or substrate depletion, b) occurred without changes in plasma glucagon or insulin, c) was specific for epinephrine but permitted subsequent responses to changes in plasma epinephrine; 3) epinephrine can serve as a physiological regulator of glucose homeostasis in man both by increasing glucose production and by decreasing glucose clearance.     

Glucose counterregulation, hypoglycemia, and intensive insulin therapy in diabetes mellitus

The prevention or correction of hypoglycemia is the result of both dissipation of insulin and activation of counterregulatory systems. In the models studied to date, glucagon and epinephrine have been shown to be the key counterregulatory factors; the potential roles of other hormones, neural factors, or substrate mechanisms in other models and during more gradual recovery from hypoglycemia remain to be defined. Deficient glucagon responses to decrements in plasma glucose, which are common in patients with IDDM and occur in some patients with NIDDM, result in altered counterregulation. But counterregulation is generally adequate, because epinephrine compensates for it. Defective glucose counterregulation due to combined deficiencies of glucagon and epinephrine secretory responses occurs in many patients, typically those with longstanding diabetes, and must be added to the list of factors known to increase the risk of hypoglycemia, at least during intensive therapy. From the material reviewed, it should be apparent that much has been learned about glucose counterregulation. It should be equally clear that much remains to be learned. Among the many possibilities, we consider four worthy of emphasis. First of all, we need to examine the physiology and pathophysiology of glucose counterregulation in additional models (e.g., during exercise) and over longer periods. Secondly, we need to determine whether central nervous system adaptation to antecedent glycemia occurs and, if so, identify its mechanisms. Thirdly, we need to develop better methods of insulin delivery or learn to correct or compensate for defective counterregulatory systems, if we are to achieve euglycemia safely in diabetic patients with defective glucose counterregulation. Finally, we need to know whether effective control of diabetes mellitus prevents development of defective glucose counterregulation.     

Control of hepatic glycogen metabolism in the rhesus monkey: effect of glucose, insulin, and glucagon administration.

The effects of intravenous glucose, insulin and glucagon admininistration on the hepatic glycogen synthase and glycogen phosphorylase systems were assessed in the anesthetized rhesus monkey. Results were correlated with measurements of hepatic cyclic AMP (cAMP) concentrations and plasma glucose, insulin, and glucagon concentrations. Both glucose and insulin administration promoted significant inactivation of phosphorylase by 1 min, which was followed by more gradual activation of synthase. Neither glucose nor insulin caused significant changes in hepatic cAMP. Marked hyperglucagonemia resulting from insulin-induced hypoglycemia did not cause increases IN in hepatic cAMP, suggesting that the elevated insulin levels possibly inhibited glucagon action on the hepatic adenylate cyclase-cAMP system. Glucagon administration caused large increases in hepatic cAMP and activation of phosphorylase within 1 min, followed by more gradual inactivation of synthase when it had been previously activated by glucose. Concomitant glucose infusion, with resulting increased plasma insulin concentrations, markedly diminished the duration of hepatic cAMP elevations following glucagon adminstration, again suggesting an insulin inhibition of glucagon action on the hepatic adenylate-cAMP system.     

Studies of insulin resistance following hypoglycemia in insulin-dependent diabetes mellitus

Insulin resistance was assessed after a hypoglycemia induced by insulin (1.5 mU X kg-1 X min-1) between 7 and 8 a.m. in 10 well-insulinized patients with insulin-dependent diabetes mellitus (IDDM). Blood glucose levels during a somatostatin (100 micrograms X h-1)-insulin (0.4 mU X kg-1 X min-1)-glucose (4.5 mg X kg-1)-infusion test (SIGIT) performed between 11 a.m. and 3 p.m. served as an indicator of total body insulin resistance. Plasma epinephrine, growth hormone, and cortisol increased in response to hypoglycemia, while blunted responses of glucagon were simultaneously registered. At the start of the subsequent SIGIT, blood glucose and plasma-free insulin concentrations were similar to those obtained in the control study without preceding hypoglycemia, and at this point all counter-regulatory hormones had returned to basal. During the SIGIT close to identical levels of plasma-free insulin and counter-regulatory hormones were registered, despite which a significant hyperglycemia was seen 2 hours after the start of the SIGIT when preceded by hypoglycemia. In a separate study, the SIGIT was shown to have a good reproducibility in IDDM patients. We conclude that hypoglycemia evokes a state of insulin resistance for several hours, as demonstrated by elevated blood glucose levels during a somatostatin-insulin-glucose-infusion test.     

Identification of type I diabetic patients at increased risk for hypoglycemia during intensive therapy

During intravenous insulin infusions (40 mU per kilogram of body weight per hour for up to 100 minutes), 9 of 22 patients with insulin-requiring diabetes mellitus had neurologic signs or symptoms of hypoglycemia, plasma glucose concentrations that were below 35 mg per deciliter (1.9 mmol per liter) and continued to decline, or both. This inadequate glucose counterregulation resulted from the combined effect of deficient glucagon and epinephrine responses. In 8 of the 9 patients with inadequate counterregulation severe hypoglycemia developed during subsequent intensive therapy, whereas such episodes occurred in only 1 of 13 patients with adequate counterregulation. Thus, an intravenous insulin-infusion test can prospectively identify patients who are at increased risk for recurrent severe hypoglycemia during intensive therapy for diabetes.     

Hypoglycemia counterregulation during sleep

STUDY OBJECTIVES: In insulin-treated patients with diabetes, episodes of severe hypoglycemia often occur during sleep, which might reflect an altered counterregulation and reduced awareness. This study examined the influence of sleep on the counterregulatory response to hypoglycemia in healthy subjects. DESIGN: Subjects participated in two experimental conditions; statistical tests relied on within subject comparisons. SETTING: University hospital sleep laboratory. PARTICIPANTS: 15 healthy young men. INTERVENTIONS: Hypoglycemia (2.8 mmol/l) was induced for 45 min by insulin infusion once during sleep and once at the same time of night while being awake. MEASUREMENTS AND RESULTS: Counterregulatory hormone concentrations (epinephrine, norepinephrine, ACTH and cortisol) and sleep recordings were obtained. Differences in the hormonal responses to hypoglycemia between sleep and wake conditions remained non-significant, indicating that sleep does not exert a primary influence on the strength of counterregulation. However, the glycemic threshold for the onset of counterregulation was significantly changed during sleep: The average onset threshold for epinephrine and norepinephrine counterregulation was 3.3 +/- 0.1 mmol/l for the wake condition and 2.7 +/- 0.1 mmol/l for the sleep condition (P < 0.001). A decrease in sleep depth coincided with the onset of the counterregulatory response, with most subjects showing signs of awakening. CONCLUSIONS: During sleep, the organism is less sensitive to hypoglycemia. Hypoglycemia per se has an awakening effect.     

Reflex adrenergic control of endocrine pancreas evoked by unloading of carotid baroreceptors in cats.

The effects of unloading of the carotid baroreceptors on arterial plasma glucose concentration as well as on portal plasma immunoreactive glucagon (IRG) and insulin (IRI) concentrations were studied in anestethized, vagotomized cats either by sectioning the sinus nerves or by lowering the pressure in the isolated carotid sinuses. Complete elimination of the carotid baroreceptor discharge by cutting the sinus nerves caused an increase in the arterial plasma glucose concentration by 100% and an increase in the portal IRG level by about 200%, whereas the portal IRI concentration decreased to 50% of its basal value. These baroreceptor-induced changes of the plasma IRG and IRI levels seemed to be graded in relation to the drop in carotid blood pressure and they were clearly detectable when the pressure was lowered from 120 to 90 mmHg in the isolated carotid sinus preparation. The described reflex hyperglycemia, hyperglucagonemia and hypoinsulinemia were mediated to the pancreas and liver mainly by the sympatho-adrenal system, since cutting the splanchnic nerves above the adrenal glands abolished the hyperglycemia and hypoinsulinemic responses and markedly depressed the magnitude of the hyperglucagonemic response. In adrenalectomized cats, complete unloading of the baroreceptors evoked both hyperglucagonemia and hypoinsulinemia although the magnitude of the hormonal responses was diminished. In animals where the pancreas and liver were sympathectomized but the adrenal glands left intact, cutting the sinus nerves evoked a doubling of the IRG level and a slight increase in plasma glucose, but no significant change of the IRI level. I.v. infusion of adrenaline (1 microgram/kg X min) or noradrenaline (5 microgram/kg X min) caused pronounced increases in IRG and plasma glucose and a clear-cut reduction of IRI. We conclude that the function of the endocrine pancreas in the cat can be influenced by variations in the blood pressure by means of a reflex control which originates from arterial baroreceptors. This reflex adjustment of the endocrine pancreas is mediated chiefly by two links of the sympatho-adrenal system, namely by catecholamine-release from the adrenal medulla and, more importantly, by a direct adrenergic nerve fibre influence on the alpha- and beta- cells.     

Lactate infusion increases brain energy content during euglycemia but not hypoglycemia in healthy men

A special characteristic of the brain is the usage of lactate as alternative fuel instead of glucose to preserve its energy homeostasis. This physiological function is valid for sufficient cerebral glucose supply, as well as presumably during hypoglycemia, given that exogenous lactate infusion suppresses hormonal counterregulation. However, it is not yet clarified whether this effect is mediated by the use of lactate as an alternative cerebral energy substrate or any other mechanism. We hypothesized that under conditions of limited access to glucose (ie, during experimental hypoglycemia) lactate infusion would prevent hypoglycemia‐induced neuroenergetic deficits in a neuroprotective way. In a randomized, double‐blind, crossover study, lactate vs placebo infusion was compared during hyperinsulinemic‐hypoglycemic clamps in 16 healthy young men. We measured the cerebral high‐energy phosphate content — ie, adenosine triphosphate (ATP), phosphocreatine (PCr) and inorganic phosphate (Pi) levels — by ³¹P‐magnetic resonance spectroscopy as well as the neuroendocrine stress response. During euglycemia, lactate infusion increased ATP/Pi as well as PCr/Pi ratios compared with baseline values and placebo infusion. During hypoglycemia, there were no differences between the lactate and the placebo condition in both ratios. Hormonal counterregulation was significantly diminished upon lactate infusion. Our data demonstrate an elevated cerebral high‐energy phosphate content upon lactate infusion during euglycemia, whereas there was no such effect during experimental hypoglycemia. Nevertheless, lactate infusion suppressed hypoglycemic hormonal counterregulation. Lactate thus adds to cerebral energy provision during euglycemia and may contribute to an increase in ATP reserves, which in turn protects the brain against neuroglucopenia under recurrent hypopglycemic conditions, eg, in diabetic patients.     

The effect of different diets and of insulin on the hormonal response to prolonged exercise

The importance of carbohydrate availability during exercise for metabolism and plasma hormone levels was studied. Seven healthy men ran on a treadmill at 70% of individual maximal oxygen uptake having eaten a diet low (F) or high (CH) in carbohydrate through 4 days. At exhaustion the subjects were encouraged to continue to run while glucose infusion increased plasma glucose to preexercise levels. Forearm venous blood, biopsies from vastus muscle and expiratory gas were analyzed. Time to exhaustion was longer in CH- (106 +/- 5 min (S.E.)) than in F-expts. (64 +/- 6). During exercise, overall carbohydrate combustion rate, muscular glycogen depletion and glucose and lactate concentrations, carbohydrate metabolites in plasma, and estimated rate of hepatic glucose production were higher, fat metabolites lower, and the decrease in plasma glucose slower in CH- than in F-expts. Plasma norepinephrine increased and insulin decreased similarly in CH- and F-expts., whereas the increase in glucagon, epinephrine, growth hormone and cortisol was enhanced in F-expts. Glucose infusion eliminated hypoglycemic symptoms but did not substantially increase performance time. During the infusion epinephrine decreased markedly and glucagon even to preexercise levels. Infusion of insulin (to 436% of preexercise concentration) in addition to glucose in F-expts. did not change the plasma levels of the other hormones more than infusion of glucose only but reduced fat metabolites in plasma. At exhaustion muscular glycogen depletion was slow, and the glucose gradient between plasma and sarcoplasma as well as the muscular glucose 6-phosphate concentration had decreased. Conclusions: The preceding diet modifies the energy depots, the state of which (as regards size, receptors and enzymes) is of prime importance for metabolism during prolonged exercise. Plentiful carbohydrate stores favor both glucose oxidation and lactate production. During exercise norepinephrine increases and insulin decreases independent of plasma glucose changes whereas receptors sensitive to glucose privation but not to acute changes in insulin levels enhance the exercise-induced secretion of glucagon, epinephrine, growth hormone and cortisol. Abolition of cerebral hypoglycemia does not inevitably increase performance time, because elimination of the hypoglycemia may not abolish muscular energy lack.     

Effects of short-term and prolonged infusions of somatostatin on endocrine pancreas, body weight and food intake in rats

Infusion of cyclic somatostatin (700 mg/kg/min) for 4 h in rat fed and libitum suppressed basal insulin but not glucagon release. It was accompanied by hypoglycemia during the first hour whereas, at the end of the infusion, hyperglycemia was present. The same dose of somatostatin applied 60 min prior to and during a 30 min load of glucose or arginine significantly inhibited their effects on insulin and glucagon release. In contrast, when this dose of somatostatin was given during a 24 h period by the i.v. route it did not inhibit glucose induced insulin release though circulating somatostatin levels were constantly and markedly elevated. Furthermore, in rats continuously infused with somatostatin for 4 days, no effect was found either on plasma concentrations of glucose, insulin, glucagon, growth hormone and cyclic AMP, or on body weight gain, food consumption or water intake. The pancreases of these animals showed normal concentrations of insulin and glucagon and a normal nuclear area of D-cells. Our experiments demonstrate that, in short-term experiments in rats, somatostatin influences insulin and glucagon release as well as glucose homeostasis. Furthermore, they suggest that during prolonged i.v. administration of somatostatin, rats develop mechanisms counteracting the effect of the peptide, e.g., peripheral tachyphylaxis.     

The evaluation of glucagon infusion algorithms for a counterregulatory system in artificial endocrine pancreas

As counterregulatory system of artificial endocrine pancreas, glucagon infusion algorithm has been developed and its usefulness has been examined in pancreatectomized dogs and a pancreatectomized diabetic patient. Glucagon infusion rate (G1nIR(t)) was determined depending on proportional plus derivative action to blood glucose concentration (BG(t] with the time delay (tau) to start infusion as follows. G1nIR(t) = Gp(BGp- BG(t-tau)) + Gd(-dBG(t-tau)) + Gc where BGp is the projected value of blood glucose concentration, Gp, and Gd are the coefficients and Gc is the constant for basal glucagon supplement. Glucagon infusions based only on proportional action (Gp/Gd/Gc/tau) = (0.2/0/0.4/10 or 0.4/0/0.4/10) failed in simulating the pattern of blood glucose or glucagon response seen in normal dogs. Glucagon infusion based on proportional plus derivative action (Gp/Gd/Gc/tau = 0.2/0.4/0.4/10) successfully mimicked the pattern of blood glucose concentration and plasma glucagon profile seen in normal dogs. This glucagon infusion algorithm has been applied to control insulin-induced hypoglycemia in a pancreatectomized patient with the same infusion parameters. Hypoglycemia was recovered to normoglycemia in 80 min and the plasma glucagon patterns showed no significant difference from those in healthy volunteers. These data indicate that glucagon infusion algorithm thus developed is effective to render hypoglycemia to normoglycemia and mimic plasma glucagon response seen in normal subjects.     

Stress hormones initiate prolonged changes in the muscle amino acid pattern.

Eight healthy volunteers were given an infusion containing cortisol, glucagon and adrenaline during 6 h. Muscle biopsies were taken before and at 6, 12 and 24 h. During the infusion serum cortisol, glucagon, glucose and insulin were increased. The stress hormone infusion induced characteristic changes in the muscle and plasma amino acid patterns similar to those seen early in protein catabolism. Muscle glutamine decreased at 12 and 24 h by -18.2 +/- 3.8 and -28.8 +/- 4.8%, respectively. The branched chain amino acids decreased at 6 h by -54.6 +/- 4.2% while increased levels (by 54.7 +/- 13.1%) were seen at 24 h. Plasma amino acids decreased during the infusion period and returned to basal during the postinfusion period. Despite a short-term infusion during 6 h the muscle amino acid pattern was still affected at 12 and 24 h and some of the changes were more accentuated at those timepoints as compared with the changes seen at 6 h.     

Reflex adrenergic control of endocrine pancreas evoked by unloading of carotid baroreceptors in cats

The effects of unloading of the carotid baroreceptors on arterial plasma glucose concentration as well as on portal plasma immunoreactive glucagon (IRG) and insulin (IRI) concentrations were studied in an-estethized, vagotomized cats either by sectioning the sinus nerves or by lowering the pressure in the isolated carotid sinuses. Complete elimination of the carotid baroreceptor discharge by cutting the sinus nerves caused an increase in the arterial plasma glucose concentration by 100% and an increase in the portal IRG level by about 200%, whereas the portal IRI concentration decreased to 50% of its basal value. These baroreceptor-induced changes of the plasma IRG and IRI levels seemed to be graded in relation to the drop in carotid blood pressure and they were clearly detectable when the pressure was lowered from 120 to 90 mmHg in the isolated carotid sinus preparation. The described reflex hyperglycemia, hyperglucago-nemia and hypoinsulinemia were mediated to the pancreas and liver mainly by the sympatho-adrenal system, since cutting the splanchnic nerves above the adrenal glands abolished the hyperglycemic and hypoinsulinemic responses and markedly depressed the magnitude of the hyperglucagonemic response. In adrenalectomized cats, complete unloading of the baroreceptors evoked both hyperglucagonemia and hypoinsulinemia although the magnitude of the hormonal responses was diminished. In animals where the pancreas and liver were sympathectomized but the adrenal glands left intact, cutting the sinus nerves evoked a doubling of the IRG level and a slight increase in plasma glucose, but no significant change of the IRI level. I.v. infusion of adrenaline (1 γg/kg × min) or noradrenaline (5 γg/kg × min) caused pronounced increases in IRG and plasma glucose and a clear-cut reduction of IRI. We conclude that the function of the endocrine pancreas in the cat can be influenced by variations in the blood pressure by means of a reflex control which originates from arterial baroreceptors. This reflex adjustment of the endocrine pancreas is mediated chiefly by two links of the sympatho-adrenal system, namely by catecholamine-release from the adrenal medulla and, more importantly. by a direct adrenergic nerve fibre influence on the α- and β-cells.     

Hyperglucagonemia after removal of lower bowel in rats

Surgical removal of the jejunum, ileum, and colon from rats (LBX) results in greatly elevated levels of plasma immunoreactive glucagon (pIRG) 24 h after surgery (0.98 +/- 0.07 ng/ml, n = 51 vs. 0.20 +/- 0.02 ng/ml, n = 34 in sham-operated controls). Such elevations in pIRG were not noted after gut transection or the removal of ileum, jejunum, or colon alone, ileum plus jejunum, or stomach plus duodenum. Coupled with the failure of adrenal demedullation, adrenalectomy or ganglionic blockade to lower pIRG in LBX animals, these findings suggest that surgical stress alone is an unlikely cause for LBX-induced hyperglucagonemia. It was also shown that alpha-cells in LBX animals retained their responsiveness to both the inhibitory effects of somatostatin and glucose infusion as well as the stimulatory effects of arginine infusion. Chromatography revealed a normal pattern of IRG in the plasma of LBX animals. It is postulated that LBX-induced hyperglucagonemia may result from the removal of an inhibitory factor present in the lower bowel.     

Effect of adrenaline on exchange of glucose in leg tissues and splanchnic area. A comparison with the metabolic response to surgical stress

Surgical trauma is accompanied by increased energy expenditure and raised arterial concentrations of adrenaline and glucose. In order to study the acute effects of an adrenaline infusion on glucose metabolism and oxygen uptake in the leg and splanchnic bed, adrenaline was administered at a rate giving plasma concentrations of adrenaline similar to those in connection with abdominal surgery. Seven healthy males participated in the study. Adrenaline 40 ng/(min X kg body weight) (0.22 nmol/(min X kg body weight] was infused producing a plasma concentration of 2.77 +/- 0.42 nmol/l (mean +/- SEM). Leg and splanchnic blood flows and the femoral and hepatic arterio-venous differences for oxygen, glucose, lactate and other metabolites were determined. Measurements were made before and between 30 and 40 min after the start of the adrenaline infusion. Following the infusion of adrenaline the leg blood flow increased by 140% and hepatic blood flow by 25%. The leg oxygen uptake increased by 30%, but no significant increase in splanchnic oxygen uptake was observed. The arterial glucose concentration rose by 35%. Splanchnic glucose output increased X 2.5, but no significant increase in leg glucose uptake was observed. Leg release of gluconeogenic substrates increased but only lactate and glycerol uptake increased in the splanchnic bed. Leg blood flow increased more than that usually seen after surgery, whereas leg oxygen uptake and splanchnic oxygen uptake was higher in the immediate postoperative period. Splanchnic glucose release increased more during the infusion than in connection with surgery. It is concluded that adrenaline at a plasma concentration similar to that during and immediately after surgery can induce changes in glucose metabolism which are of the same order or more pronounced than those seen in connection with abdominal surgery.     

Glucoregulation during insulin and glucagon deficiency: role of catecholamines

Glucose production decreases markedly following acute reduction in insulin and glucagon secretion (induced by somatostatin). After about an hour, however, glucose production is restored nearly to basal rates. To study the mechanism by which this occurs, islet hormone deficiency was superimposed on beta-adrenergic blockade. It was found that the hypoglycemia that accompanies insulin and glucagon deficiency is an adequate stimulus for catecholamine secretion. During combined hormone deficiency and beta-blockade, glucose production fell and remained very low for 2-3 h. This resulted in a profound hypoglycemia (glucose less than 30 mg/dl). We conclude from these studies that restoration of glucose production during sustained insulin and glucagon deficiency is not attributable to a) onset of insulin deficiency because insulin is equally depressed in both experimental settings, b) glucose autoregulation even though adequate substrate is available, or c) an alpha-adrenergic mechanism because plasma catecholamines were very high and alpha-receptors were not blocked. Rather, the glucose counterregulation during insulin and glucagon deficiency must be heavily dependent on a beta-adrenergic mechanism.     

The effect of propranalol on the calorigenic response in brown adipose tissue of new-born rabbits to catecholamines, glucagon, corticotrophin and cold exposure

1. Experiments measuring the rate of oxygen consumption of unanaesthetized new-born rabbits and the blood flow in brown adipose tissue of anaesthetized new-born rabbits are described.2. The increase in rate of oxygen consumption caused by I.V. infusion of noradrenaline, adrenaline and isoprenaline (2 mug/kg.min for 10 min) was blocked by propranalol (I.V. 1 mg/kg) but the increase caused by cold exposure was not. A larger dose of propranalol (5 mg) blocked the calorigenic response to cold exposure as well.3. Infusion of glucagon (I.V. 4 mug/kg.min for 10 min) caused a large increase in the rate of the rabbit's oxygen consumption and in blood flow through its brown adipose tissue. These responses, which reached a maximum within 10 min from the start of the infusion, were not blocked by propranalol (1 or 5 mg/kg).4. Infusion of corticotrophin (I.V. 1 i.u./kg.min for 10 min) also caused a large increase in the rate of oxygen consumption of new-born rabbits. The response reached a maximum about 20 min from the start of the infusion and it was not blocked by propranalol (5 mg/kg).5. These results support the conclusion that noradrenaline is released at sympathetic endings in brown adipose tissue and that the increase in blood flow caused by noradrenaline is secondary to its metabolic action on the tissue. They also suggest the possibility that glucagon and corticotrophin may act directly on brown adipose tissue and stimulate heat production during cold exposure.