Reduced epinephrine clearance and glycemic sensitivity to epinephrine in older individuals.

To test the hypothesis that glycemic sensitivity to epinephrine is reduced in older individuals and to assess the impact of a sedentary lifestyle on responses to the hormone, we performed 30-min sequential intravenous infusions of epinephrine (0, 41, 82, 164, 246, and 328 pmol. kg-1. min-1) in young (n = 10) and older (n = 23) healthy subjects. We performed these again after 12 mo of physical training, which raised peak O2 consumption from 24.4 +/- 1.0 to 30.4 +/- 1.4 ml. kg-1. min-1 (P < 0.01) in most of the older subjects (n = 21). During epinephrine infusions, plasma epinephrine concentrations were higher (P = 0.0001) in older than in young subjects (e.g., final values of 7,280 +/- 500 vs. 4,560 +/- 380 pmol/l, respectively), indicating that the clearance of epinephrine from the circulation was reduced in the older individuals. Plasma epinephrine concentration-response curves disclosed reduced glycemic sensitivity to the hormone in the older subjects (P = 0.0001), a finding plausibly attributed to increased sympathetic neural activity, as evidenced here by higher plasma norepinephrine concentrations (P = 0.0001) in the older subjects and consequent desensitization of cellular responsiveness to catecholamines. Training did not correct reduced epinephrine clearance, reduced glycemic sensitivity to epinephrine, or raised norepinephrine levels. We conclude that aging is associated with reduced clearance of epinephrine from the circulation and reduced glycemic sensitivity to epinephrine, the latter plausibly attributed to an age-associated increase in sympathetic neural norepinephrine release. These age-associated changes are not the result of a sedentary lifestyle.

Abrupt discontinuation of cycled parenteral nutrition is safe.

PURPOSE: Abrupt discontinuation of total parenteral nutrition (TPN) has been recommended but is not widely practiced because of fear of hypoglycemia. METHODS: To determine whether hormonal counterregulatory mechanisms prevent hypoglycemia, we studied 12 patients (10 with inflammatory bowel disease, of which 6 received dexamethasone) after both abrupt and tapered discontinuation of 3:1 TPN solution in a clinical research facility. Venous blood was drawn before reduction of TPN rate in the tapered group or 15 minutes before and at abrupt discontinuation in the abrupt group and every 15 minutes for 1.5 hours. RESULTS: Glucose decreased from 152 +/- 56 (baseline) to 100 +/- 22 mg/dl 90 minutes after gradual discontinuation of TPN, compared with 135 +/- 45 to 96 +/- 15 mg/dl at 90 minutes after abrupt discontinuation, with no significant differences in mean glucose values. Mean epinephrine, norepinephrine, insulin, glucagon, growth hormone, cortisol, symptom score, and vital signs were not statistically different between the two groups. DISCUSSION: Hypoglycemia does not occur after abrupt discontinuation of TPN. The same changes in counterregulatory hormones were seen whether discontinuation was tapered or abrupt. In stable patients, TPN solutions can be abruptly discontinued.

Simplified measurement of norepinephrine kinetics: application to studies of aging and exercise training.

We assessed simplified approaches to measurement of steady-state norepinephrine (NE) kinetics (short, nonprimed infusions of [3H]NE or of unlabeled NE and arterialized venous sampling), then reexamined the kinetic mechanism(s) of the age-associated increase in plasma NE, and tested the hypothesis that the latter is the result of a sedentary lifestyle. We studied 17 young (21-28 yr) and 21 elderly (60-76 yr) subjects and a subset (n = 8) of the latter again after 1 yr of physical training. NE appearance rates (Ra) and NE metabolic clearance rates (MCRs), calculated from arterialized venous data, were not significantly different from those calculated from arterial data, whereas those calculated from venous data were substantially (approximately 50%) higher. NE Ra and NE MCR, determined from infusions of unlabeled NE were approximately 20% higher than those determined with [3H]NE, a finding plausibly attributed to approximately 20% suppression of endogenous NE appearance. Arterialized venous plasma NE concentrations were significantly higher in the elderly as a result of significantly higher NE Ra and lower NE MCR. However, arterial NE Ra was not increased, and venous NE MCR was not decreased significantly in the elderly. In the subset of elderly subjects, 1 yr of physical training, which increased peak O2 consumption by 24%, did not decrease plasma NE or NE Ra or increase NE MCR. Therefore, 1) arterial sampling provides no practical advantage over arterialized venous sampling in the measurement of NE kinetics. 2) The use of unlabeled NE infusions to determine NE kinetics overestimates NE Ra and NE MCR by approximately 20%.(ABSTRACT TRUNCATED AT 250 WORDS)

Attenuated glucose recovery from hypoglycemia in the elderly.

Advanced age is a risk factor for hypoglycemia caused by sulfonylureas (and insulin) used to treat diabetes mellitus. Therefore, we hypothesized that there is an age-associated impairment of glucose counterregulation and further that this is the result of a sedentary life-style. To test these hypotheses, glycemic and neuroendocrine responses to hypoglycemia, produced by 0.05 U/kg body wt insulin i.v. were measured in nondiabetic elderly subjects (age 65.1 +/- 0.9 yr n = 23)--and in a subset (n = 11) again after 1 yr of physical training (which increased VO2 max by 5.2 +/- 0.9 ml.kg-1.min-1, P less than 0.05)--and compared with these responses in nondiabetic young subjects (23.8 +/- 0.6 yr, n = 18). Recovery from hypoglycemia was attenuated (analysis of variance P less than 0.001) in the elderly (plasma glucose recovery rate 29.4 +/- 2.2 vs. 42.7 +/- 5.0 microM/min, P less than 0.02). This attenuation was the result of a smaller counterregulatory increment in glucose production (maximum increment 13.3 +/- 1.1 vs. 17.2 +/- 1.1 mumol.kg-1.min-1; P less than 0.05) rather than a greater increment in glucose utilization in the elderly. The attenuated glucose recovery was associated with higher plasma insulin concentrations (maximum increment 1385 +/- 122 vs. 940 +/- 72 pM, P less than 0.01) and reduced glucagon responses to hypoglycemia (maximum increment 43 +/- 6 vs. 66 +/- 12 ng/L). The epinephrine, norepinephrine, cortisol, and growth hormone responses were similar, although the epinephrine response was slightly delayed and the growth hormone response appeared smaller in the elderly.(ABSTRACT TRUNCATED AT 250 WORDS)

Failure of nocturnal hypoglycemia to cause daytime hyperglycemia in patients with IDDM.

To test the hypothesis that nocturnal hypoglycemia causes postprandial hyperglycemia the next day (the Somogyi phenomenon) in patients with insulin-dependent diabetes mellitus (IDDM), we studied 10 moderately well controlled patients, who were on their usual therapeutic regimens, from 2000 to 2000 on three occasions. On a control day, samples were obtained without intervention. On another day, nocturnal hypoglycemia was prevented (by intravenous infusion of glucose, if necessary, from 2200 to 0400 to keep plasma glucose levels at greater than 5.6 mM). On another day, nocturnal hypoglycemia was induced (by stepped intravenous insulin infusions between 2200 and 0200 to reduce plasma glucose levels to less than 2.8 mM). After nocturnal hypoglycemia (1.9 +/- 0.2 mM), fasting (0800), morning (0800-1100), afternoon (1200-1500), evening (1600-2000), and entire-day (0800-2000) plasma glucose concentrations were no higher than those after prevention of nocturnal hypoglycemia or sampling only. On the control day, fasting and daytime plasma glucose levels were directly related to the preceding 2200 (r = 0.723, P less than 0.02, and r = 0.762, P = 0.01, respectively) and nocturnal nadir (r = 0.714, P less than 0.02, and r = 0.728, P less than 0.02) plasma glucose concentrations. Daytime plasma glucose levels were unrelated to peak nocturnal plasma glucagon, epinephrine, norepinephrine, growth hormone, or cortisol concentrations. We conclude that nocturnal hypoglycemia does not appear to cause clinically important daytime hyperglycemia in patients representative of most patients with IDDM.

Glucagon, not insulin, may play a secondary role in defense against hypoglycemia during exercise.

The sympathochromaffin system, probably sympathetic neural norepinephrine, plays a primary role in the prevention of hypoglycemia during exercise in humans. Our previous data indicated that changes in pancreatic islet hormones are not normally critical but decrements in insulin, increments in glucagon, or both become critical when catecholamine actions are blocked pharmacologically. To distinguish between the role of insulin and that of glucagon in this secondary line of defense against hypoglycemia during exercise in humans, glucoregulation during moderate exercise (approximately 55% of maximum O2 consumption over 60 min) was studied in people who could not decrease insulin but could increase glucagon, i.e., patients with insulin-dependent diabetes mellitus (IDDM). While receiving constant intravenous infusions of regular insulin, in individualized doses shown to result in stable plasma glucose concentrations of approximately 95 mg/dl before exercise, patients with IDDM were studied under two conditions: 1) a control study (n = 13) and 2) an adrenergic blockade study (propranolol infusion, n = 8). In the control study, mean plasma glucose concentrations did not change (from 95 +/- 2 to 100 +/- 11 mg/dl) during exercise despite constant plasma free insulin levels. In the adrenergic blockade study plasma glucose declined (from 96 +/- 2 to 74 +/- 7 mg/dl, P less than 0.01) but stabilized; hypoglycemia did not occur. Exercise-associated increments in plasma glucagon were comparable in the two studies. These data confirm that decrements in insulin are not critical to the prevention of hypoglycemia during moderate exercise in humans and indicate that compensation for deficient catecholamine action does not require decrements in insulin.(ABSTRACT TRUNCATED AT 250 WORDS)

Plasma glucose concentrations at the onset of hypoglycemic symptoms in patients with poorly controlled diabetes and in nondiabetics.

We tested the hypothesis that during decrements in plasma glucose concentration, symptoms of hypoglycemia may occur at higher glucose concentrations in patients with poorly controlled insulin-dependent diabetes mellitus than in persons without diabetes. Symptoms of hypoglycemia and counterregulatory neuroendocrine responses were quantified during hypoglycemic and euglycemic clamp studies in eight patients with insulin-dependent diabetes mellitus selected because their hemoglobin A1 levels were above 10 percent. These data were compared with similar observations in 10 nondiabetic subjects studied previously. Glycemic thresholds--the plasma glucose concentrations during each hypoglycemic clamp study at which a given symptom or biochemical measurement first exceeded its 95 percent confidence interval determined in the euglycemic clamp studies--were calculated for each variable. The mean (+/- SE) glycemic threshold for the symptoms of hypoglycemia was 4.3 +/- 0.3 mmol per liter (78 +/- 5 mg per deciliter) in patients with poorly controlled diabetes--significantly higher (P less than 0.001) than the value of 2.9 +/- 0.1 mmol per liter (53 +/- 2 mg per deciliter) in subjects without diabetes. The mean glycemic thresholds for growth hormone, epinephrine, and cortisol secretions were not significantly different in the two groups. Thus, during decreases in the plasma glucose concentration, patients with poorly controlled insulin-dependent diabetes mellitus may experience symptoms of hypoglycemia at higher plasma glucose concentrations than persons without diabetes. The mechanism underlying this observation remains to be defined.

Effects of lack of exercise on insulin secretion and action in trained subjects.

We employed the hyperglycemic clamp technique to investigate the effects of short-term inactivity on insulin secretion in nine (8 men, 1 woman) well-trained subjects. A 3-h hyperglycemic clamp (plasma glucose approximately 180 mg/100 ml) was performed approximately 16 h after a usual training bout and again 14 days after stopping exercise training. There was no significant change in body composition during this short period of inactivity. The mean plasma insulin response to an identical glycemic stimulus was 67% higher after 14 days without exercise (45 +/- 7 after vs. 27 +/- 4 microU/ml before stopping exercise training). Marked increases in the early (0-10 min, 150 +/- 28 vs. 101 +/- 15 microU.ml-1.min) and late (10-180 min, 6,051 +/- 1,257 vs. 3,521 +/- 749 microU.ml-1.min) incremental insulin areas were observed as a result of the physical inactivity. Incremental areas for C-peptide were also elevated significantly in the inactive state for early (12 +/- 2.0 vs. 7 +/- 1 ng.ml-1.min) and late (567 +/- 90 vs. 467 +/- 85 ng.ml-1.min) phases. Urinary excretion of C-peptide increased from 12.1 +/- 1.5 ng/240 min in the exercising state to 21.8 +/- 3.6 ng/240 min in the inactive state. Rates of whole body glucose disposal were not different between exercising and inactive states, indicating a large increase in resistance to the action of insulin. These findings indicate that the decreased insulin secretory response to a glucose stimulus in people who exercise regularly is a relatively short-term effect of exercise.

Effects of exercise and lack of exercise on insulin sensitivity and responsiveness.

Insulin action is enhanced in people who exercise regularly and vigorously. In the present study, the hyperinsulinemic, euglycemic clamp procedure was used to determine whether this enhanced insulin action is due to an increased sensitivity and/or an increased responsiveness to insulin. To avoid the variability that exists between individuals and complicates cross-sectional studies, the same subjects were studied in the trained exercising state and again after 10 days of physical inactivity. When the plasma insulin concentration was maintained at approximately 78 microU.ml-1 (a submaximal level), glucose disposal rate averaged 8.7 +/- 0.5 mg.kg-1.min-1 before and 6.7 +/- 0.6 mg.kg-1.min-1 after 10 days of activity (P less than 0.001). When the plasma insulin concentration was maintained at approximately 2,000 microU.ml-1 (a maximally effective concentration), the rate of glucose disposal was not significantly different before (15.3 +/- 0.5 mg.kg-1.min-1) compared with after (14.5 +/- 0.4 mg.kg-1.min-1) 10 days without exercise. These results provide evidence that the reversal of enhanced insulin action that occurs within a few days when exercise-trained individuals stop exercising is due to a decrease in sensitivity to insulin, not to a decrease in insulin responsiveness.

Delayed extra-adrenal epinephrine secretion after bilateral adrenalectomy in rats.

Regulated systemic extra-adrenal epinephrine secretion has been demonstrated in long-term bilaterally adrenalectomized humans. To determine whether this is demonstrable immediately after adrenalectomy and therefore presumably ongoing when the adrenal medullas are intact or if it develops over time after the adrenal medullas are removed, we measured plasma catecholamine concentrations before and serially after bilateral adrenalectomy with cortical reimplantation in rats. We found plasma epinephrine concentrations to decrease from 244 +/- 41 pg/ml to levels that were not convincingly detectable, using a single-isotope derivative assay with a detection limit of 10 pg/ml, for up to 1 wk after bilateral adrenalectomy with cortical reimplantation. Plasma epinephrine concentrations increased thereafter, becoming detectable in all animals and averaging 31 +/- 6 pg/ml 4 wk after adrenalectomy. Thus extra-adrenal epinephrine secretion appears to be a delayed response to removal of the adrenal medullas and cannot be assumed to be ongoing when the adrenal medullas are intact.

Insulin action and secretion in endurance-trained and untrained humans.

To evaluate insulin sensitivity and responsiveness, a two-stage hyperinsulinemic euglycemic clamp procedure (insulin infusions of 40 and 400 mU.m-2.min-1) was performed on 11 endurance-trained and 11 untrained volunteers. A 3-h hyperglycemic clamp procedure (plasma glucose approximately 180 mg/dl) was used to study the insulin response to a fixed glycemic stimulus in 15 trained and 12 untrained subjects. During the 40-mU.m-2.min-1 insulin infusion, the glucose disposal rate was 10.2 +/- 0.5 mg.kg fat-free mass (FFM)-1.min-1 in the trained group compared with 8.0 +/- 0.6 mg.kg FFM-1.min-1 in the untrained group (P less than 0.01). In contrast, there was no significant difference in maximally stimulated glucose disposal: 17.7 +/- 0.6 in the trained vs. 16.7 +/- 0.7 mg.kg FFM-1.min-1 in the untrained group. During the hyperglycemic clamp procedure, the incremental area for plasma insulin was lower in the trained subjects for both early (0-10 min: 140 +/- 18 vs. 223 +/- 23 microU.ml-1.min; P less than 0.005) and late (10-180 min: 4,582 +/- 689 vs. 8,895 +/- 1,316 microU.ml-1.min; P less than 0.005) insulin secretory phases. These data demonstrate that 1) the improved insulin action in healthy trained subjects is due to increased sensitivity to insulin, with no change in responsiveness to insulin, and 2) trained subjects have a smaller plasma insulin response to an identical glucose stimulus than untrained individuals.

Glycemic thresholds for activation of glucose counterregulatory systems are higher than the threshold for symptoms.

To define glycemic thresholds for activation of glucose counterregulatory systems and for symptoms of hypoglycemia, we measured these during stepped reductions in the plasma glucose concentration (in six 10-mg/dl hourly steps) from 90 to 40 mg/dl under hyperinsulinemic clamp conditions, and compared these with the same measurements during euglycemia (90 mg/dl) under the same conditions over 6 h in 10 normal humans. Arterialized venous plasma glucose concentrations were used to calculate glycemic thresholds of 69 +/- 2 mg/dl for epinephrine secretion, 68 +/- 2 mg/dl for glucagon secretion, 66 +/- 2 mg/dl for growth hormone secretion, and 58 +/- 3 mg/dl for cortisol secretion. In contrast, the glycemic threshold for symptoms was 53 +/- 2 mg/dl, significantly lower than the thresholds for epinephrine (P less than 0.001), glucagon (P less than 0.001), and growth hormone (P less than 0.01) secretion. Thus, the glycemic thresholds for activation of glucose counterregulatory systems during decrements in plasma glucose lie within or just below the physiologic plasma glucose concentration range, and are substantially higher than the threshold for hypoglycemic symptoms in normal humans. These findings provide further support for the concept that glucose counterregulatory systems are involved in the prevention, as well as the correction, of hypoglycemia.

Epinephrine is not critical to prevention of hypoglycemia during exercise in humans.

We documented stability of plasma glucose concentrations and glucose production and utilization rates, and levels of other metabolic substrates and regulatory factors, during the islet clamp (somatostatin infusion with glucagon and insulin replacement) in the absence of an intervention in five normal humans and further applied this technique to the study of glucoregulation during moderate exercise. Based on previous evidence that sympathochromaffin activation plays a primary role in the prevention of hypoglycemia during exercise, the role of adrenomedullary catecholamines was assessed by exercise (60% of maximum oxygen consumption for 60 min) studies in four bilaterally adrenalectomized, epinephrine-deficient humans under two conditions: control (saline infusion) and islet clamp. Increased glucose utilization and production rates were matched and plasma glucose was unchanged during exercise under both conditions. Thus adrenomedullary catecholamines including epinephrine are not critical to glucoregulation during moderate exercise in humans even when changes in insulin and glucagon are prevented. These findings provide further support for the suggestion that sympathetic neural norepinephrine is the operative catecholamine in the prevention of hypoglycemia during exercise in humans.

Glucoregulation during exercise: hypoglycemia is prevented by redundant glucoregulatory systems, sympathochromaffin activation, and changes in islet hormone secretion.

During mild or moderate nonexhausting exercise, glucose utilization increases sharply but is normally matched by increased glucose production such that hypoglycemia does not occur. To test the hypothesis that redundant glucoregulatory systems including sympathochromaffin activation and changes in pancreatic islet hormone secretion underlie this precise matching, eight young adults exercised at 55-60% of maximal oxygen consumption for 60 min on separate occasions under four conditions: (a) control study (saline infusion); (b) islet clamp study (insulin and glucagon held constant by somatostatin infusion with glucagon and insulin replacement at fixed rates before, during and after exercise with insulin doses determined individually and shown to produce normal and stable plasma glucose concentrations prior to each study); (c) adrenergic blockage study (infusions of the alpha- and beta-adrenergic antagonists phentolamine and propranolol); (d) adrenergic blockade plus islet clamp study. Glucose production matched increased glucose utilization during exercise in the control study and plasma glucose did not fall (92 +/- 1 mg/dl at base line, 90 +/- 2 mg/dl at the end of exercise). Plasma glucose also did not fall during exercise when changes in insulin and glucagon were prevented in the islet clamp study. In the adrenergic blockade study, plasma glucose declined initially during exercise because of a greater initial increase in glucose utilization, then plateaued with an end-exercise value of 74 +/- 3 mg/dl (P less than 0.01 vs. control). In contrast, in the adrenergic blockade plus islet clamp study, exercise was associated with glucose production substantially lower than control and plasma glucose fell progressively to 58 +/- 7 mg/dl (P less than 0.001); end-exercise plasma glucose concentrations ranged from 34 to 72 mg/dl. Thus, we conclude that: (a) redundant glucoregulatory systems are involved in the precise matching of increased glucose utilization and glucose production that normally prevents hypoglycemia during moderate exercise in humans. (b) Sympathochromaffin activation, perhaps sympathetic neural norepinephrine release, plays a primary glucoregulatory role by limiting glucose utilization as well as stimulating glucose production. (c) Changes in pancreatic islet hormone secretion (decrements in insulin, increments in glucagon, or both) are not normally critical but become critical when catecholamine action is deficient. (d) Glucoregulation fails, and hypoglycemia can develop, both when catecholamine action is deficient and when changes in islet hormones do not occur during exercise in humans.

External and internal standards in the single-isotope derivative (radioenzymatic) measurement of plasma norepinephrine and epinephrine.

In plasma from normal humans (n = 9, 35 samples) and from patients with diabetes mellitus (n = 12, 24 samples) single-isotope derivative (radioenzymatic) plasma norepinephrine and epinephrine concentrations calculated from external standard curves constructed in a normal plasma pool were identical to those calculated from internal standards added to an aliquot of each plasma sample. In plasma from patients with end-stage renal failure receiving long-term dialysis (n = 34, 109 samples), competitive catechol-O-methyltransferase (COMT) inhibitory activity resulted in a systematic error when external standards in a normal plasma pool were used, as reported previously; values so calculated averaged 21% (+/- 12%, SD) lower than those calculated from internal standards. However, when external standard curves were constructed in plasma from a given patient with renal failure and used to calculate that patient's values, or in a renal failure plasma pool and used to calculate all renal failure values, norepinephrine and epinephrine concentrations were not significantly different from those calculated from internal standards. We conclude: (1) External standard curves constructed in plasma from a given patient with renal failure can be used to measure norepinephrine and epinephrine in plasma from that patient; further, external standards in a renal failure plasma pool can be used for assays in patients with end-stage renal failure receiving long-term dialysis. (2) Major COMT inhibitory activity is not present commonly if samples from patients with renal failure are excluded. Thus, it would appear that external standard curves constructed in normal plasma can be used to measure norepinephrine and epinephrine precisely in samples from persons who do not have renal failure.(ABSTRACT TRUNCATED AT 250 WORDS)

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.

The human sympathochromaffin system.

Hypoglycemia stimulates adrenomedullary epinephrine secretion; standing stimulates sympathetic neural norepinephrine release. In five bilaterally adrenalectomized persons plasma epinephrine, measured with a sensitive single-isotope derivative assay, rose from 15 +/- 2 to 35 +/- 7 pg/ml (P less than 0.02) during hypoglycemia but did not increase during standing. In contrast, plasma norepinephrine rose during standing but not during hypoglycemia. Thus, in humans 1) extra-adrenal epinephrine secretion is regulated and derived from innervated cells other than sympathetic postganglionic neurons; 2) because the plasma levels of epinephrine in adrenalectomized individuals even in response to the potent stimulus of hypoglycemia are below physiological thresholds, any biological actions of extra-adrenal epinephrine in adults must be paracrine rather than endocrine in nature; 3) hypoglycemia does not appear to stimulate the sympathetic nervous system. In view of these findings, we propose that extra-CNS catecholamine-producing tissues be termed the sympathochromaffin system consisting of two components: 1) the sympathetic nervous system that releases the neurotransmitter norepinephrine from its postganglionic neurons, and 2) the chromaffin tissues, including the adrenal medullae, that contain cells that secrete epinephrine, norepinephrine, or dopamine. The plasma epinephrine concentration is a valid measure of its chromaffin tissue (predominantly adrenomedullary) secretion, whereas the plasma norepinephrine concentration is an index of sympathetic neuronal activity under some but not all conditions.

Roles of glucagon and epinephrine in hypoglycemic and nonhypoglycemic glucose counterregulation in humans.

Studies of two models of human glucose counterregulation, glucose recovery from insulin-induced hypoglycemia and the transition from exogenous glucose delivery to endogenous glucose production late after glucose ingestion, indicate that the principles of rapid hypoglycemic and nonhypoglycemic glucose counterregulation in these models are the same. 1) Neither is solely explicable on the basis of dissipation of insulin; 2) glucagon plays a primary counterregulatory role in both; 3) epinephrine compensates largely for deficient glucagon secretion in both; and 4) counterregulation fails to occur only in the absence of both glucagon and epinephrine in both. Thus, prevention as well as correction of hypoglycemia is effectively accomplished by redundant glucose counterregulatory systems, primarily glucagon and secondarily epinephrine, coupled with dissipation of insulin in humans. Other hormones, neural mechanisms, or autoregulation may be involved but need not be invoked and are not sufficiently potent to prevent or correct hypoglycemia when both of the key glucose counterregulatory hormones, glucagon and epinephrine, are deficient. Although confirmed in that they predict the impact of disease-related deficiencies of glucagon, epinephrine, or both, the extent to which these principles can be generalized to additional models of glucose counterregulation remains to be established. However, they provide a basis for plausible, testable hypotheses concerning the physiology and pathophysiology of glucose counterregulation.