Role of counterregulatory hormones in the catabolic response to stress.

Patients with major injury or illness develop protein wasting, hypermetabolism, and hyperglycemia with increased glucose flux. To assess the role of elevated counterregulatory hormones in this response, we simultaneously infused cortisol (6 mg/m2 per h), glucagon (4 ng/kg per min), epinephrine (0.6 microgram/m2 per min), and norepinephrine (0.8 micrograms/m2 per min) for 72 h into five obese subjects receiving only intravenous glucose (150 g/d). Four obese subjects received cortisol alone under identical conditions. Combined infusion maintained plasma hormone elevations typical of severe stress for 3 d. This caused a sustained increase in plasma glucose (60-80%), glucose production (100%), and total glucose flux (40%), despite persistent hyperinsulinemia. In contrast, resting metabolic rate changed little (9% rise, P = NS). Urinary nitrogen excretion promptly doubled and remained increased by approximately 4 g/d, reflecting increased excretion of urea and ammonia. Virtually all plasma amino acids declined. The increment in nitrogen excretion was similar in three additional combined infusion studies performed in 3-d fasted subjects not receiving glucose. Cortisol alone produced a smaller glycemic response (20-25%), an initially smaller insulin response, and a delayed rise in nitrogen excretion. By day 3, however, daily nitrogen excretion was equal to the combined group as was the elevation in plasma insulin. Most plasma amino acids rose rather than fell. In both infusion protocols nitrogen wasting was accompanied by only modest increments in 3-methylhistidine excretion (approximately 20-30%) and no significant change in leucine flux. We conclude: (a) Prolonged elevations of multiple stress hormones cause persistent hyperglycemia, increased glucose turnover, and increased nitrogen loss; (b) The sustained nitrogen loss is no greater than that produced by cortisol alone; (c) Glucagon, epinephrine, and norepinephrine transiently augment cortisol-induced nitrogen loss and persistently accentuate hyperglycemia; (d) Counterregulatory hormones contribute to, but are probably not the sole mediators of the massive nitrogen loss, muscle proteolysis, and hypermetabolism seen in some clinical settings of severe stress.     

Elevation of plasma epinephrine concentrations inhibits proteolysis and leucine oxidation in man via beta-adrenergic mechanisms.

The role of elevated plasma epinephrine concentrations in the regulation of plasma leucine kinetics and the contribution of beta-receptors were assessed in man. Epinephrine (50 ng/kg per min) was infused either alone or combined with propranolol (beta-blockade) into groups of six subjects fasted overnight; leucine flux, oxidation, and net plasma leucine forearm balance were determined during 180 min. Constant plasma insulin and glucagon concentrations were maintained in all studies by infusing somatostatin combined with insulin and glucagon replacements. Plasma leucine concentrations decreased from baseline during epinephrine infusion by 27 +/- 5 mumol/liter (P less than 0.02) due to a 22 +/- 6% decrease in leucine flux (P less than 0.05 vs. controls receiving saline) and to an increase in the metabolic clearance rate of leucine (P less than 0.02). Leucine oxidation decreased by 36 +/- 8% (P less than 0.01 vs. controls). beta-Blockade abolished the effect of epinephrine on leucine flux and oxidation. Net forearm release of leucine increased during epinephrine (P less than 0.01), suggesting increased muscle proteolysis; the fall of total body leucine flux was therefore due to diminished proteolysis in nonmuscle tissues, such as splanchnic organs. Nonoxidative leucine disappearance as a parameter of protein synthesis was not significantly influenced by epinephrine. Plasma glucose and FFA concentrations increased via beta-adrenergic mechanisms (P less than 0.001). The results suggest that elevation of plasma epinephrine concentrations similar to those observed in severe stress results in redistribution of body proteins and exerts a whole body protein-sparing effect; this may counteract catabolic effects of other hormones during severe stress.     

Effects of dopexamine in comparison with fenoterol on carbohydrate,fat and protein metabolism in healthy volunteers

Objective In critically ill patients adrenergic agonists are used to treat haemodynamic disorders. Their metabolic actions should be considered in controlling metabolic homeostasis. Dopexamine has assumed effects on carbohydrate, fat and protein metabolism. The aim of this study was to define its metabolic actions and compare these with those of fenoterol by using a stable isotope dilution technique.Design Prospective, randomized experimental study.Setting Experimental section of a university anaesthesiology department.Participants Twenty-seven healthy male volunteers in three groups with nine participants each.Interventions Participants received a 4-h infusion of dopexamine (2.25 µg/kg per min), fenoterol (at least 0.025 µg/kg per min) or saline.Measurements and results Before and every 80 min during drug infusion, we measured endogenous glucose production and the plasma appearance rates for leucine and urea. In addition, we measured plasma concentrations of glucose, lactate, free fatty acids (FFAs), noradrenaline, adrenaline, insulin, glucagon and potassium. Endogenous glucose production did not differ among the groups. Glucose plasma concentration and glucose clearance remained constant during the dopexamine infusion. Fenoterol increased glucose plasma concentration and decreased glucose clearance. Lactate, FFAs, insulin and noradrenaline plasma concentrations were increased and the rate of leucine appearance was decreased by both drugs. The rate of urea appearance did not differ from the control group.Conclusions Dopexamine has no or only weak effects on carbohydrate metabolism, its effects on fat and protein metabolism are comparable to those of fenoterol. This metabolic profile may be advantageous in increasing cardiac output in patients with impaired glucose tolerance.     

Epinephrine plasma metabolic clearance rates and physiologic thresholds for metabolic and hemodynamic actions in man.

To determine the plasma epinephrine thresholds for its metabolic and hemodynamic actions and plasma epinephrine metabolic clearance rates, 60-min intravenous epinephrine infusions at nominal rates of 0.1, 0.5, 1.0, 2.5, and 5.0 microgram/min were performed in each of six normal human subjects. These 30 infusions resulted in steady-state plasma epinephrine concentrations ranging from 24 to 1,020 pg/ml. Plasma epinephrine thresholds were 50-100 pg/ml for increments in heart rate, 75-125 pg/ml for increments in blood glycerol and systolic blood pressure, 150-200 pg/ml for increments in plasma glucose (the resultant of increments in glucose production and decrements in glucose clearance), blood lactate, blood beta-hydroxybutyrate, and diastolic blood pressure, and greater than 400 pg/ml for early decrements in plasma insulin. Changes in blood alanine, plasma glucagon, plasma growth hormone, and plasma cortisol were not detected. At steady-state plasma epinephrine concentrations of 24-74 pg/ml, values overlapping the basal normal range, the mean (+/-SE) plasma metabolic clearance rate of epinephrine was 52 +/- 4 ml x min-1 x kg-1; this value rose to 89 +/- 6 ml x min-1 x kg-1 (P less than 0.01) at steady-state epinephrine concentrations of 90-1,020 pg/ml. We conclude that in human subjects: (a) the plasma epinephrine thresholds for its hemodynamic and metabolic actions lie within the physiologic range, (b) epinephrine and norepinephrine accelerate their own metabolic clearance, and (c) epinephrine is 10 times more potent than norepinephrine.     

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.     

Vascular and metabolic effects of circulating epinephrine and norepinephrine. Concentration-effect study in dogs.

Vascular and metabolic effects of circulating epinephrine and norepinephrine have been studied in relation to the plasma concentration of these amines in dogs. Intravenous infusion of epinephrine or norepinephrine (0.1, 0.5, and 2.5 nmol x kg-1 x min-1) raised the plasma concentration of the infused amine by 2.5 , 13, and 63 nM from resting levels of 2.4 and 3.6 nM, respectively. Blood flow to isolated adipose tissue; skeletal muscle preparations; and plasma levels of glycerol, glucose, and cyclic AMP were measured. Epinephrine and norepinephrine displayed a distinct selectivity with regard to both vascular and metabolic effects. Epinephrine caused significant vasoconstriction in adipose tissue already at a plasma concentration of 5 nM, whereas no significant effect was seen on skeletal muscle vascular resistance. Norepinephrine, on the other hand, caused significant vasoconstriction in skeletal muscle at 5 nM but had no vasoconstrictor effect in adipose tissue. Epinephrine was more potent than norepinephrine in increasing plasma cyclic AMP and glucose, whereas the converse was true for plasma glycerol. Epinephrine had significant effects on plasma cyclic AMP at 5 nM and on plasma glucose and glycerol at 15 nM. Norepinephrine, on the other hand, had significant effects on plasma glycerol at 5 nM, plasma cyclic AMP at 15 nM and plasma glucose only at 65 nM. It is suggested that these response patterns are related to a preferential action of epinephrine on beta 2-adrenoceptors and a preferential action of norepinephrine on beta 1-adrenoceptors. Our results support the view that both epinephrine and norepinephrine may act as circulating hormones, because vascular and metabolic effects of both amines were seen at plasma concentrations encountered during various kinds of stress in animals and man.     

Lipolysis during fasting. Decreased suppression by insulin and increased stimulation by epinephrine.

These studies were designed to determine whether the insulin resistance of fasting extends to its antilipolytic effects and whether fasting enhances the lipolytic effects of adrenergic stimulation independent of changes in plasma hormone and substrate concentrations. Palmitate flux was determined isotopically ([1-14C]palmitate) before and during epinephrine infusion in normal volunteers after a 14-h (day 1) and an 84-h (day 4) fast. Using a pancreatic clamp, constant plasma hormone and glucose concentrations were achieved on both study days in seven subjects. Six subjects were infused with saline and served as controls. During the pancreatic clamp, palmitate flux was greater (P less than 0.01) on day 4 than day 1, despite similar plasma insulin, glucagon, growth hormone, cortisol, epinephrine, norepinephrine, and glucose concentrations. The lipolytic response to epinephrine was greater (P less than 0.05) on day 4 than day 1 in both groups of subjects. In conclusion, lipolysis during fasting is less completely suppressed by insulin and more readily stimulated by epinephrine.     

The role of adrenergic mechanisms in the substrate and hormonal response to insulin-induced hypoglycemia in man.

Sequential determinations of glucose outflow and inflow, and rates of gluconeogenesis from alanine, before, during and after insulin-induced hypoglycemia were obtained in relation to alterations in circulating epinephrine, norepinephrine, glucagon, cortisol, and growth hormone in six normal subjects. Insulin decreased the mean (+/-SEM) plasma glucose from 89+/-3 to 39+/-2 mg/dl 25 min after injection, but this decline ceased despite serum insulin levels of 153+/-22 mul/ml. Before insulin, glucose inflow and outflow were constant averaging 125.3+/-7.1 mg/kg per h. 15 min after insulin, mean glucose outflow increased threefold, but then decreased at 25 min, reaching a rate 15% less than the preinsulin rate. Glucose inflow decreased 80% 15 min after insulin, but increased at 25 min, reaching a maximum of twice the basal rate. Gluconeogenesis from alanine decreased 68% 15 min after insulin, but returned to preinsulin rates at 25 min, and remained constant for the next 25 min, after which it increased linearly. A fourfold increase in mean plasma epinephrine was found 20 min after insulin, with maximal levels 50 times basal. Plasma norepinephrine concentrations first increased significantly at 25 min after insulin, whereas significantly increased levels of cortisol and glucagon occurred at 30 min, and growth hormone at 40 min after insulin. Thus, insulin-induced hypoglycemia in man results from both a decrease in glucose production and an increase in glucose utilization. Accelerated glycogenolysis produced much of the initial, posthypoglycemic increment in glucose production. The contribution of glycogenolysis decreased with time, while that of gluconeogenesis from alanine increased. Of the hormones studied, only the increments in plasma catecholamines preceded or coincided with the measured increase in glucose production after hypoglycemia. It therefore seems probable that adrenergic mechanisms play a major role in the initiation of counter-regulatory responses to insulin-induced hypoglycemia in man.     

Role of cortisol in the pathogenesis of deficient counterregulation after antecedent hypoglycemia in normal humans.

The aim of this study was to determine the role of increased plasma cortisol levels in the pathogenesis of hypoglycemia-associated autonomic failure. Experiments were carried out on 16 lean, healthy, overnight fasted male subjects. One group (n = 8) underwent two separate, 2-d randomized experiments separated by at least 2 mo. On day 1 insulin was infused at a rate of 1.5 mU/kg per min and 2 h clamped hypoglycemia (53 +/- 2 mg/dl) or euglycemia (93 +/- 3 mg/dl) was obtained during morning and afternoon. The next morning subjects underwent a 2-h hyperinsulinemic (1.5 mU/kg per min) hypoglycemic (53 +/- 2 mg/dl) clamp study. In the other group (n = 8), day 1 consisted of morning and afternoon 2-h clamped hyperinsulinemic euglycemia with cortisol infused to stimulate levels of plasma cortisol occurring during clamped hypoglycemia (53 mg/dl). The next morning (day 2) subjects underwent a 2-h hyperinsulinemic hypoglycemic clamp identical to the first group. Despite equivalent day 2 plasma glucose and insulin levels, steady state epinephrine, norepinephrine, pancreatic polypeptide, glucagon, ACTH and muscle sympathetic nerve activity (MSNA) values were significantly (R < 0.01) blunted after day 1 cortisol infusion compared to antecedent euglycemia. Compared to day 1 cortisol, antecedent hypoglycemia produced similar blunted day 2 responses of epinephrine, norepinephrine, pancreatic polypeptide and MSNA compared to day 1 cortisol. Antecedent hypoglycemia, however, produced a more pronounced blunting of plasma glucagon, ACTH, and hepatic glucose production compared to day 1 cortisol. We conclude that in healthy overnight fasted men (a) antecedent physiologic increases of plasma cortisol can significantly blunt epinephrine, norepinephrine, glucagon, and MSNA responses to subsequent hypoglycemia and (b) these data suggest that increased plasma cortisol is the mechanism responsible for antecedent hypoglycemia causing hypoglycemia associated autonomic failure.     

Regulation of glucose turnover during exercise in pancreatectomized, totally insulin-deficient dogs. Effects of beta-adrenergic blockade.

To examine whether glucose metabolic clearance increases and whether catecholamines influence glucose turnover during exercise in total insulin deficiency, 24-h fasted and insulin-deprived pancreatectomized dogs were studied before and during exercise (60 min; 100 m/min; 10% slope) with (n = 8) and without (n = 8) propranolol infusion (PI, 5 micrograms/kg-min). Exercise with or without PI was accompanied by four and fivefold increments in norepinephrine and epinephrine respectively, while glucagon (extrapancreatic) fell slightly. Basal plasma glucose and FFA concentrations and rates of tracer-determined (3[3H]glucose) hepatic glucose production (Ra) and total glucose clearance (including urinary glucose loss) were 459 +/- 24 mg/dl, 1.7 +/- 0.5 mmol/liter, 7.8 +/- 0.9 mg/kg-min and 1.6 +/- 0.1 ml/kg-min, respectively. When corrected for urinary glucose excretion, basal glucose metabolic clearance rate (MCR) was 0.7 +/- 0.1 mg/kg-min and rose twofold (P less than 0.0001) during exercise. Despite lower lactate (3.3 +/- 0.6 vs. 6.6 +/- 1.3 mmol/liter; P less than 0.005) and FFA levels (1.1 +/- 0.2 vs. 2.2 +/- 0.2 mmol/liter; P less than 0.0001) with PI, PI failed to influence MCR during exercise. Ra rose by 3.7 +/- 1.7 mg/kg-min during exercise (P less than 0.02) while with PI the increase was only 1.9 +/- 0.7 mg/kg-min (P less than 0.002). Glucose levels remained unchanged during exercise alone but fell slightly with PI (P less than 0.0001). Therefore, in total insulin deficiency, MCR increases marginally with exercise (13% of normal); the beta adrenergic effects of catecholamines that stimulate both FFA mobilization and muscle glycogenolysis do not regulate muscle glucose uptake. The exercise-induced rise in hepatic glucose production does not require an increase in glucagon levels, but is mediated partially by catecholamines. Present and previous data in normal and alloxan-diabetic dogs, suggest that (a) in total insulin deficiency, control of hepatic glucose production during exercise is shifted from glucagon to catecholamines and that this may involve catecholamine-induced mobilization of peripheral substrates for gluconeogenesis and/or hepatic insensitivity to glucagon, and (b) insulin is not essential for a small exercise-induced increase in muscle glucose uptake, but normal insulin levels are required for the full response. Furthermore, the catecholamines appear to regulate muscle glucose uptake during exercise only when sufficient insulin is available to prevent markedly elevated FFA levels. We speculate that the main role of insulin is not to regulate glucose uptake by the contracting muscle directly, but to restrain lipolysis and thereby also FFA oxidation in the muscle.     

Influence of Continuous Physiologic Hyperinsulinemia on Glucose Kinetics and Counterregulatory Hormones in Normal and Diabetic Humans

The effects of continuous infusions of insulin in physiologic doses on glucose kinetics and circulating counterregulatory hormones (epinephrine, norepinephrine, glucagon, cortisol, and growth hormone) were determined in normal subjects and diabetics. The normals received insulin at two dose levels (0.4 and 0.25 mU/kg per min) and the diabetics received the higher dose (0.4 mU/kg per min) only.In all three groups of studies, continuous infusion of insulin resulted in an initial decline in plasma glucose followed by stabilization after 60-180 min. In the normal subjects, with the higher insulin dose there was a fivefold rise in plasma insulin. Plasma glucose fell at a rate of 0.73+/-0.12 mg/min for 45 min and then stabilized at 55+/-3 mg/dl after 60 min. The initial decline in plasma glucose was a result of a rapid, 27% fall in glucose output and a 33% rise in glucose uptake. Subsequent stabilization was a result of a return of glucose output and uptake to basal levels. The rebound increment in glucose output was significant (P < 0.05) by 30 min after initiation of the insulin infusion and preceded, by 30-45 min, a significant rise in circulating counterregulatory hormones.With the lower insulin infusion dose, plasma insulin rose two- to threefold, plasma glucose initially fell at a rate of 0.37+/-0.04 mg/min for 75 min and stabilized at 67+/-3 mg/dl after 75 min. The changes in plasma glucose were entirely a result of a fall in glucose output and subsequent return to base line, whereas glucose uptake remained unchanged. Plasma levels of counterregulatory hormones showed no change from basal throughout the insulin infusion.In the diabetic group (plasma glucose levels 227+/-7 mg/dl in the basal state), the initial rate of decline in plasma glucose (1.01+/-0.15 mg/dl) and the plateau concentration of plasma glucose (59+/-5 mg/dl) were comparable to controls receiving the same insulin dose. However, the initial fall in plasma glucose was almost entirely a result of suppression of glucose output, which showed a twofold greater decline (60+/-6%) than in controls (27+/-5%, P <0.01) and remained suppressed throughout the insulin infusion. In contrast, the late stabilization in plasma glucose was a result of a fall in glucose uptake to values 50% below basal (P < 0.001) and 39% below that observed in controls at termination of the insulin infusion (P < 0.01). Plasma norepinephrine and glucagon failed to rise during the insulin infusion, whereas plasma epinephrine, cortisol, and growth hormone rose to values comparable to controls receiving the same insulin dose.It is concluded that (a) in normal and diabetic subjects, physiologic hyperinsulinemia results in an initial decline followed by stabilization of plasma glucose despite ongoing infusion of insulin; (b) in the normal subjects, a rebound increase in glucose output is the initial or principal mechanism counteracting the fall in plasma glucose and occurs (with an insulin dose of 0.25 mU/kg per min) in the absence of a rise in circulating counterregulatory hormones; (c) in diabetics, although the changes in plasma glucose are comparable to controls, the initial decline is a result of an exaggerated suppression of glucose output, whereas the stabilization of plasma glucose occurs primarily as a consequence of an exaggerated fall in glucose uptake; and (d) failure of plasma norepinephrine as well as glucagon to rise in the diabetics may contribute to the exaggerated suppression of glucose output.     

Mechanisms of postprandial glucose counterregulation in man. Physiologic roles of glucagon and epinephrine vis-a-vis insulin in the prevention of hypoglycemia late after glucose ingestion.

The transition from exogenous glucose delivery to endogenous glucose production late after glucose ingestion is not solely attributable to dissipation of insulin and, therefore, must also involve factors that actively raise the plasma glucose concentration--glucose counterregulatory factors. We have shown that the secretion of two of these, glucagon and epinephrine, is specific for glucose ingestion and temporally related to the glucose counterregulatory process. To determine the physiologic roles of glucagon and epinephrine in postprandial glucose counterregulation, we produced pharmacologic interventions that resulted in endogenous glucagon deficiency with and without exogenous glucagon replacement, adrenergic blockade, and adrenergic blockade coupled with glucagon deficiency starting 225 min after the ingestion of 75 g of glucose in normal subjects. Also, we assessed the effect of endogenous epinephrine deficiency alone and in combination with glucagon deficiency late after glucose ingestion in bilaterally adrenalectomized subjects. Glucagon deficiency resulted in nadir plasma glucose concentrations that were approximately 30% lower (P less than 0.01) than control values, but did not cause hypoglycemia late after glucose ingestion. This effect was prevented by glucagon replacement. Neither adrenergic blockade nor epinephrine deficiency alone impaired the glucose counterregulatory process. However, combined glucagon and epinephrine deficiencies resulted in a progressive fall in mean plasma glucose to a hypoglycemic level late after glucose ingestion; the final glucose concentration was 40% lower (P less than 0.02) than the control (epinephrine deficient) value in these patients, and was nearly 50% lower (P less than 0.001) than the control value and approximately 30% lower (P less than 0.05) than the glucagon-deficient value in normal subjects. We conclude (a) the transition from exogenous glucose delivery to endogenous glucose production late after glucose ingestion is the result of the coordinated diminution of insulin secretion and the resumption of glucagon secretion. (b) Epinephrine does not normally play a critical role in this process, but enhanced epinephrine secretion compensates largely and prevents hypoglycemia when glucagon secretion is deficient.     

Adrenergic Mechanisms for the Effects of Epinephrine on Glucose Production and Clearance in Man

THE PRESENT STUDIES WERE UNDERTAKEN TO ASSESS THE ADRENERGIC MECHANISMS BY WHICH EPINEPHRINE STIMULATES GLUCOSE PRODUCTION AND SUPPRESSES GLUCOSE CLEARANCE IN MAN: epinephrine (50 ng/kg per min) was infused for 180 min alone and during either alpha (phentolamine) or beta (propranolol)-adrenergic blockade in normal subjects under conditions in which plasma insulin, glucagon, and glucose were maintained at comparable levels by infusion of somatostatin (100 mug/h), insulin (0.2 mU/kg per min), and variable amounts of glucose. In additional experiments, to control for the effects of the hyperglycemia caused by epinephrine, variable amounts of glucose without epinephrine were infused along with somatostatin and insulin to produce hyperglycemia comparable with that observed during infusion of epinephrine. This glucose infusion suppressed glucose production from basal rates of 1.8+/-0.1 to 0.0+/-0.1 mg/kg per min (P < 0.01), but did not alter glucose clearance. During infusion of epinephrine, glucose production increased transiently from a basal rate of 1.8+/-0.1 to a maximum of 3.0+/-0.2 mg/kg per min (P < 0.01) at min 30, and returned to near basal rates at min 180 (1.9+/-0.1 mg/kg per min). Glucose clearance decreased from a basal rate of 2.0+/-0.1 to 1.5+/-0.2 ml/kg per min at the end of the epinephrine infusion (P < 0.01). Infusion of phentolamine did not alter these effects of epinephrine on glucose production and clearance. In contrast, infusion of propranolol completely prevented the suppression of glucose clearance by epinephrine, and inhibited the stimulation of glucose production by epinephrine by 80+/-6% (P < 0.001). These results indicate that, under conditions in which plasma glucose, insulin, and glucagon are maintained constant, epinephrine stimulates glucose production and inhibits glucose clearance in man predominantly by beta adrenergic mechanisms.     

Impact of exogenous beta-adrenergic receptor stimulation on hepatosplanchnic oxygen kinetics and metabolic activity in septic shock

OBJECTIVE: To investigate the impact of exogenous beta-adrenergic receptor stimulation on splanchnic blood flow, oxygen kinetics, glucose-precursor flux, and liver metabolism in septic shock. DESIGN: Prospective trial. SETTING: University hospital intensive care unit. PATIENTS: Six patients with hyperdynamic (cardiac index >4.0 L/min/m2) septic shock, all requiring norepinephrine to maintain blood pressure >65 mm Hg. INTERVENTIONS: We compared norepinephrine and phenylephrine titrated to achieve similar systemic hemodynamics and gas exchange. Splanchnic hemodynamics, oxygen kinetics, and metabolic parameters were measured before, during, and after replacing norepinephrine with phenylephrine. MEASUREMENTS AND MAIN RESULTS: Splanchnic blood flow and oxygen kinetics were derived from the steady-state indocyanine-green clearance based on hepatic dye extraction and arterial and hepatic venous blood gases. Endogenous glucose production rate was derived from the plasma appearance rate of stable-isotope-labeled glucose using a primed-constant infusion. Splanchnic lactate, alanine (high-performance liquid chromatography) uptake, and hepatic monoethylglycinexylidide (MEGX) (fluorescence polarization immunoassay) formation rates were calculated from splanchnic blood flow and arterial-hepatic venous concentration differences. Replacing norepinephrine with phenylephrine induced no change in systemic hemodynamics or gas exchange. While splanchnic oxygen consumption and alanine uptake rate remained unaffected, splanchnic blood flow, oxygen delivery, and lactate uptake rate were significantly decreased. Glucose production rate also decreased significantly. A return to norepinephrine restored splanchnic blood flow, oxygen delivery, and lactate uptake rate to baseline values, while glucose production rate remained depressed. Hepatic MEGX formation rate was not influenced during the investigation. CONCLUSIONS: Exogenous beta-adrenergic receptor stimulation determines splanchnic blood flow, oxygen delivery, and glucose precursor flux but not splanchnic oxygen utilization in septic shock. Gluconeogenesis is not directly affiliated to hepatosplanchnic oxygen kinetics. The different response of glucose and MEGX production rates, metabolic pathways of the periportal and perivenous region, may document intrahepatic heterogeneity associated with hepatocellular metabolic compartmentation.     

Effects of epinephrine, norepinephrine, or the combination of norepinephrine and dobutamine on gastric mucosa in septic shock.

OBJECTIVES: To compare in the same patient with septic shock, respective effects of epinephrine, norepinephrine, and the combination of norepinephrine and dobutamine (5 microg/kg/min) on systemic hemodynamic parameters and gastric mucosal perfusion using gastric tonometry and laser-Doppler flowmetry techniques. DESIGN: Prospective, controlled, randomized, crossover study. SETTING: University hospital intensive care unit. PATIENTS: Twelve patients with septic shock. INTERVENTIONS: Each patient received in a random succession epinephrine, norepinephrine, and norepinephrine plus dobutamine. Dosages of epinephrine and norepinephrine were adjusted to achieve a mean arterial pressure between 70 and 80 mm Hg. A laser-Doppler probe and a tonometer were introduced into the gastric lumen. MEASUREMENTS AND MAIN RESULTS: The increase in gastric mucosal perfusion detected by laser-Doppler flowmetry was higher with epinephrine and the combination of norepinephrine and dobutamine than with norepinephrine alone (p < .05). In addition, the ratio of gastric mucosal perfusion (local oxygen delivery) to systemic oxygen delivery was increased after norepinephrine plus dobutamine as compared with norepinephrine alone and epinephrine (p< .05). Although values of intramucosal pH and gastroarterial PCO2 tended to be higher with norepinephrine plus dobutamine compared with those obtained with norepinephrine and epinephrine, differences were not statistically significant. CONCLUSIONS: For the same mean arterial pressure in patients with septic shock, our study showed that administration of epinephrine increased gastric mucosal perfusion more than norepinephrine administration alone. Addition of dobutamine (5 microg/kg/ min) to norepinephrine improved gastric mucosal perfusion. This result could be explained by a vasodilating effect of dobutamine on gastric mucosal microcirculation.     

Enhanced glycemic responsiveness to epinephrine in insulin-dependent diabetes mellitus is the result of the inability to secrete insulin. Augmented insulin secretion normally limits the glycemic, but not the lipolytic or ketogenic, response to epinephrine in humans.

To determine if the enhanced glycemic response to epinephrine in patients with insulin-dependent diabetes mellitus (IDDM) is the result of increased adrenergic sensitivity per se, increased glucagon secretion, decreased insulin secretion, or a combination of these, plasma epinephrine concentration-response curves were determined in insulin-infused (initially euglycemic) patients with IDDM and nondiabetic subjects on two occasions: once when insulin and glucagon were free to change (control study), and again when insulin and glucagon were held constant (islet clamp study). During the control study, plasma C-peptide doubled, and glucagon did not change in the nondiabetic subjects, whereas plasma C-peptide did not change but glucagon increased in the patients. The patients with IDDM exhibited threefold greater increments in plasma glucose, largely the result of greater increments in glucose production. This enhanced glycemic response was apparent with 30-min increments in epinephrine to plasma concentrations as low as 100-200 pg/ml, levels that occur commonly under physiologic conditions. During the islet clamp study (somatostatin infusion with insulin and glucagon replacement at fixed rates), the heightened glycemic response was unaltered in the patients with IDDM, but the nondiabetic subjects exhibited an enhanced glycemic response to epinephrine indistinguishable from that of patients with IDDM. In contrast, the FFA, glycerol, and beta-hydroxybutyrate responses were unaltered. Thus, we conclude the following: Short, physiologic increments in plasma epinephrine cause greater increments in plasma glucose in patients with IDDM than in nondiabetic subjects, a finding likely to be relevant to glycemic control during the daily lives of such patients as well as during the stress of intercurrent illness. Enhanced glycemic responsiveness of patients with IDDM to epinephrine is not the result of increased sensitivity of adrenergic receptor-effector mechanisms per se nor of their increased glucagon secretory response; rather, it is the result of their inability to augment insulin secretion. Augmented insulin secretion, albeit restrained, normally limits the glycemic response, but not the lipolytic or ketogenic responses, to epinephrine in humans.     

Defective glucose counterregulation after subcutaneous insulin in noninsulin-dependent diabetes mellitus. Paradoxical suppression of glucose utilization and lack of compensatory increase in glucose production, roles of insulin resistance, abnormal neuroendocrine responses, and islet paracrine interactions.

To characterize glucose counterregulatory mechanisms in patients with noninsulin-dependent diabetes mellitus (NIDDM) and to test the hypothesis that the increase in glucagon secretion during hypoglycemia occurs primarily via a paracrine islet A-B cell interaction, we examined the effects of a subcutaneously injected therapeutic dose of insulin (0.15 U/kg) on plasma glucose kinetics, rates of glucose production and utilization, and their relationships to changes in the circulating concentrations of neuroendocrine glucoregulatory factors (glucagon, epinephrine, norepinephrine, growth hormone, and cortisol), as well as to changes in endogenous insulin secretion in 13 nonobese NIDDM patients with no clinical evidence of autonomic neuropathy. Compared with 11 age-weight matched nondiabetic volunteers in whom euglycemia was restored primarily by a compensatory increase in glucose production, in the diabetics there was no compensatory increase in glucose production (basal 2.08 +/- 0.04----1.79 +/- 0.07 mg/kg per min at 21/2 h in diabetics vs. basal 2.06 +/- 0.04----2.32 +/- 0.11 mg/kg per min at 21/2 h in nondiabetics, P less than 0.01) despite the fact that plasma insulin concentrations were similar in both groups (peak values 22 +/- 2 vs. 23 +/- 2 microU/ml in diabetics and nondiabetics, respectively). This abnormality in glucose production was nearly completely compensated for by a paradoxical decrease in glucose utilization after injection of insulin (basal 2.11 +/- 0.03----1.86 +/- 0.06 mg/kg per min at 21/2 h in diabetics vs. basal 2.08 +/- 0.04----2.39 +/- 0.11 mg/kg per min at 21/2 h nondiabetics, P less than 0.01), which could not be accounted for by differences in plasma glucose concentrations; the net result was a modest prolongation of hypoglycemia. Plasma glucagon (area under the curve [AUC] above base line, 12 +/- 3 vs. 23 +/- 3 mg/ml X 12 h in nondiabetics, P less than 0.05), cortisol (AUC 2.2 +/- 0.5 vs. 4.0 +/- 0.7 mg/dl X 12 h in nondiabetics, P less than 0.05), and growth hormone (AUC 1.6 +/- 0.4 vs. 2.9 +/- 0.4 micrograms/ml X 12 h in nondiabetics, P less than 0.05) responses in the diabetics were decreased 50% while their plasma norepinephrine responses (AUC 49 +/- 12 vs. 21 +/- 5 ng/ml X 12 h in nondiabetics, P less than 0.05) were increased twofold (P less than 0.05) and their plasma epinephrine responses were similar to those of the nondiabetics (AUC 106 +/- 17 vs. 112 +/- 10 ng/ml X 12 h in nondiabetics). In both groups of subjects, increases in plasma glucagon were inversely correlated with plasma glucose concentrations (r = -0.80 in both groups, P less than 0.01) and suppression of endogenous insulin secretion (r = -0.57 in nondiabe     

Effects of epinephrine and norepinephrine on hemodynamics,oxidative metabolism,and organ energetics in endotoxemic rats

OBJECTIVE: To determine whether epinephrine increases lactate concentration in sepsis through hypoxia or through a particular thermogenic or metabolic pathway. DESIGN: Prospective, controlled experimental study in rats. SETTING: Experimental laboratory in a university teaching hospital. INTERVENTIONS: Three groups of anesthetized, mechanically ventilated male Wistar rats received an intravenous infusion of 15 mg/kg Escherichia coli O127:B8 endotoxin. Rats were treated after 90 min by epinephrine ( n=14), norepinephrine ( n=14), or hydroxyethyl starch ( n=14). Three groups of six rats served as time-matched control groups and received saline, epinephrine, or norepinephrine from 90 to 180 degrees min. Mean arterial pressure, aortic, renal, mesenteric and femoral blood flow, arterial blood gases, lactate, pyruvate, and nitrate were measured at baseline and 90 and 180 min after endotoxin challenge. At the end of experiments biopsy samples were taken from the liver, heart, muscle, kidney, and small intestine for tissue adenine nucleotide and lactate/pyruvate measurements. MEASUREMENTS AND RESULTS: Endotoxin induced a decrease in mean arterial pressure and in aortic, mesenteric, and renal blood flow. Plasmatic and tissue lactate increased with a high lactate/pyruvate (L/P) ratio. ATP decreased in liver, kidney, and heart. The ATP/ADP ratio did not change, and phosphocreatinine decreased in all organs. Epinephrine and norepinephrine increased mean arterial pressure to baseline values. Epinephrine increased aortic blood flow while renal blood low decreased with both drugs. Plasmatic lactate increased with a stable L/P ratio with epinephrine and did not change with norepinephrine compared to endotoxin values. Nevertheless epinephrine and norepinephrine when compared to endotoxin values did not change tissue L/P ratios or ATP concentration in muscle, heart, gut, or liver. In kidney both drugs decreased ATP concentration. CONCLUSIONS: Our data demonstrate in a rat model of endotoxemia that epinephrine-induced hyperlactatemia is not related to cellular hypoxia.     

Influence of physiologic hyperglucagonemia on basal and insulin-inhibited splanchnic glucose output in normal man.

To evaluate the effects of physiologic hyperglucagonemia on splanchnic glucose output, glucagon was infused in a dose of 3 ng/kg per min to healthy subjects in the basal state and after splanchnic glucose output had been inhibited by an infusion of glucose (2 mg/kg per min). In the basal state, infusion of glucagon causing a 309 +/- 25 pg/ml rise in plasma concentration was accompanied by a rapid increase in splanchnic glucose output to values two to three times basal by 7-15 min. The rise in arterial blood glucose (0.5-1.5 mM) correlated directly with the increment in splanchnic glucose output. Despite continued glucagon infusion, and in the face of stable insulin levels, splanchnic glucose output declined after 22 min, returning to basal levels by 30-45 min. In the subjects initially receiving the glucose infusion, arterial insulin concentration rose by 5-12 muU/ml, while splanchnic glucose output fell by 85-100%. Infusion of glucagon causing an increment in plasma glucagon concentration of 272 +/- 30 pg/ml reversed the inhibition in splanchnic glucose production within 5 min. Splanchnic glucose output reached a peak increment 60% above basal levels at 10 min, and subsequently declined to levels 20-25% below basal at 30-45 min. These findings provide direct evidence that physiologic increments in plasma glucagon stimulate splanchnic glucose output in the basal state and reverse insulin-mediated inhibition of splanchnic glucose production in normal man. The transient nature of the stimulatory effect of glucagon on splanchnic glucose output suggests the rapid development of inhibition or reversal of glucagon action. This inhibition does not appear to depend on increased insulin secretio.     

Influence of amino acid administration on whole-body leucine kinetics and resting metabolic rate in postabsorptive normal subjects

1. We have investigated the effect of an amino acid mixture (Vamin 14; 57.4 +/- 10.2 mumol h-1 kg-1) on whole-body leucine kinetics, calculated by a steady-state reciprocal pool model, and resting metabolic rate in eight postabsorptive normal subjects. 2. Vamin 14 infusion increased whole-body leucine flux (P less than 0.001), leucine employed for protein synthesis (P less than 0.001), leucine oxidation (P less than 0.001), metabolic clearance rate of alpha-ketoisocaproic acid (P less than 0.05) and levels of all three branched-chain amino acids (P less than 0.001) compared with the basal situation. In contrast, whole-body proteolysis was reduced (P less than 0.05). 3. Resting metabolic rate was increased during Vamin 14 infusion (P less than 0.05) and was positively correlated with whole-body protein synthesis (n = 16, r = 0.6342, P less than 0.01; y = 0.605x + 173.7), as was the change in metabolic rate with the change in protein synthesis (n = 8, r = 0.772, P less than 0.05; y = 0.493x - 10.85). 4. Overall, Vamin 14 infusion was associated with increased blood glucose (P less than 0.001), although the observed increase in plasma glucagon (t = 2.012) and plasma insulin (t = 1.683) failed to reach statistical significance. 5. These data lend a measure of support to the hypothesis that the apparent increase in whole-body protein synthesis in insulin-dependent diabetic (type I) subjects during insulin withdrawal may be substrate related.