Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, Tennessee 37232-0615
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ABSTRACT |
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The role of epinephrine and norepinephrine in
contributing to the alterations in hepatic glucose metabolism during a
70-h stress hormone infusion (SHI) was investigated in four groups of
chronically catheterized (20-h-fasted) conscious dogs. SHI increased
glucagon (~5-fold), epinephrine (~10-fold), norepinephrine (~10-fold), and cortisol (~6-fold) levels. Dogs received either all
the hormones (SHI; n = 5), all the
hormones except epinephrine (SHIEpi;
n = 6), or all the hormones except
norepinephrine (SHI
NE; n = 6).
In addition, six dogs received saline only (Sal). Glucose production
(Ra) and gluconeogenesis were
assessed after a 70-h hormone or saline infusion with the use of tracer
([3-3H]glucose and
[U-14C]alanine) and
arteriovenous difference techniques. SHI increased glucose levels
(108 ± 2 vs. 189 ± 10 mg/dl) and
Ra (2.6 ± 0.2 vs. 4.1 ± 0.3 mg · kg
1 · min
1)
compared with Sal. The absence of an increase in epinephrine markedly
attenuated these changes (glucose and
Ra were 140 ± 6 mg/dl and 2.7 ± 0.4 mg · kg
1 · min
1,
respectively). Only 25% of the blunted rise in
Ra could be accounted for by an
attenuation of the rise in net hepatic gluconeogenic precursor uptake
(0.9 ± 0.1, 1.5 ± 0.1, and 1.1 ± 0.2 mg · kg
1 · min
1
for Sal, SHI, and SHI
Epi, respectively). The absence of an
increase in norepinephrine did not blunt the rise in arterial glucose
levels, Ra, or net hepatic
gluconeogenic precursor uptake (they rose to 195 ± 21 mg/dl, 3.7 ± 0.5 mg · kg
1 · min
1,
and 1.7 ± 0.2 mg · kg
1 · min
1,
respectively). In summary, during chronic SHI, the rise in epinephrine exerts potent stimulatory effects on glucose production principally by
enhancing hepatic glycogenolysis, although the rise in circulating norepinephrine has minimal effects.
gluconeogenesis; cortisol; glycogenolysis
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INTRODUCTION |
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THE METABOLIC RESPONSE to stress is accompanied by marked increases in counterregulatory hormone levels. We recently reported that chronic stress hormone infusion (SHI; a combined infusion of glucagon, epinephrine, norepinephrine, and cortisol for 70 h) in the dog created marked hyperglycemia and accelerated glucose production (Ra) (23). The increase in Ra was due to a combined increase in glycogenolysis (30%) and gluconeogenesis (70%). The latter resulted from increases in net hepatic gluconeogenic precursor uptake and the efficiency of hepatic gluconeogenesis as well as renal gluconeogenesis.
The role glucagon and cortisol play in this response has been addressed. During SHI, glucagon facilitates the gluconeogenic pathway by augmenting gluconeogenic precursor entry into the liver as well as by enhancing the efficiency of gluconeogenesis (23). In contrast, cortisol increases the supply of gluconeogenic precursors reaching the liver and augments hepatic glycogen stores despite concomittant elevations in the other counterregulatory hormones (14). To date, however, the role that elevated circulating catecholamine levels play in driving the metabolic response to SHI has not been examined.
Epinephrine is known to play an important role in augmenting hepatic glucose production during acute stresses (e.g., hypoglycemia and endotoxemia) (7, 15). The epinephrine-induced increase in glucose production is due both to an increase in hepatic glycogenolysis and gluconeogenesis. The latter is mainly driven by an increase in lactate delivery from peripheral tissues (30). Interestingly, although glucagon cannot effectively antagonize insulin suppression of glucose production (29), epinephrine is effective (31). As insulin levels increase in response to SHI, the potential for epinephrine to play a central role in the metabolic response to chronic stress may be enhanced compared with other counterregulatory hormones.
Circulating norepinephrine levels can also increase markedly in response to stress (8). Hepatic glycogenolysis is less responsive to acute increases in circulating norepinephrine than epinephrine (8). However, hepatic gluconeogenesis is responsive to high levels of norepinephrine, such as can be seen at the adrenergic nerve terminal (~3,000 pg/ml). The enhancement in gluconeogenesis is due to combined increases in gluconeogenic precursor (lactate, glycerol) release by peripheral tissues, net hepatic fractional extraction of lactate by the liver, and net hepatic gluconeogenic efficiency.
The chronic effects of catecholamines on hepatic glucose metabolism
have not been well studied, especially in settings in which other
counterregulatory hormones are also elevated. Chronic -adrenergic
stimulation does not increase glucose production in humans (26). Yet
during infection, in which multiple stress hormones are elevated,
-adrenergic blockade (propranolol) attenuates the stress-induced
rise in Ra (18). The aim of the
present study was to examine the impact the individual circulating
catecholamines (epinephrine and norepinephrine) have in bringing about
the metabolic response to chronic SHI.
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METHODS |
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Animal preparation. Experiments were carried out on 20-h-fasted conscious mongrel dogs (23 ± 2 kg) receiving a diet consisting of Kal-Kan meat (Vernon, CA) and Purina dog chow (St. Louis, MO) once daily. The composition of the diet was 52% carbohydrate, 31% protein, 11% fat, and 6% fiber, based on dry weight. The dogs were housed in a facility that met American Association for the Accreditation of Laboratory Animal Care guidelines, and the protocols were approved by the Vanderbilt University Medical Center Animal Care Committee.
Two weeks before an experiment, a laparotomy was performed with the animals under general anesthesia (acepromazine 0.55 mg/kg, pentobarbital sodium 25 mg/kg). Silastic catheters (0.03-in. ID; Dow Corning, Midland, MI) were placed into the inferior vena cava for the chronic infusion of hydrocortisone, epinephrine, and norepinephrine and into a splenic vein for the chronic infusion of glucagon. Blood sampling catheters (0.04-in. ID) were inserted into the femoral artery, the portal vein, the right renal vein, and the left hepatic vein for blood sampling, as previously described (23). In addition, Doppler flow probes were placed around the portal vein and the hepatic artery, after the gastroduodenal vein was ligated, to divert all portal venous drainage through the portal vein flow probe. The sampling and infusion catheters and the Doppler leads were placed under the skin before closure of the incision. The dogs received penicillin G intramuscularly (106 U) immediately after wound closure to minimize the possibility of infection. All animals studied had 1) a good appetite (consuming the entire ration), 2) normal stools, 3) a hematocrit above 35%, and 4) a leukocyte count below 18,000/mm3.Experimental design.
On day
0 (14 days after surgery), after a
20-h fast, the subcutaneous ends of the infusion catheters were freed
from their subcutaneous pockets through small skin incisions made with
animals under local anesthesia (2% lidocaine), and the dog was placed in a jacket (Alice King Chatham, Los Angeles, CA) containing two pockets into each of which was placed a portable infusion pump (Auto
Syringe, Travenol Laboratories, Hooksett, NH). Hydrocortisone was
dissolved in saline and was infused with one pump at a rate of 4 µg · kg1 · min
1
(240 µl/h) into the inferior vena cava. Epinephrine and
norepinephrine were dissolved in saline containing ascorbic acid (0.7 mg/ml), and both were infused at a rate of 0.08 µg · kg
1 · min
1
(240 µl/h) into the inferior vena cava using the other pump. Glucagon
(5 ng · kg
1 · min
1;
4 ml/h) was infused into the portal vein with the use of a portable INFU-MED 200 infusion pump (Medex Ambulatory Systems, Broomfield, CO).
Four groups of dogs were studied. One group was infused with all of the
hormones (SHI; n = 5). Six dogs
received all of the hormones except epinephrine (SHI
Epi), and
six dogs received all of the hormones except norepinephrine
(SHI
NE). Six dogs were infused with saline only (Saline). All
the solutions were prepared and filtered (0.2 µm) under sterile
conditions before infusion, as previously described (23). Fresh
solutions were prepared every 12 h on each of the 3 infusion days. On
the 3rd day, after an overnight (20-h) fast, the sampling catheters and
flow probe leads were freed from their subcutaneous pockets with
animals under a local anesthetic (2% lidocaine), and basal metabolism was assessed.
Experimental protocol.
On day
3 an Angiocath (18 gauge; Deseret
Medicine, Sandy, UT) was inserted percutaneously into a cephalic vein.
A primed (50 µCi) constant infusion of purified
[3-3H]glucose (0.4 µCi/min) and infusions of
[U-14C]alanine (0.4 µCi/min), p-aminohippuric acid (0.3 mg · kg1 · min
1),
and indocyanine green (0.1 mg · m
2 · min
1)
were begun, using the right cephalic vein, and continued throughout the
entire experiment. The experiment consisted of two periods, an
equilibration period (
120 to 0 min) and a basal period (0 to 60 min). Femoral artery and portal, renal, and hepatic vein blood samples
were taken every 15 min during the basal period. At the end of the
basal period, the dog was euthanized and liver biopsies were rapidly
(within 3-5 min after euthanasia) taken from each lobe of the
liver and immediately frozen in liquid nitrogen for later analysis of
liver glycogen content and tracer glucose incorporation into glycogen.
In the SHI group an additional study was performed after the basal
period. Thus glycogen data were not obtained in that group. Instead
glycogen data from a previously reported SHI group were therefore used
for comparison (22).
Tracer methods and calculations.
The rates of total glucose production and utilization were calculated
according to the method of Wall et al. (33) as simplified by DeBodo et
al. (11). Net hepatic glucose output was calculated using the formula
[H (Fa × A + Fp × P)] × HBF,
where H, A, and P are the blood glucose concentrations in the hepatic
vein, femoral artery, and portal vein, respectively, and
Fa and
Fp represent the fractional
contribution of the hepatic artery and portal vein, respectively, to
total hepatic blood flow (HBF). Plasma glucose concentrations were
converted to whole blood concentrations using a correction factor of
0.73, as previously reported (24).
Processing of blood samples.
The method for collection and immediate processing of blood samples has
been previously described (5). Radioactivity in plasma glucose was
measured using established methods (5). Blood lactate, glycerol, and
alanine were analyzed using the method of Lloyd et al. (20). Plasma
glucose was assayed immediately using a Beckman glucose analyzer.
Plasma treated with 500 kallikrein inhibitory units of Trasylol (FBA
Pharmaceuticals, NY) was assayed for immunoreactive glucagon using 30K
antiserum of Aguilar-Parada et al. (1) [coefficient of variation
(CV) of 8%]. Immunoreactive insulin (34) was assayed using a
sephadex-bound antibody technique (Pharmacia Diagnostics, Piscataway,
NJ; CV of 11%). Plasma cortisol was assayed with Clinical Assays Gamma
Cost radioimmunoassay (RIA) kit (CV of 6%) (12). Plasma collected from
blood samples that were immediately treated with ethylene
glycol-bis(-aminoethyl ether)-N,N,N',N'-tetraacetic
acid and glutathione was assayed for epinephrine and norepinephrine
using high-performance liquid chromatography (HPLC) techniques (CV of
14%) (21), as modified by Davis et al. (10). Doppler-determined blood
flow was obtained with the use of an ultrasonic, range-gated, pulsed
Doppler flow meter designed by Hartley et al. and described by Hartley
et al. (16) and Ishida et al. (17). Indocyanine green dye was measured spectrophotometrically (810 nm) to estimate total hepatic blood flow
(19). In cases in which Doppler flow probes were not functional (1 of
5, 2 of 6, 3 of 6, and 3 of 6 in SHI, SHI
Epi, SHI
NE, and Saline, respectively), indocyanine green dye was used to assess total
hepatic blood flow, and the fractional contribution of hepatic artery
blood flow to total hepatic blood flow was asssumed to equal the
mean determined with Doppler flow probes in the respective group.
p-Aminohippuric acid was measured as
described by Brun (2) to estimate renal blood flow. The labeled
and unlabeled concentrations of plasma alanine and lactate were
determined using a short column ion exchange chromatographic system
(6). Hepatic glycogen content was determined using an enzymatic method
(4).
Materials. Glucagon was purchased from Eli Lilly (Indianapolis, IN). Epinephrine, norepinephrine, and p-aminohippuric acid were obtained from Sigma Chemical (St. Louis, MO). Hydrocortisone was purchased from Abbott Laboratories (North Chicago, IL). Glucagon 30K antiserum was obtained from the University of Texas Southwestern Medical School (Dallas, TX). Purified glucagon and 125I-labeled glucagon for RIA were obtained from Novo Research Institute (Copenhagen, Denmark). Cortisol assay kits were obtained from Upjohn Diagnostics (Kalamazoo, MN). [3-3H]glucose (HPLC purified) and [U-14C]alanine were purchased from NEN Research Products (Wilmington, DE).
Data analysis. The reported data represent means ± SE of the average steady-state values during the basal period on day 3. Data were analyzed using analysis of variance with post hoc analysis using Tukey's honestly significant difference multiple comparisons procedure (Systat, Cambridge, MA).
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RESULTS |
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Hormone levels and glucose metabolism.
SHI increased arterial plasma glucagon, epinephrine, norepinephrine,
and cortisol (Table 1) relative to the
levels evident in saline-infused dogs. When epinephrine was not
included in the SHI (SHIEpi), the plasma epinephrine level was
not altered, but the plasma glucagon, norepinephrine, and cortisol
levels increased as expected. When norepinephrine was omitted from the
SHI (SHI
NE), the plasma norepinephrine level decreased slightly,
and the plasma glucagon, epinephrine, and cortisol levels increased as
expected (Table 1).
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Hepatic gluconeogenesis.
Total hepatic blood flow was similar in SHI, SHIEpi, and Saline
(28 ± 3, 29 ± 4, and 31 ± 2 ml · kg
1 · min
1,
respectively) but was mildly elevated in SHI
NE (40 ± 4 ml · kg
1 · min
1).
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Intestinal and renal glucose metabolism.
Net intestinal glucose uptake was not altered by SHI (0.5 ± 0.1, 0.5 ± 0.1, 0.4 ± 0.1, and 0.9 ± 0.3 mg · kg1 · min
1
for Saline, SHI, SHI
Epi, and SHI
NE, respectively).
Likewise, the production of lactate and alanine by the intestine was
not altered by SHI (1.7 ± 0.9, 2.3 ± 0.3, 2.4 ± 0.7, and
1.6 ± 0.7 µmol · kg
1 · min
1
for lactate and 1.3 ± 0.2, 0.6 ± 0.1, 0.5 ± 0.1, and 0.7 ± 0.1 µmol · kg
1 · min
1
for alanine, respectively). There was minimal net glycerol exchange across the intestine (data not presented).
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DISCUSSION |
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During chronic (70-h) SHI, epinephrine plays an important role in sustaining the observed increase in glucose metabolism, although circulating norepinephrine appears to play little, if any, role. The absence of an increase in epinephrine attenuated the SHI-induced rise in both hepatic gluconeogenesis and glycogenolysis. In contrast, the absence of an increase in circulating norepinephrine had no effect on the SHI-induced changes in glucose metabolism.
The SHI-induced increase in net hepatic glucose output requires a
concomitant increase in both epinephrine and glucagon. In the acute
setting, these two hormones, when combined, can overcome the
antagonistic effects of insulin (25). Whether this effect persists
chronically is unknown. Surprisingly, the combined chronic infusions of
cortisol, glucagon, and norepinephrine (SHIEpi) were unable to
sustain an increase in net hepatic glucose output. The net release of
glucose by the liver reflects a balance between hepatic glucose
production and hepatic glucose uptake. Because hepatic glucose uptake
was unaffected by the infusion of glucagon, cortisol, and
norepinephrine, it can be concluded that these hormones alone were
unable to enhance glucose production. We previously observed that, when
glucagon was omitted from the SHI infusion, net hepatic glucose output
also did not increase (22). In that case, however, the failure to
increase net hepatic glucose output resulted from an increase in
hepatic glucose uptake that equaled the rise in hepatic glucose
production. Thus both glucagon and epinephrine must increase to sustain
an increase in net hepatic glucose output over a prolonged period.
Although, acutely, epinephrine has more potent stimulatory effects on
gluconeogenesis than glucagon (30, 32), its chronic stimulatory effects
on this process appear to be less substantive than that of glucagon
when multiple stress hormones are increased. In the acute setting,
epinephrine's ability to mobilize gluconeogenic precursors and NEFA
from peripheral tissues is the sole mechanism by which it enhances
gluconeogenesis (13, 30). Glucagon, on the other hand, relies on its
ability to enhance both the uptake of gluconeogenic precursors by the
liver and their intrahepatic conversion to glucose (29). It is by this
mechanism that glucagon chronically stimulates gluconeogenesis during
SHI (22). Despite epinephrine's known potent stimulatory effects on
lactate release from peripheral tissues in the acute setting, the
absence of an increase in epinephrine (SHIEpi) in the present
study led to only a modest fall in its arterial level and a more marked
fall in net hepatic lactate uptake. The SHI-induced rise in
gluconeogenesis (both net hepatic gluconeogenic precursor uptake and
gluconeogenic efficiency) was attenuated by only ~50% when
epinephrine was absent from the infusate. This is in unmistakable
contrast to what was seen when glucagon was omitted from the SHI,
namely that neither net hepatic gluconeogenic precursor uptake nor
hepatic gluconeogenic efficiency increased (22). Thus, although
epinephrine does contribute to the SHI-induced increase in
gluconeogenesis, glucagon is the primary hormone that facilitates this
process in the chronic multihormone setting.
In contrast to its modest effect on gluconeogenesis, epinephrine plays
a persistant and substantial role in sustaining the SHI-induced rise in
hepatic glycogenolysis. Hepatic glucose production is equal to the sum
of glycogenolysis and gluconeogenesis. In SHIEpi gluconeogenesis
increased even though hepatic glucose production did not increase
significantly. Thus, in SHI
Epi, hepatic glycogenolysis may have
fallen despite marked increases in plasma glucagon and norepinephrine.
We previously reported that, when glucagon was not infused, the stress
hormone-induced increase in hepatic glycogen mobilization persisted
(22). These data suggest that glucagon does not contribute to the rise
in hepatic glycogenolysis during SHI. The lack of an effect of glucagon
on hepatic glycogenolysis during SHI is consistent with the potent inhibitory effects of insulin, which increases during SHI, on glucagon-stimulated hepatic glycogenolysis (29). The primacy of
epinephrine in driving hepatic glycogenolysis during SHI is also
consistent with the observation that, in the acute setting, epinephrine
can overcome the suppressive effect of insulin on hepatic glycogen
breakdown (31). Thus the sustained rise in glycogenolysis seen during
SHI is principally supported by the rise in epinephrine.
Hepatic glycogen stores increase in response to SHI. The omission of
epinephrine from the SHI cocktail further increased liver glycogen
stores (16 mg/g). This increase is consistent with the attenuated
rise in hepatic glycogenolysis seen when epinephrine was not infused. A
similar increase was observed when glucagon was not infused during SHI
(
29 mg/g) (14, 22). However, glucagon does this by limiting hepatic
glucose uptake and subsequent glycogen synthesis rather than by
increasing glycogen breakdown. Thus epinephrine and glucagon complement
one another in attenuating the glycogen accretion mediated by excess
cortisol.
Surprisingly, norepinephrine did not amplify the stress hormone-induced
increase in hepatic glucose production. In the acute setting
norepinephrine is considerably less potent than epinephrine in
stimulating hepatic glycogenolysis (8, 30). However, norepinephrine can
efficiently enhance hepatic gluconeogenesis by increasing gluconeogenic
efficiency and by switching a liver that is releasing lactate to one
that is consuming it (8). In the present study gluconeogenesis was
already enhanced by the combined effects of glucagon and epinephrine.
Thus the effects of norepinephrine on gluconeogenesis may be
inconsequential. In fact, norepinephrine may not exert a sustained
stimulatory effect on gluconeogenesis, because the combined infusions
of epinephrine, norepinephrine, and cortisol were unable to enhance
gluconeogenesis (22). Given that the hyperglycemia tended to be higher
in SHINE than SHI, norepinephrine may exert a protective role in
limiting hyperglycemia induced by SHI. Although this study addresses
the impact on hepatic glucose metabolism of increases in circulating
norepinephrine during SHI, the impact of norepinephrine released by the
nerve terminal remains to be defined.
The SHI-induced increase in net fractional hepatic alanine extraction was not altered by the selective absence of a rise in either catecholamine. Although in an acute setting the infusion of norepinephrine can increase net fractional hepatic alanine extraction (8), its role in enhancing net fractional hepatic alanine extraction during SHI appears to be minimal. We reported previously that the chronic absence of an increase in glucagon prevented the SHI-induced increase in net hepatic alanine fractional extraction (22). Thus the accompanying hyperglucagonemia seen during chronic stress is the primary determinant of the increase in hepatic amino acid transport.
Surprisingly, epinephrine had a greater effect on NEFA availability
than did norepinephrine. Omission of norepinephrine had no effect on
SHI-stimulated lipolysis or NEFA availability. In contrast, lipolysis
and NEFA availability were decreased during SHI when the increase in
epinephrine (SHIEpi) was absent. Acute increases in
norepinephrine have been shown to increase both glycerol and NEFA
levels (9), although similar increases in epinephrine do not lead to a
sustained rise in either glycerol or NEFA levels (28). This may be
explained in part by the greater rise in the arterial glucose levels
seen after epinephrine infusion. The greater hyperglycemia seen after
epinephrine infusion may inhibit lipolysis and enhance
reesterification, thereby lowering NEFA levels (3, 27). In the present
study greater hyperglycemia cannot explain the attenuated response in
SHI
Epi, because the arterial glucose levels were lower in
SHI
Epi compared with SHI
NE. The mechanism for the
differential chronic and acute effects of these circulating hormones on
fat metabolism remains to be established.
The increase in norepinephrine may have contributed to the stress
hormone-induced increase in renal glucose production. We have
previously reported that SHI increased renal glucose production (0.3 to
0.9 mg · kg1 · min
1)
and omission of glucagon prevented this increase (22). Note that in the
present study, as well as in previous studies, the kidney remained a
net consumer of glucose because of an increase in renal glucose uptake
(0.5 to 1.8 mg · kg
1 · min
1)
(22). In the present study, in the absence of an increase in
epinephrine, renal glucose production remained unaltered, although in
SHI
NE renal glucose production was suppressed. These data, when
combined with our previous report (22), suggest that both glucagon and
norepinephrine contribute to the increase in renal glucose production
seen during SHI.
Thus, of the two circulating catecholamines, epinephrine plays the greater role by augmenting hepatic glucose production. Although an acute increase in epinephrine augments hepatic glucose production by increasing gluconeogenesis, its chronic effects in a setting in which other stress hormones are elevated are quite different. It mediates its chronic effects principally by enhancing hepatic glycogenolysis.
Perspective. We have now completed a series of studies examining the chronic interaction of glucagon, cortisol, epinephrine, and norepinephrine in regulating carbohydrate metabolism in the conscious dog (14, 22, 23). These stress hormones work in concert to maintain hyperglycemia during chronic stress in part by increasing hepatic glucose production (both glycogenolysis and gluconeogenesis). Glucagon plays a central role by increasing the efficiency of hepatic gluconeogenesis and by facilitating gluconeogenic precursor entry into the liver. It also limits hepatic glucose uptake, thus allowing increases in gluconeogenesis to be manifest as a net increase in glucose release by the liver. Epinephrine also plays a central role by enhancing hepatic glycogenolysis. Despite its very potent acute effects on gluconeogenic precursor supply, these actions play a relatively minor role chronically. Cortisol augments hepatic glycogen stores despite marked increases in other counterregulatory hormones. In addition, it maintains the gluconeogenic precursor supply, thus supporting the glucagon- and, to a lesser extent, epinephrine-mediated increase in gluconeogenesis. Interestingly, circulating norepinephrine does not play a major role in augmenting hepatic glucose metabolism during chronic stress. In summary, no one hormone plays the central role in the chronic enhancement in glucose metabolism during stress. Rather, these hormones complement one another to allow an efficient stimulation of hepatic metabolism. These studies cannot address the relative importance of a given stress hormone in a particular stress, because the impact of an individual hormone will depend on the specific stress and the accompanying endocrine response.
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ACKNOWLEDGEMENTS |
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The authors are grateful for the technical assistance of Eric Allen, Pat Donahue, and Pamela Venson in the Diabetes Research and Training Center core laboratories.
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FOOTNOTES |
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These studies were supported by National Institute of Diabetes and Digestive and Kidney Diseases Grant R01-DK-18243 (to A. D. Cherrington) and by the Diabetes Research and Training Center 2-P60-DK-20593. O. P. McGuinness was supported by a Juvenile Diabetes Foundation Career Development Award.
Address for reprint requests: O. P. McGuinness, 702 Light Hall, Dept. Molecular Physiology and Biophysics, Vanderbilt Univ., Nashville, TN 37232-0615.
Received 21 January 1997; accepted in final form 10 June 1997.
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