P. E. Cryer

Influence of body fat distribution on free fatty acid metabolism in obesity.

UNLABELLED In order to determine whether differences in body fat distribution result in specific abnormalities of free fatty acid (FFA) metabolism, palmitate turnover, a measure of systemic adipose tissue lipolysis, was measured in 10 women with upper body obesity, 9 women with lower body obesity, and 8 nonobese women under overnight postabsorptive (basal), epinephrine stimulated and insulin suppressed conditions. RESULTS Upper body obese women had greater (P less than 0.005) basal palmitate turnover than lower body obese or nonobese women (2.8 +/- 0.2 vs. 2.1 +/- 0.2 vs. 1.8 +/- 0.2 mumol.kg lean body mass (LBM)-1.min-1, respectively), but a reduced (P less than 0.05) net lipolytic response to epinephrine (59 +/- 7 vs. 79 +/- 5 vs. 81 +/- 7 mumol palmitate/kg LBM, respectively). Both types of obesity were associated with impaired suppression of FFA turnover in response to euglycemic hyperinsulinemia compared to nonobese women (P less than 0.005). These specific differences in FFA metabolism may reflect adipocyte heterogeneity, which may in turn affect the metabolic aberrations associated with different types of obesity. These findings emphasize the need to characterize obese subjects before studies.

Role of Glucagon, Catecholamines, and Growth Hormone in Human Glucose Counterregulation: EFFECTS OF SOMATOSTATIN AND COMBINED α- AND β-ADRENERGIC BLOCKADE ON PLASMA GLUCOSE RECOVERY AND GLUCOSE FLUX RATES AFTER INSULIN-INDUCED HYPOGLYCEMIA

To further characterize mechanisms of glucose counterregulation in man, the effects of pharmacologically inducd deficiencies of glucagon, growth hormone, and catecholamines (alone and in combination) on recovery of plasma glucose from insulin-induced hypoglycemia and attendant changes in isotopically ([3-(3)H]glucose) determined glucose fluxes were studied in 13 normal subjects. In control studies, recovery of plasma glucose from hypoglycemia was primarily due to a compensatory increase in glucose production; the temporal relationship of glucagon, epinephrine, cortisol, and growth hormone responses with the compensatory increase in glucose appearance was compatible with potential participation of all these hormones in acute glucose counterregulation. Infusion of somatostatin (combined deficiency of glucagon and growth hormone) accentuated insulin-induced hypoglycemia (plasma glucose nadir: 36+/-2 ng/dl during infusion of somatostatin vs. 47+/-2 mg/dl in control studies, P < 0.01) and impaired restoration of normoglycemia (plasma glucose at min 90: 73+/-3 mg/dl at end of somatostatin infusion vs. 92+/-3 mg/dl in control studies, P<0.01). This impaired recovery of plasma glucose was due to blunting of the compensatory increase in glucose appearance since glucose disappearance was not augmented, and was attributable to suppression of glucagon secretion rather than growth hormone secretion since these effects of somatostatin were not observed during simultaneous infusion of somatostatin and glucagon whereas infusion of growth hormone along with somatostatin did not prevent the effect of somatostatin. The attenuated recovery of plasma glucose from hypoglycemia observed during somatostatin-induced glucagon deficiency was associated with plasma epinephrine levels twice those observed in control studies. Infusion of phentolamine plus propranolol (combined alpha-and beta-adrenergic blockade) had no effect on plasma glucose or glucose fluxes after insulin administration. However, infusion of somatostatin along with both phentolamine and propranolol further impaired recovery of plasma glucose from hypoglycemia compared to that observed with somatostatin alone (plasma glucose at end of infusions: 52+/-6 mg/dl for somatostatin-phentolamine-propranolol vs. 72+/-5 mg/dl for somatostatin alone, P < 0.01); this was due to further suppression of the compensatory increase in glucose appearance (maximal values: 1.93+/-0.41 mg/kg per min for somatostatin-phentolamine-propranolol vs. 2.86+/-0.32 mg/kg per min for somatostatin alone, P < 0.05). These results indicate that in man (a) restoration of normoglycemia after insulin-induced hypoglycemia is primarily due to a compensatory increase in glucose production; (b) intact glucagon secretion, but not growth hormone secretion, is necessary for normal glucose counterregulation, and (c) adrenergic mechanisms do not normally play an essential role in this process but become critical to recovery from hypoglycemia when glucagon secretion is impaired.

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.

Hormonal mechanisms in acute glucose counterregulation: The relative roles of glucagon, epinephrine, norepinephrine, growth hormone, and cortisol

Abstract The roles of glucagon, catecholamines, cortisol, and growth hormone in acute glucose counterregulation in man were examined by studying the relationship between compensatory changes in glucose production and utilization and increases in the circulating concentrations of these hormones after insulin administration. Restoration of normoglycemia following insulin-induced hypoglycemia was due primarily to a compensatory increase in glucose production; from the known actions of the hormones studied, the time required for the onset of their action, and the time at which increases in their circulating concentrations were observed, only glucagon and the catecholamines could have participated in this compensatory change. Nevertheless, growth hormone and cortisol as well as the catecholamines could have contributed to restoration of normoglycemia in a subsidiary manner by accelerating the return of glucose utilization to basal rates. These potential roles for glucagon, catecholamines, growth hormone, and cortisol were examined by studying the effects of pharmacologically- or surgically-induced conditions in which increases in the circulating levels of these hormones (or the consequences thereof) were not possible following insulin-induced hypoglycemia: isolated glucagon deficiency (infusion of somatostatin plus growth hormone) blunted the compensatory increase in glucose production and impaired restoration of normoglycemia. Neither isolated growth hormone deficiency (infusion of somatostatin plus glucagon), adrenergic blockade (infusion of phentolamine and propranolol), nor adrenalectomy influenced compensatory changes in glucose turnover or affected restoration of normoglycemia. Superimposition of growth hormone deficiency upon glucagon deficiency (infusion of somatostatin without hormone replacement) did not exacerbate the effect of isolated glucagon deficiency. However, glucagon deficiency in the presence of either adrenalectomy or adrenergic blockade caused further impairment in restoration of normoglycemia compared to that observed with isolated glucagon deficiency. The results of these studies thus indicate that the major acute glucose counterregulatory hormones in man are glucagon and catecholamines. During recovery of plasma glucose from insulin-induced hypoglycemia, increases in plasma glucagon, but not in plasma cortisol and growth hormone, are essential for normal glucose counterregulation. Adrenergic mechanisms, specifically adrenomedullary epinephrine, become critical to recovery from hypoglycemia when glucagon secretion is impaired.

Epinephrine and norepinephrine are cleared through beta-adrenergic, but not alpha-adrenergic, mechanisms in man

Although catecholamines are rapidly removed from the extracellular fluid, the role of adrenergic mechanisms in the clearance of epinephrine and norepinephrine has not been defined. In five normal human subjects, mean (+/- SE) plasma epinephrine concentrations did not change during control infusions, rose from 21 +/- 6 pg/ml to 834 +/- 84 pg/ml during the infusion of epinephrine (50 ng/kg/min) over 180 min and to 853 +/- 112 pg/ml during the infusion of epinephrine plus phentolamine (500 micrograms/min after a 5.0 mg loading dose infused over 2 min), but to 2400 +/- 104 pg/ml during the infusion of epinephrine plus propranolol (80 micrograms/min after a 5.0 mg loading dose infused over 2 min), indicating that beta-adrenergic blockade sharply reduces the clearance of epinephrine in man. In separate studies in seven subjects, similar increments in plasma epinephrine occurred during the infusion of epinephrine alone and the clearance of epinephrine was comparably reduced during the infusion of epinephrine plus propranolol and during the infusion of epinephrine plus propranolol plus phentolamine, suggesting that the reduction of epinephrine clearance produced by beta-adrenergic blockade during epinephrine infusion is not mediated by an alpha-adrenergic reduction of blood flow to organs of epinephrine clearance. Endogenous plasma norepinephrine concentrations doubled during the infusion of phentolamine without propranolol but rose to nearly fourfold higher values during the infusion of phentolamine with propranolol indicating that beta-adrenergic blockade reduces the clearance of norepinephrine as well as that of epinephrine. These findings indicate that epinephrine and norepinephrine are cleared through beta-adrenergic, but not alpha-adrenergic, mechanisms in man.

Adrenergic mechanisms of catecholamine action on glucose homeostasis in man

To assess the adrenergic mechanisms responsible for the effect of epinephrine on glucose production and glucose clearance in man, epinephrine (50 ng/kg/min) was infused in the presence and absence of alpha adrenergic (phentolamine) and beta adrenergic (propranolol) antagonists under conditions when plasma glucose, insulin, and glucagon levels were allowed to vary and when they were clamped by a concurrent infusion of glucose, somatostatin, and insulin. When plasma glucose, insulin, and glucagon were permitted to vary during beta adrenergic blockade, plasma glucose and glucose production increased, respectively, 32% and 42% less and plasma epinephrine concentrations were threefold greater than those during infusion of epinephrine alone; plasma insulin decreased during beta blockade but increased during infusion of epinephrine alone; glucose clearance was comparably suppressed in both instances. When alpha adrenergic blockade was superimposed on beta blockade, the increase in glucose production and the decrease in both plasma insulin and glucose clearance observed during infusion of epinephrine alone was virtually abolished. In contrast, when plasma glucose, insulin, and glucagon were clamped, beta adrenergic blockade completely prevented the suppression of glucose clearance by epinephrine and inhibited the stimulation of glucose production by epinephrine by 80% whereas alpha adrenergic blockade had no effect on either of these parameters. These results indicate that in man, epinephrine increases glucose production and decreases glucose clearance by both alpha and beta adrenergic actions. The alpha adrenergic effects could be accounted for by inhibition of insulin secretion. The mechanism for the beta adrenergic effects remains to be defined but may reflect a direct action of epinephrine on hepatic and peripheral tissues.

Isoflurane and Whole Body Leucine, Glucose, and Fatty Acid Metabolism in Dogs

Following 4 h of general anesthesia with halothane [1.5 minimum alveolar concentration (MAC)]-nitrous oxide (50% in oxygen), whole body protein synthesis is decreased and the rate of leucine oxidation is increased in dogs. To evaluate the effects of general anesthesia with isoflurane on whole body fuel metabolism and the effects of duration of anesthesia on these processes, eight dogs were studied, once in the conscious state (over 9 h) and again prior to and during isoflurane anesthesia (1.5 MAC) for 3.5 h (n = 8). Three additional dogs were studied in the conscious state and over 5 h of anesthesia. Changes in protein, fatty acid, and glucose metabolism were estimated using isotope dilution techniques, employing simultaneous infusions of L-[1-14C]leucine, [6-3H]glucose and [9,10-3H]palmitate. Ten minutes after the beginning of the administration of isoflurane, total leucine carbon flux, leucine oxidation, and leucine incorporation into proteins decreased (P less than 0.05), resulting in a slight decrease in the ratio of leucine oxidation to nonoxidative leucine disappearance (LOX/NOLD, P less than 0.05), an indicator of leucine catabolism. Throughout the 5 h of anesthesia, whole body protein synthesis remained decreased (P less than 0.01), whereas leucine flux and oxidation increased progressively throughout the remainder of the study, resulting in a more than 80% increase in the ratio of LOX/NOLD. After 10 min of isoflurane anesthesia, both plasma free fatty acid concentrations and palmitate turnover had decreased by more than 70% (P less than 0.001) and remained suppressed (P less than 0.001) throughout the remainder of the anesthesia, consistent with decreased lipolysis. Glucose production was increased 10 min (P less than 0.05) following induction of anesthesia and peripheral glucose utilization was decreased following 3.5 h of isoflurane anesthesia (P less than 0.05). These data strongly suggest a widespread and immediate metabolic effect of isoflurane anesthesia, which includes peripheral insulin resistance to glucose disposal, decreased lipolysis, and a progressive increase in protein wasting with increasing duration of anesthesia.

Counterregulatory Hormones: Molecular, Biochemical, and Physiologic Aspects

Normal nutrient homeostasis depends on the balance between the effects of insulin and those of the counterregulatory hormones.1–4 Classically these hormones have been defined as those that oppose the actions of insulin, and they include glucagon, catecholamines, growth hormone, and cortisol. Of the catecholamines (i.e., epinephrine and norepinephrine), epinephrine is currently considered to act as a circulating hormone, whereas norepinephrine probably acts mainly as a neurotransmitter. Although thyroxine and triiodothyronine affect various aspects of metabolism,5 circulating thyroid hormone levels are not acutely altered by nutrient signals, and fluctuations in their daily secretion do not influence metabolic processes. For these reasons, thyroxine and triiodothyronine are not generally considered among the classic counterregulatory hormones.