Thermic effect of epinephrine: A role for endogenous insulin

Thermic Effect of Epinephrine:

A Role for Endogenous

Insulin

Manfred J. Miiller, Kevin J. Acheson, Veronique Piolino, Nicolas Jeanpretre, Albert G. Burger, and Eric Jequier The contribution of the basal insulin concentration to the metabolic response to epinephrine was measured in eight, postabsorptive, healthy volunteers before and during epinephrine (0.05 pg/ kg fat-free mass [FFM] x min) and somatostatin (500 pg/h) infusion with and without insulin (0.1 mu/kg body weight [BW] x min) replacement. At basal plasma insulin concentrations, epinephrine increased oxygen consumption, heart rate, heart work, hepatic glucose production, glycogen breakdown in liver and muscle, and glucose oxidation, and the arterial plasma concentrations of glucose, lactate, and free fatty acids. Similar effects were observed during hypoinsulinemia, but epinephrine’s actions on oxygen consumption and plasma concentrations of free fatty acids were disproportionally enhanced. We conclude that epinephrine-induced thermogenesis is partially inhibited by basal plasma insulin concentrations. Copyright 0 1992 by W. B. Saunders Company

C energy expenditure. l-4The thermic effect of pharmacological doses of epinephrine, which result in plasma ATECHOLAMINES

ARE major determinants

of daily

concentrations rarely achieved even in major stress, has been discussed for about 90 years. However, the physiological action of epinephrine on thermogenesis has been documented only recently.5-7 This effect may be explained by the P-adrenergic action of epinephrine on cellular oxygen consumption. However, since epinephrine is also known to alter the secretion and action of insulin, part of its effect may result from an interaction of both hormones and/or an altered utilization or mobilization of fuels induced by these hormones. Indeed, an increased thermogenie response to epinephrine has been reported in 48-hourstarved humans7 and in children with type I diabetes mellitus.8 The latter finding was shown to be independent of the glycemic control of the patients.x The use of the “pancreatic-” or “islet-clamp technique” (ie, inhibiting pancreatic hormone secretion by somatostatin infusion with or without concomitant peripheral replacement of insulin and/or glucagon) in healthy volunteers showed that the response to epinephrine was unaltered in the absence of changes in plasma insulin concentrations during epinephrine infusions.“ In this report, we wanted to investigate the effect of hypoinsulinemia on epinephrine-induced thermogenesis. Regarding the use of a suitable experimental protocol, the islet clamp may lead to erroneous conclusions, since somatostatin decreased plasma insulin within 3 to 5 minutes, but the biological effects of insulin disappeared with an apparent half-life of 40 to 50 minutes.lOJ1 There is evidence that part of insulin’s effect is still present during short-term hypoinsulinemia brought about by somatostatin infusion.12 We therefore used a sequential-clamp protocol in healthy volunteers, and followed the thermic effect of epinephrine during a more prolonged hypoinsulinemia that took into account the From the Medizinische Hochschule Hannover, Hannover, Germany; the Nestle Research Center, Vers-chez-les Blanc, Institute de Physiologic, University Lausanne, Lausanne, Switzerland; and the Hopital Cantonal de Geneve. Geneve, Switzerland. Address reprint requests to Manfred .I. Miiller, MD, Medizinische Hochschule Hannover, Abt. Gastroenterologie und Hepatologie, Konstar@-Guttschow-Str. 8, D 3000 Hannover 61, Germany. Copyright 0 1992 by W.B. Saunders Company 0026-0495l9214106-0003$03.00/0 582

biological half-life of insulin. Our data demonstrate that the effect of epinephrine on energy expenditure is enhanced by hypoinsulinemia and thus support previous data obtained in starved human subjects and in patients with type I diabetes mellitus.7,8 SUBJECTS AND METHODS

Subjects Eight. healthy, male subjects with an average agr of 26 * 4 years, a height of 174 ? 6 cm, a weight of 67 % 8 kg, and a fat-free mass (FFM) of 56.6 2 5.3 kg (estimated by skinfold measurements) volunteered for this study. No subject had an individual or family medical history of diabetes mellitus, cardiac disorder, or thyroid dysfunction. None were taking any medication, and a recent cardiogram had shown no cardiac abnormalities. All subjects were asked to refrain from physical exercise for 3 days before the tests and to consume a diet with sufficient carbohydrate to provide at least 200 g carbohydrate per day during this time. All subjects were informed of the nature, purpose, and possible risks of the study before giving their written consent to participate. The study protocol had previously been reviewed and accepted by the Ethical Committee of the Faculty of Medicine, Lausanne University. Experimental Protocol All experiments were performed after an overnight fast. Each subject spent the night before the study in a room adjoining that in which the test was to be performed. On the morning of the test, the subject was awakened at 5:45 AM and, after voiding, was transferred to the test room, where two peripheral venous catheters were inserted; one was inserted in an antecubital vein for the infusion of all test substances, and the other was inserted retrogradely in a wrist vein for blood sampling. The hand was then placed in a box heated at 60°C to achieve arterialization of the venous blood. At the same time, electrodes were placed on the subject’s chest for on-line monitoring of the electrocardiogram (Hewlett-Packard HP 7830A, Boeblingen, Germany) and continuous heart-rate recording (Baumann CEM, Fleurier, Switzerland). Arterial blood pressure was measured automatically every IO minutes using a cuff placed on the arm that was free of catheters (Dynamap, Applied Medical Research, Tampa, FL). At -120 minutes. 3-“H-glucose was given as a primed (20 FCi), constant infusion (0.20 pCi/min).‘? Continuous respiratoryexchange measurements were begun. and continued for the duration of the protocollj-ls (Fig 1). After 1 hour of baseline measurements, the last 30 minutes of which corresponded to period I. endogenous insulin secretion was inhibited by infusion of somatostatin at 500 kg/h (Stilamin, Serono, Aubonne. Switzerland) until the end of the experiment. Basal insulin was replaced by exogenous insulin (0.1 mu/kg body weight [SW] x min; Actrapid HM, Novo

Metabohsm, Vol41.

No 6 (June),

1992:

pp

582-587

EPINEPHRINE/INSULIN

INTERACTIONS

IN THERMOGENESIS

HORMONE

583

INFUSIONS

epinephrine insulin 1 somatostatin 4 Period

Period

f 1 I I

1 2 / 3 I I

Period

; 4 I

I I

; 5 ;

1.4-

cl-3? r; 212-

1.1 .J

Fig 1. Time-course of changes in energy expenditure, nonprotein respiratory quotient, and heart rate during the different periods of experimental protocol. Data are given as means f SD. n = 8.

Heart Rate

-60

0

Industri, Bagsvaerd, Denmark) that was infused in a primed, continuous manner.‘*,13 Plasma glucose was maintained at euglycemia by determining its plasma concentration every 5 minutes and periodically adjusting an intravenous infusion of a 20%-glucose solution (Hausmann Laboratories, St. Gallen, Switzerland).‘-‘J4 The time between 60 and 90 minutes was considered to be period 2. After 90 minutes of “euinsulinemic-euglycemia,” epinephrine (Suprarenin, Hoechst, Frankfurt. Germany) was infused at 0.05 *g/kg FFM x min for 30 minutes (ie, period 3). After 150 minutes, the insulin infusion was stopped and the experiment was continued in hypoinsulinemic conditions. The time between 270 and 300 minutes was considered to be period 4. At 300 minutes, epinephrine was again infused at 0.05 pglkg FFM x min for 30 minutes (ie, period 5) and the test was terminated at 360 minutes. Infitsates The tracer infusate was prepared by diluting 150 PCi sterile, pyrogene-free, D-(3-3H)-tritiated glucose (New England Nuclear, Boston, MA) in 75 mL sterile physiological saline. Ten milliliters of this solution was used for the priming dose, and the remainder was infused at a rate of 0.1086 mL/min using a continuous infusion pump (Harvard Apparatus, South Natick, MA). Somatostatin, 3.25 mg, was dissolved in 93.5 mL sterile 0.9% NaCl (Vifor, Geneva, Switzerland) to which 4 mL of the subject’s own blood was added (total volume, 97.5 mL), to prevent adherence of the hormone to the container and tubing. Somatostatin was infused at 0.25 mL/min (ie, 500 pg/h) using an Imed 928 volumetric infusion pump (Milton, Abingdon, England). Forty international units insulin (ie, 1 mL) was diluted 1:lO with 0.9% NaCI, and 0.0075 mL/kg BW of this solution was mixed to a volume of 150 mL with 0.9% NaCI, to which 6 mL of the subject’s own blood had been added. The solution was infused using an Imed 960 volumetric infusion pump (Milton). At the end of the insulin infusion, a sample of the

60

120

180

240

300 Time(minutes.1

360

infusate was taken, centrifuged, and analyzed. Epinephrine, 500 kg, was diluted 1:lO in 0.9% NaCI, to which 0.5 mL ascorbic acid (100 mg/mL; Redoxon, Hoffmann La Roche, Base], Switzerland) had been added. The solution was infused at 0.05 kg/kg FFM x min using a Harvard compact infusion pump, model 975 (Harvard Apparatus). The epinephrine solutions were mixed separately for each infusion. At the end of each infusion period, a sample of the infusate was taken and immediately frozen at -80°C until analysis.16The actual infusion rate was 0.045 pg/kg FFM x min, with a coefficient of variation of 11%. Three different batches of a 20% glucose solution were used throughout the study. The glucose concentration of each batch was confirmed by dilution and analysis. Blood and Urine Samples Two samples were taken in the basal state (period 1). In addition to the 5-minute plasma glucose samples, blood was taken at 30-minute intervals throughout the test and analyzed for insulin, glucagon, lactate, and free fatty acids. Samples for the analysis of labeled glucose were drawn every 30 minutes and at lo-minute intervals during periods 1, 2, 3, 4, and 5. Plasma catecholamines were analyzed from samples taken in the fasting period and at the beginning and end of each epinephrine infusion period. Blood urea was determined at the beginning and at the end of each test, and the calculated changes in the blood urea nitrogen pool were used to correct the rate of urinary nitrogen excretion.14J5 Urine was collected overnight and at the end of the experiment and was analyzed for nitrogen. Analyses Plasma glucose was analyzed in duplicate on a Beckman II glucose analyzer (Beckman Instruments, Fullerton, CA) and insulin, C-peptide, and glucagon were analyzed by radioimmunoassays as described previously. 14,1hFree fatty acids and lactate were

MULLER ET AL

584

measured by standard enzymatic methods.“,14 Plasma catecholamines were determined by high-performance liquid chromatography (HPLC).14 Measurements of plasma glucose specific activity were performed in duplicate as described previously.‘2.‘6,‘7 Briefly, 0.5 mL plasma was deproteinized (Somogyi’s method) and 0.8 mL of the protein-free supernatant was evaporated to dryness in a vacuum at -70°C for 12 hours to eliminate ‘HzO; the residue was then dissolved in 1 mL Hz0 and radioactivity was measured after the addition of 10 mL liquid scintillant (Beckman). To determine the doses of the infused tracer accurately, three separate 1:lOO dilutions of each injectate and another 50 JJ,L injectate mixed with 500 PL preinfusate plasma, which then followed the same treatment. were run in parallel through the Somogyi procedure and counted together with the plasma samples. The 3Hz0 content of the infusate was less than 1% of total activity and all calculations were corrected accordingly. The recovery efficiency was calculated and the plasma counts were corrected accordingly. Each sample was counted for at least 12 minutes.

Data Analyses Energy expenditure and substrate oxidation rates were calculated as previously described. I5 The amount of glucose metabolized was calculated from the glucose infusion rate and the change in the using a twoglucose pool. 13.14Glucose kinetics were calculated compartment model assuming a total glucose-distribution volume of 200 mL/kg BW.‘6J7 Hepatic glucose production was calculated from the difference between the isotopically determined rate of glucose appearance and the amount of glucose infused. Since glucose oxidation exceeded isotopically determined glucose disposal during epinephrine infusion, the difference between both parameters was taken as an index of intracellular glycogen mobilization in liver and skeletal muscle (periods 3 and 5). During periods 1, 2, and 4, the difference between glucose disposal and glucose oxidation was positive and was considered to reflect nonoxidative glucose disposal. For statistical analysis, the raw data were reduced to five mean values for each measured variable, ie, to five 30-minute periods (Fig 1). All data were tested for normality using the Shapiro-Wilk test, and comparisons were performed using Bonferroni’s multiplecomparison testI*; (Tables 1 and 2 ). The effects of insulin and

epmephrine alone and the interactions between these two hormones with the metabolic parameters measured were analyzed using a univariate ANOVA for repealed measures (Table 3). All statistical analyses were performed using the SAS statistical package (Statistical Analysis System, Gary, NC). RESULTS

When compared with the basal state (period l), somatostatin infusion plus replacement of physiological amounts of insulin (period 2) resulted in a decrease in plasma glucagon and C-peptide concentrations, while only minor changes in plasma insulin, catecholamines, and lactate were observed (Table 1). Energy expenditure decreased slightly (NS), while the nonprotein respiratory quotient and heart rate did not change (Fig 1). Since hepatic glucose production decreased, glucose had to be infused to maintain euglycemia (Tables 1 and 2). Glucose disposal, glucose oxidation, and nonoxidative glucose metabolism (period 1. 0.57 * 0.16 v period 2, 0.71 ~fr0.26 mg/kg x min; NS) increased slightly during period 2. At that time, plasma free fatty acid concentrations had decreased (Table I) while lipid oxidation remained unchanged. When compared with data obtained during period 3, epinephrine infusion (period 3) increased metabolic rate, the nonprotein respiratory quotient, heart rate (Fig l), plasma glucose (Table 1). hepatic glucose production (Table 2), glucose oxidation (+33 mg/min, calculated as the mean surface area obtained over 60 minutes; P < .05 1’ period 2), plasma lactate, and free fatty acids (Table 1) at reduced lipid oxidation rates (Table 2). Since glucose oxidation exceeded glucose disposal during period 3 (Table 2), glycogen had to be mobilized (glucose oxidation minus glucose disposal, 0.14 -t 0.35 mg/kg x min; Table 2) to meet the cellular energy demands. Concomitantly, diastolic blood pressure decreased (Table I). During hypoinsulinemia (period 4, Table I), energy expenditure and the nonprotein respiratory quotient de-

Table 1. Mean Plasma Substrate, Hormone, Heart Rate, and Blood Pressure Data Obtained During Different Periods of Test (n = 8, Mean f SEM) Parameter Glucose (mmol/L)

FFA (pmol/L)

Period 1

5.3 -L 0.1 514240

Lactate (mmol/L)

P

Period2

P

Period3

Period4

P

Period5

NS

5.2 2 0.1

*

6.4 ? 0.3

5.8 ? 0.3

*

7.6 ? 0.3

*

313?45

*

926 % 45

778 % 40

*

1,805 + 100

0.7 * 0.1

NS

0.8 + 0.1

t

10.2 ‘- 0.9

NS

17.3 + 4.0

NS

C-peptide (g/L)

1.3 r 0.1

*

Glucagon (ng/LI

91 ?5

t

56 r 6

NS

46 ? 4

45 % 3

NS

46 ? 4

NS

242 2 34

NS

261 2 35

252 + 46

NS

315 +- 57

Insulin (mu/L)

Norepinephrine

(ng/L)

224 +- 19

0.3 z!z0.04

NS

Epinephrine IngiL)

91 *II

NS

75 & 8

l

Heart rate (bpm)

66 & 1

NS

66 -t 2

l

127 c 3

NS

127 -t 3

Diastolic BP (mm Hg)

76 2 1

NS

Mean arterial BP (mm Hg)

93 -c 2

NS

6,161 r 126

NS

Systolic BP (mm Hg)

Heart work (mm Hg x bpm)

1.3 t- 0.1 17.1 2 4.0 0.3 2 0.04

0.8 + 0.03

*

1.4 * 0.2

3.8 ? 0.3

NS

4.1 * 0.3

0.2 + 0.02

NS

0.1 2 0.03

960 2 194

74 + IO

t

77 t 2

66 + 2

*

NS

132 & 3

127 + 4

77 + 2

*

70 + 2

94 2 6

NS

91 I! 2

6,273 2 161

NS

6,869 -c 271

NOTE. Period 1. basal values; Period 2, values obtained during inhibition of endogenous

902 -c 127 78 2 2

NS

132 2 3

76 2 2

t

68 2 2

93 + 2

NS

6,129?

248

l

89 2 2 7,019 + 286

insulin secretion and replacement with exogenous

insulin; Period 3. insulin replacement and epinephrine infusion (0.05 pg/kg FFM x min); Period 4, hypoinsulinemia; Period 5, hypoinsulinemia and epinephrine infusion (0.05 kg/kg FFM x min); Heart work, heart rate x mean arterial blood pressure (mm Hg x bpm).

lP < .05. tP < .Ol. SP < ,001.

EPINEPHRINE/INSULIN

INTERACTIONS

IN THERMOGENESIS

585

Table 2. Mean Data for Glucose Kinetics and Substrate Oxidation Rates Obtained During Different Periods of Test (Mean f SEM, N = 8) Parameter

Ra

Period

1

Period

P

2.12 -c 0.07

NS

2

P

2.48 i 0.31

t

-

t

1.97 f 0.39

*

HGP

2.12 + 0.7

*

0.51 t 0.16

t

M

Period

3

3.41 I? 0.21 -1.64

Period

4

1.75 2 0.12

Period5

P

*

t 1.10

0.36 2 0.15

$

5.08 + 0.98

1.39 2 0.25

*

-

2.73 r 0.15-4.02

r 0.32

6.75 r 0.38

Rd

2.12 + 0.07

NS

2.50 -t 0.31

NS

2.98 & 0.33

1.69 t 0.11

NS

1.98 IT 0.16

MCR

2.23 2 0.07

NS

2.66 +- 0.33

NS

3.13 ? 0.36

1.63 % 0.11

NS

1.85 + 0.12

GlucOx

1.55 2 0.19

NS

1.79 -’ 0.10

*

3.12 ? 0.25

0.89 % 0.07

*

2.38 z 0.2

LipOx

1.01 -t 0.10

NS

1.00 + 0.07

*

0.65 t 0.14

1.32 2 0.09

*

1.01 z 0.14

-

NOTE. See Table 1 for period designations. Abbreviations: Ra, rate of glucose appearance; M, glucose metabolized as derived from clamp data; HGP, hepatic glucose production; Rd, glucose disposal rate; MCR, metabolic clearance rate of glucose: GlucOx, glucose oxidized; LipOx, lipid oxidized: data in mg/kg BW x min.

lP < .05. tP < .Ol. SP < .OOl.

creased further (P < .OOl, Fig l), resulting in a depressed carbohydrate oxidation (52 2 8 mg/min) at increased plasma free fatty acid concentrations (Table 1) and lipid oxidation (90 5 8 mg/min) (P < .05 v period 1 and P < .005 v period 2, Table 2). Thus, fat had become the principal energy source during period 4. When compared with period 2 (ie, pre-epinephrine infusion period), the rate of hepatic glucose production increased (P < .05). Infusing epinephrine at reduced plasma insulin and glucagon concentrations (Table 1, period 5) resulted in increases in energy expenditure (P < .Ol), heart rate (P < .05, Fig l), heart work (Table l), plasma glucose (Table l), hepatic glucose production (Table 2), glucose oxidation (Fig 1, Table 2), glycogen mobiIization (glucose oxidation minus glucose disposal, 0.40 f 0.26 mg/kg x min), and plasma lactate and free fatty acids (Table l), and resulted in a decrease in diastolic blood pressure (Table 2) and lipid oxidation (Table 2). Table 3 summarizes the significance levels (P values) obtained for the effect of insulin, per se, and epinephrine, per se, and their combined effects on measured metabolic Table 3. Effects of Insulin and Epinephrine Alone and Interactions Between the Two Hormones on Metabolic Parameters

Parameter Energy

expenditure

Effectof

Effect

Insulin

Epinephrine

of

Interaction

Between

InsuliniEpinephrine

.58

.OOOl

,016

CHOOX

.0003

.OOOl

.46

LIPOX

,002

,002

.62

Ra

,026

.0002

.896

Rd

.0027

.OOOl

,938

MCR

.OOOl

.OOOl

.8051

Plasma glucose

.OOOl

.OOOl

.0054

Insulin

,012

,969

,526

FFA

.OOOl

.OOOl

,015

Lactate

,863

.000&l

,127

C-peptide

.0005

,063

.3778

Glucagon

.023

.057

,099

Epinephrine

.568

.0008

,593

Norepinephrine

,304

.0109

.2118

NOTE. A univariate ANOVAfor

repeated measures was performed. P

values less than .05 indicate an effect. Abbreviations:

CHOOX, glucose oxidation; LIPOX, lipid oxidation;

Ra, rate of glucose appearance;

Rd, rata of glucose disappearance;

MCR, metabolic clearance rate of glucose; FFA, free fatty acids.

parameters. It can be seen that in the presence of both of these hormones, only energy expenditure, plasma glucose, and plasma free fatty acids were significantly influenced. DISCUSSION

Basal glucagon does not influence the metabolic response to epinephrine, 19whereas various metabolic effects of epinephrine are enhanced in subjects with starvationinduced hypoinsulinemia7J0~21 and in patients with type I diabetes me11itus.8~22-2s These data give supporting evidence for the hypothesis that basal insulin suppresses some of the metabolic effects of epinephrine. Our present experimental data support this hypothesis (Fig 1). The mechanisms of the thermic effect of epinephrine include increases in heart work, hepatic glucose production, lipolysis, and substrate cycling, and alterations in the endogenous fuel mix. Epinephrine obviously enhanced heart work and glucose production (Fig 1, Tables 1 and 2), while increases in plasma lactate (Table 1) may indicate increased Cori-cycle activity. 26Enhanced lipolysis (Table 1) and lipid oxidation at concomitantly increased triglyceridefree fatty acid recycling also contribute to whole-body energy expenditure,27,28 whereas epinephrine either decreases29,30or has no effect on protein oxidation.31 It is tempting to speculate that the contribution of the metabolism of individual substrates to epinephrine-induced energy expenditure differs between a well-insulinized state (period 3) and insulinopenia (period 5). Glucose is the principal energy source during a well-insulinized state (period 2, Fig l), but it was replaced by fat oxidation during hypoinsulinemia (period 4, Fig 1). Nevertheless, short-term epinephrine infusion causes similar increases in glucose oxidation at basal (period 3, Fig 1) and at reduced plasma insulin concentrations (period 5, Fig l), suggesting that glucose is the preferred fuel during acute stress situations, which are independent of the metabolic state. Increased glucose oxidation is brought about by epinephrine-induced increases in hepatic gIucose output and by glycogen mobilization in liver and muscle. The magnitude of epinephrine-stimulated hepatic glucose output is independent of basal insulin (Table 2), which fits with previous data on postabsorptive and 4-day-starved man.“* Since epinephrine-induced increases in glucose oxidation exceed the

586

MULLER ET AL

increase in plasma glucose disposal (Table 2, periods 3 and 5), epinephrine’s effect on glycogen breakdown is obvious. Since an exaggerated thermic effect of epinephrine has been reported for starvation,’ type I diabetes mellitus,8 and this effect may contribute to the severe hyperthyroidism; 13~)4 tissue wasting observed in these situations during an additional intervening stress (eg, an infection). In contrast, the thermic effect of epinephrine is reduced during tissue anabolism and hyperinsulinemia (eg, with overfeeding, obesity, type II diabetes mellitus, and during insulin infusions).3J5 Although reduced thermogenesis may be considered as a secondary phenomenon in obesity, this may predispose subjects to gain weight. If one assumes a common mechanism, then increased or decreased plasma insulin concentrations are associated with decreased or increased epinephrine-induced thermogenesis in most of these situations3,7.8.23(Table 3). However, this is not true for hyperthyroidism.t3,33,34 In addition, insulin resistance may also contribute to decreased thermogenesis in obesity,” but insulin resistance may occur during both tissue anabolism (eg, obesity) and tissue catabolism (eg, starvation; Table 3). Alterations in the thermic effect of epinephrine are associated with changes in body energy stores; thus, decreases in glycogen and fat stores are associated with an increase in epinephrine’s effect, while increases in glycogen and fat stores are associated with a decrease in epinephrine’s effect. Furthermore, it is tempting to speculate that a reduction in the size of glycogen stores reduces glucose oxidation, which predisposes cells to undergo lipolysis and

lipid oxidation, and thus exaggerates both the lipolytic and the thermic effect of epinephrine. In contrast, glycogen repletion predisposes one to the condition of positive fat balance, and thus may be associated with a reduced lipolytic and thermic response to epinephrine. The determinants of body energy stores include substrate supply, insulin. and thyroid hormones, whereas epinephrine mainly determines energy fluxes.jh Since insulin is also known to increase sympathetically mediated thermogenesis, it might also influence the balance between the two branches of the sympathoadrenal system.’ With hyperinsulinemia. sympathetically mediated thermogenesis is more important than the effect of circulating epinephrine. thus decreasing the thermogenic effect of epinephrine. With hypoinsulinemia, sympathetically mediated thermogenesis is decreased, resulting in a greater response to epinephrine. We conclude that the thermic effect of epinephrine is enhanced by insulinopenia, suggesting that basal insulin camouflages some of the effects of circulating catccholamines on energy expenditure. This effect might provide a rationale for stress-induced tissue wasting during hypoinsulinemia. In contrast, moderate increases in basal plasma insulin concentrations (ie, plasma insulin levels of -20 FUlmL) decrease the thermic response to epinephrinc infusions.35 Hyperinsulinemia may thus contribute to energy retention and weight-gain. Although insulin, per se, does not affect energy expenditure in man,14 basal plasma insulin concentrations affect epinephrine-induced thermogenesis, and thus, energy balance.

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