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The cardiovascular, metabolic and hormonal changes accompanying acute starvation in men and women

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Abstract

The effect of fasting for 12, 36 and 72 h was studied in twenty-nine healthy subjects (seventeen women and twelve men). Measurements were made of cardiovascular variables, metabolic rate, respiratory exchange ratio, plasma metabolites, insulin, thyroid hormones and catecholamines. During starvation there were no significant changes in blood pressure, whilst heart rate (beats/min) increased at 36 h and remained elevated after 72 h (12 h 62.5 (SE 1.8), 36 h 68.0 (SE 1.9), 72 h 69.2 (SE 1.8); P < 0.001). Forearm blood flow (FBF) increased progressively from 3.32 (SE 0.20) to 6.21 (SE 0.46) ml/100 ml per min (P < 0.001). Resting metabolic rate (kJ/min) was significantly increased after 36 h of starvation (12 h 4.60 (SE 0.14), 36 h 4.88 (SE 0.13), P < 0.001), but was not significantly different from the 12 h value after 72 h (72 h 4.72 (SE 0.15) P = 0.06). The respiratory exchange ratio fell progressively from 0.80 to 0.76 to 0.72 (P < 0.001). Blood glucose fell, whilst plasma glycerol and beta-hydroxybutyrate rose and plasma lactate did not change. Plasma insulin and free triiodothyronine fell during starvation. Plasma adrenaline and noradrenaline were unchanged at 36 h, but were significantly increased after 72 h. Both sexes showed a similar pattern of response to starvation, although absolute values of blood pressure, forearm blood flow, metabolic rate and plasma catecholamines were higher in men than women. Acute starvation produces profound cardiovascular and metabolic changes which are not explained by the accompanying hormonal changes.
British
Journal
of
Nutrition
(1994),
71,
431441
437
The cardiovascular, metabolic and hormonal changes
accompanying acute starvation in men and women
BY
J.
WEBBER
AND
I.
A. MACDONALD
Department
of
Physiology and Pharmacology, University
of
Nottingham Medical School,
Clifton Boulevard, Nottingham NG7
2UH
(Received
5
February
1993
-
Revised
28
April
1993
-
Accepted
10
May
1993)
The effect of fasting for
12,36
and
72
h was studied in twenty-nine healthy subjects (seventeen women
and twelve men). Measurements were made of cardiovascular variables, metabolic rate, respiratory
exchange ratio, plasma metabolites, insulin, thyroid hormones and catecholamines. During starvation
there were no significant changes in blood pressure, whilst heart rate (beatslmin) increased at
36
h and
remained elevated after
72
h
(12
h
625
(SE
I%), 36
h
68.0
(SE
1.9), 72
h
69.2
(SE
1.8);
P
<
0.001).
Forearm blood flow (FBF) increased progressively from
3.32
(SE
0.20)
to
6.21
(SE
0.46)
m1/100 ml per
min
(P
<
0.001).
Resting metabolic rate (kJ/min) was significantly increased after
36
h of starvation
(12
h
4.60
(SE
0.14), 36
h
4.88
(SE
0.13),
P
<
0.001),
but was not significantly different from the
12
h value
after
72
h
(72
h
4.72
(SE
0.15)
P
=
0.06).
The respiratory exchange ratio fell progressively from
0.80
to
0.76
to
0.72
(P
<
0.001).
Blood glucose fell, whilst plasma glycerol and /3-hydroxybutyrate rose and
plasma lactate did not change. Plasma insulin and free triiodothyronine fell during starvation. Plasma
adrenaline and noradrenaline were unchanged at
36
h, but were significantly increased after
72
h. Both
sexes showed
a
similar pattern of response to starvation, although absolute values of blood pressure,
forearm blood flow, metabolic rate and plasma catecholamines were higher in men than women. Acute
starvation produces profound cardiovascular and metabolic changes which are not explained by the
accompanying hormonal changes.
Starvation: Metabolic rate: Sex differences: Man
There is increasing evidence that the sympathetic nervous system
(SNS)
and catecholamines
released from the adrenal medulla play a role in the control of energy expenditure in man.
This regulatory function may be of major importance in the adaptations which occur
during under- and overnutrition. It has long been known that prolonged undernutrition
and fasting lead to a reduction in resting metabolic rate (RMR). This is due both to a
decrease in body mass and to a fall in the energy expenditure
of
the remaining body tissue.
The mediators
of
this latter process are uncertain but may include changes in thyroid
hormone levels.
Demonstrating the role of the
SNS
in controlling energy expenditure in the resting state
in healthy, normally-nourished individuals has been difficult. Some studies have shown a
small reduction in RMR during P-blockade (Welle
et
al.
1991), whilst others have failed to
show such an effect (Vernet
et
al.
1987). However, a clearer picture emerges when one
examines stimulated thermogenesis. The
SNS
is activated following glucose ingestion
(Berne
et
al.
1989) and P-blockade reduces the increment in metabolic rate seen in this
situation (Astrup
et
al.
1989). Although RMR in the normally-fed state may not be much
influenced
by
sympathoadrenal activity, manipulation of nutritional intake may cause
more marked changes. Experimental work in rats has shown that fasting leads to
suppression of
SNS
activity (as assessed by the turnover rate of tritiated noradrenaline in
specific tissues; Landsberg
&
Young, 198.5), whilst refeeding reverses these changes. In man
438
J.
WEBBER AND
I.
A. MACDONALD
a similar pattern of changes in whole-body plasma noradrenaline turnover has been
demonstrated during underfeeding and overfeeding (O'Dea
et
al.
1982).
The physiological changes accompanying short-term starvation in man have not been
well characterized. During early starvation there is a profound natriuresis and only after
a period of
3-5
d does Na conservation occur (Boulter
et
al.
1973). Thus, unless salt
supplementation is provided during this time-period, an obligatory diuresis and consequent
volume depletion will occur. This will lead to compensatory cardiovascular reflexes
and concomitant activation of the
SNS,
hence confounding any nutritionally-related
(starvation) SNS changes. Where Na intake has remained constant, dieting and consequent
weight loss in obese patients has been shown to reduce blood pressure as well as indices of
SNS
activity (Jung
et
al.
1979; Andersson
et
al.
1991).
In
normal-weight subjects the picture
is
less clear. Recent work has suggested there may be a paradoxical increase
in
RMR early
in starvation (Mansell
&
Macdonald, 1990) as well as increased limb blood flow. What
factors mediate these changes are uncertain and in that study none of the hormonal changes
seen could explain the observed alterations. In addition, recent studies have suggested there
may be significant gender differences in the responses to metabolic stresses such as fasting
(Clore
et
al.
1989) and hypoglycaemia (Amiel
et
al.
1993). The present study was designed,
therefore, to examine the metabolic and physiological correlates of short periods of
starvation in men and women, and to see whether changes
in
plasma catecholamines or
other hormones could provide a satisfactory explanation of them.
METHODS
Twenty-nine healthy (twelve men), non-obese subjects (women
:
mean body mass index
(weight/height2) 23.2
(SE
06) kg/m2, mean age 21.7
(SE
0.7) years; men: mean body mass
index 22.5
(SE
0.7) kg/m2, mean age
25%
(SE
1.2) were recruited for the study. None was
taking any medication other than the oral contraceptive pill. All gave written informed
consent to the study which was approved by the University of Nottingham Medical School
Ethical Committee.
The subjects were each studied
on
three occasions, after either a 12, 36, or 72 h fast, the
12 h (overnight) fast being taken as the postabsorptive control period against which the
values at 36 and 72 h were compared. The studies were done in random order and there was
a gap of at least 7 d normal food intake between each fasting period. All the women were
studied during the follicular phase of the menstrual cycle. During the fasting period subjects
were allowed water
ad
Zib.,
proprietary flavoured carbonated drinks (One Cal; RHM
Foods, Hartlepool) and black decaffeinated tea and coffee without sugar. Whilst fasting,
subjects consumed 80 mmol Na and
50
mmol
K
daily as slow-release tablets to minimize
the potentially confounding effects of fluid deprivation and intravascular volume depletion
on
SNS
activity and cardiovascular reflexes.
Studies took place in a temperature-controlled room
(28")
with the subjects wearing a T-
shirt and shorts only.
On
arrival subjects rested supine whilst intravenous cannulas were
inserted under local anaesthetic, and the monitoring equipment attached. For blood
sampling a cannula was inserted retrogradely into a vein on the dorsum of the hand and
kept patent with a slow-running infusion of saline (154 mmol NaCl/l). This hand rested in
a warm-air box (55-60") to obtain 'arterialized' venous blood samples (McGuire
et
al.
1976). Continuous recordings of
0,
consumption and CO, production were made using a
ventilated-canopy indirect calorimeter (Fellows
&
Macdonald, 1985). From the respiratory
exchange data, calculations of metabolic rate (Weir, 1949) and respiratory exchange ratio
(RER) were made. Heart rate (HR) was recorded from an electrocardiogram, and brachial
arterial blood pressure was measured using an automated sphygmomanometer (Accutorr
ACUTE
STARVATION
AND
METABOLIC
CHANGES IN
MAN
439
1A; Datascope Corporation, Paramus, NJ, USA). Right forearm blood flow (FBF) was
determined by venous occlusion plethysmography using a mercury-in-rubber strain gauge
(Whitney, 1953) with an arterial occlusion cuff at the wrist.
Indirect calorimetry was commenced after the subjects had been supine for at least
30 min and was continued for
1
h. The mean values for the last 30 min were used in the
calculation of RMR and RER. During the last 30 min measurements of FBF and blood
pressure were taken. At the end of this period two samples of arterialized venous blood
were withdrawn 10min apart. Immediately after each blood sample had been taken
arterialized glucose concentrations (YSI 23 AM
;
Yellow Springs Industries, Ohio 45387,
USA) were measured. A portion of each arterialized blood sample was deproteinized in
0.1 M-HC~O,, the supernatant fraction being stored at -20" for later analysis of lactate
(coefficient of variation (CV) 7.2
YO),
P-hydroxybutyrate (CV 5.6
YO)
and glycerol (CV
7.0%) levels (Lloyd
et
al.
1978). The remainder of the arterialized blood sample was
centrifuged at 4" and the plasma separated. Plasma (2 ml) was mixed with 75 pl EGTA
glutathione (antioxidant) and stored at
-
80" for subsequent determination of adrenaline
and noradrenaline concentrations using HPLC with electrochemical detection (Macdonald
&
Lake, 1985). Intra-assay CV were 6 and 4% for adrenaline and noradrenaline
respectively; inter-assay values were
10
and
8
YO
respectively. Plasma was stored at -20"
for subsequent determination of free triiodothyronine (FT3
;
CV
6.0
YO)
and free thyroxine
(FT4; CV 3.9
YO
;
Amerlex M; Kodak Clinical Diagnostics Limited, Mandeville House,
Amersham, Bucks.) and insulin levels (CV 11.7
YO,
mean control 7.1 mU/I; Coat-a-Count;
DPL Division, Euro/DPC Limited, Abingdon Business Park, Abingdon, Oxon.).
Statistical analysis of the results was performed
by
one-way analysis of variance
(ANOVA) to look at the changes over time for the group as a whole and for men and
women separately, and by multivariate analysis of variance (MANOVA) to compare men
and women and their responses. When significant differences were found with ANOVA
paired
t
tests were used to compare individual time points. The package Minitab (Minitab
Inc., State College, PA, USA) was used for all statistical calculations.
RESULTS
There was a gap of at least
1
week of normal dietary intake between each period of starvation
and in no subject were all three studies completed in a period less than
5
weeks. The studies
were carried out using a randomized, balanced design, with no discernible order effect.
Cardiovascular changes
There was no significant change in systolic blood pressure (SBP) during the 72
h
of
starvation (Fig.
1).
SBP was higher in men than women both basally (1 11.8
v.
103.4
mm
Hg,
P
<
0.001) and at 36 and 72 h of starvation (sex effect
P
<
0.001, MANOVA). There was
no sex difference in the SBP response to starvation. Diastolic blood pressure (DBP) tended
to fall progressively over this time-period (from 54.3 to 52.9 to 52.3 mm Hg) but this did
not reach significance (time effect
P
=
0.14,
ANOVA). DBP was higher in men than women
(sex effect
P
=
0.002, MANOVA), but the response to starvation was the same in both
sexes.
HR increased during starvation from 62.5 to 68.0 to 69.2 beats/min (time effect
P
<
O.OO!,
ANOVA). The HR at 36 h was significantly greater than that at 12 h
(P
=
O.OOl),
but
there was no further significant increase at 72 h
(P
=
0.35). There was no sex difference in
HR, nor in the HR response to starvation.
FBF rose progressively from 3-32 to 4.87 to 6.21 m1/100 ml per min (time effect
P
<
0.001, ANOVA). FBF at 36 h was greater than at
12
h
(P
<
0.001) and that at 72 h was
440
J.
WEBBER
AND
I.
A.
MACDONALD
r
lo
r
75
4
70
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65
60
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55
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A
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v)
10
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W
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c
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120
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115
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110
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.-
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T
12
36 72
12
36 72
Duration
of
starvation
(h)
Fig. 1. Mean heart rate, forearm blood flow, systolic blood pressure and diastolic blood pressure for the group
as a whole
(O),
and for men
(m)
and women
(H)
separately, after 12, 36 and 72 h of starvation. Values are means
with their standard errors represented by vertical bars. Mean values for the 36 and 72
h
periods were significantly
different from that at 12 h, for the group as a whole, and for men and women separately:
*
P
<
0.05,
**
P
<
0.01,
***
P
<
0.001.
For
details
of
subjects and procedures, see pp. 438439.
greater than the 36 h value
(P
=
0.003).
FBF was higher in men than women (sex effect
P
<
0.001, MANOVA) and there was a greater increase in response to starvation in men
(sex
x
time effect
P
=
0.03,
MANOVA).
Metabolic
changes
For the group as a whole RMR rose from 4.60 kJ/min at 12 h to
4.88
kJ/min at 36 h and
then fell again to a value of 4.72 kJ/min at 72 h (Fig. 2; time effect
P
<
0.001, ANOVA).
The 36 h value was significantly greater than that at 12 h
(P
<
0.001),
but the 72 h value
was not significantly different from the 12 h value
(P
=
0.06).
At 72 h the RMR was less
than that at 36 h
(P
=
0025). Absolute RMR (kJ/min) was greater in men than women
(sex effect
P
<
0.001, MANOVA), but there was no sex difference in the fasting response.
When men and women were analysed separately RMR did not change significantly in men
over the 72 h period (time effect
P
=
0.204, ANOVA), but in women there was a significant
ACUTE STARVATION AND METABOLIC CHANGES
IN
MAN
44
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[:
0.80
C
m
z
#
0.75
>.
0
L
5
0.70
.-
a
v)
0.65
12
36 72
Duration
of
starvation
(h)
Fig.
2.
Mean resting metabolic rate and respiratory exchange ratio for the group as a whole
(O),
and for men
(m)
and women
(a)
separately, after
12,
36
and
72
h of starvation. Values are means with their standard errors
represented by vertical bars. Mean values for the
36
and
72
h periods were significantly different from that at
12
h,
for the group as
a
whole, and for men and women separately:
*P
<
0.05,
***Pi
0.001.
For
details of subjects
and procedures, see pp.
438439.
change (time effect
P
<
0.001,
ANOVA).
RER
fell progressively (Fig. 2; time effect
P
<
0.001, ANOVA). There were no sex differences in
RER,
or its pattern
of
change during
fasting.
Blood glucose fell from 4.48 to 3.81 to 3.10 mmol/l (Fig. 3; time effect
P
<
0.001,
ANOVA). There were no sex differences in blood glucose, or its pattern
of
change during
starvation.
Blood glycerol rose during starvation (Fig. 3
;
time effect
P
<
0.001, ANOVA). There was
a significant difference between the 12 and 36 h values
(P
<
O.OOl), but not between the 36
and 72 h values
(P
=
0.72).
Both sexes had similar values of glycerol at all time-points.
Blood lactate did not vary during starvation (Fig. 3). There were no sex differences in
absolute values, or in response to starvation.
There was a progressive rise
in
P-hydroxybutyrate levels during starvation (Fig. 3
;
time
effect
P
<
0.001, ANOVA). No sex differences were demonstrated for P-hydroxybutyrate.
Hormonal changes
Plasma adrenaline levels increased during starvation (Fig.
4;
time effect
P
=
0.015,
ANOVA). There was no significant difference between the 12 h and 36
h
values
(P
=
0.068), but the 72 h value was greater than that at 12 h
(P
=
0.006). Adrenaline was
higher in men than in women (sex effect
P
=
0.017,
MANOVA). The change in adrenaline
over starvation was not different in the two sexes.
442
J.
WEBBER
AND
I.
A. MACDONALD
o.8
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4.5
E
4.0
E
-
0.6
-
-
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0
=;
-
E
8
3.5
al
o,
3.0
-I
E
-
0.4
-
a
0
3
-0
0
0
c1
c
Q
0
m
-
0.2
2.5
2.0
0.0
'r
***
T
**
T
"
12
36
72
-
0
30
>
-
0
20
10
0
12
36
72
Duration
of
starvation
(h)
Fig. 3. Mean blood glucose, lactate, P-hydroxybutyrate and glycerol for the group as a whole
(n),
and for men
)
separately, after
12,
36 and
72
h
of
starvation. Values are means with their standard errors
represented by vertical bars. Mean values for the 36 and
72
h periods were significantly different from that at
12
h,
for the group as a whole, and for men and women separately:
**
P
<
0.01,
***
P
<
0.001.
For details of subjects
and procedures, see pp.
438439.
Plasma noradrenaline levels changed with starvation (Fig. 4; time effect
P
<
0.001,
ANOVA). There was no change in levels at 36 h compared with those at 12 h
(P
=
0.89),
but the levels at
72
h were significantly greater than those at both
12
and 36 h
(P
=
0.002
and
P
<
0.001
respectively). Noradrenaline levels were higher in men than women (sex
effect
P
=
0.001,
MANOVA). The response
to
starvation was the same in men and women.
Plasma insulin fell progressively during starvation (Fig.
5;
time effect
P
<
0.001,
ANOVA). There were no sex differences in absolute values or the response to starvation.
FT3 levels gradually fell (Fig.
5;
time effect
P
<
0.001, ANOVA). FT3 levels were
significantly higher in men compared with women (sex effect
P
<
0.001,
MANOVA). There
was no sex difference in the response to starvation. FT4 levels did not change during
starvation (Fig.
5).
FT4 was higher in men than women (sex effect
P
<
0.001,
MANOVA).
There was no sex difference over time.
ACUTE STARVATION AND METABOLIC CHANGES IN MAN
443
1.2
r
*
T
2
1.0
-
0.8
0.6
a,
m
$!
0.4
U
(II
z
b
0.2
0.0
12
36
72
Duration
of
starvation
(h)
Fig. 4. Mean plasma noradrenaline and adrenaline for the group as a whole
(O),
and for men
(m)
and women
(H)
separately, after
12,
36 and
72
h
of
starvation. Values are means with their standard
errors
represented by
vertical bars. Mean values for the 36 and
72
h periods were significantly different from that at
12
h,
for
the group
as a whole, and
for
men and women separately:
*
P
<
0.05,
**
P
<
0.01.
For
details
of
subjects and procedures,
see pp. 438439.
FT3
:
FT4 fell with starvation from 0.40 to 0.35 to 0-27 at
12,
36
and 72 h respectively
(time effect
P
<
0.001, ANOVA).
DISCUSSION
The present study confirms previous work concerning the cardiovascular, metabolic and
hormonal changes accompanying acute starvation. In providing data on all these variables
it also allows inferences to be made concerning the relationships between them. There was
no significant change in SBP over the 72 h fast, but there was a tendency for DBP to fall.
This dissociation between the effects of acute starvation on SBP and DBP has been noted
previously in studies on healthy men (Bennett
et
al.
1984). The explanation is probably the
marked limb vasodilatation that is seen in starvation rather than any effect due to volume
depletion, this being prevented by concomitant salt supplementation. In the current study
FBF rose progressively, almost doubling by 72 h. Heart rate also increased significantly by
36
h, but there was no further change by 72 h.
An increasing number of studies have demonstrated the increase in RMR seen after
3648
h of starvation (Mansell
&
Macdonald, 1990; Mansell
et
al.
1990), in contrast to the
decrease found after more prolonged starvation and undernutrition (Benedict, 19
15).
Our
study confirms this observation and shows that the effect is a transient one which is mostly
reversed by
72
h. The likely cause of this elevation in RMR is the energy requirements of
gluconeogenesis and ketogenesis, both
of
which are metabolically relatively expensive
444
J.
WEBBER
AND
I.
A. MACDONALD
'"1
T
"[
0'5
I
0.4
e
0.3
t
t
0.2
0
0.1
0.0
72 12
36
72
Duration
of
starvation
(h)
Fig.
5.
Mean plasma insulin, triiodothyronine
(FT3),
free thyroxine
(FT4)
and
FT3:FT4
for the group as a whole
(O), and for men
(m)
and women
(m)
separately, after
12,
36
and
72
h of starvation. Values are means with their
standard errors represented by vertical bars. Mean values for the
36
and
72
h periods were significantly different
from that at
12
h, for the group as a whole, and for men and women separately:
*
P
<
0.05,
**P
<
0.01,
***
P
<
0001.
For
details of subjects and procedures, see pp.
438439.
processes. That our subjects were truly fasting is shown by the progressive fall in RER and
in blood glucose, whilst P-hydroxybutyrate rose progressively. Blood glycerol rose
reflecting increasing lipolysis at 36 h but there was no further change at
72
h, perhaps
because
of
the increasing utilization of glycerol as a gluconeogenic substrate and
also
due
to feedback inhibition of lipolysis by the high blood ketone levels (Moller
et
al.
1990).
The continued fall in plasma insulin and FT3 levels whilst FT4 remained unchanged
corroborates the findings of other workers (Palmblad
et
al.
1977;
Beer
et
al.
1989).
Although thyroid hormones are likely to have a role in the reduced metabolic rate of
prolonged starvation, changes in their plasma levels cannot explain the elevated RMR of
early starvation, nor the increase in resting HR seen in the present study.
Plasma adrenaline and noradrenaline were both significantly elevated after the
72
h fast
relative to the overnight fasted levels. However, whereas adrenaline levels tended to rise
ACUTE STARVATION AND METABOLIC CHANGES
IN
MAN
445
Table 1.
The relative changes in the cardiovascular system, thermogenesis and plasma
hormones from
12
to
36
h and from
36
to
72
h of starvation*
Changes from Changes from
12
to
36
h
36
to
72
h
Heart rate
SBP
DBP
Forearm blood
flow
Resting metabolic rate
Noradrenaline
Adrenaline
Ins
u
1
in
FT3
FT4
u
t
t
1
u
1
t
t
t
1
t
t
1
1
1
1
u
u
u
u
t,
Increase;
1,
decrease;
-,
no change;
SBP,
systolic blood pressure;
DBP,
diastolic blood pressure;
FT3,
free
*
For
details of subjects and procedures, see pp.
438439.
triiodothyronine;
FT4,
free thyroxine.
progressively from 12 to 36 to 72 h, plasma noradrenaline was unchanged at 36 h. Thus,
whereas RMR is most elevated after 36 h, plasma noradrenaline, an indirect marker of
SNS
activity, is unchanged at this time. It would seem unlikely, therefore, that activation of the
SNS
is responsible for this rise in RMR. However, plasma catecholamine levels may not
accurately represent sympathoadrenal activity. Plasma noradrenaline represents the
spillover
of
the neurotransmitter from sympathetic post-ganglionic neurones, with the
majority of noradrenaline being cleared by presynaptic re-uptake or
by
local metabolism
(Esler
et al.
1990). Thus, an increase in plasma levels may be due to increased production
(enhanced
SNS
activity/increased rate of spillover) or decreased clearance. Other workers
have assessed
SNS
activity by means
of
measuring muscle efferent sympathetic activity
(MSA). Using this technique Anderson
et al.
(1988) showed that a 48 h fast in obese
subjects caused an increase in both plasma noradrenaline (venous) and in MSA, although
despite this apparent enhancement of
SNS
activity
SBP
and
DBP
fell dramatically. It
should be noted here that the response
of
obese subjects to fasting may be quite different
to normal-weight volunteers. In addition there may be changes in adrenergic sensitivity
during starvation which may counteract or enhance any changes in
SNS
activity. Mansell
et al.
(1990) showed that the thermogenic and lipolytic responses to an adrenaline infusion
were enhanced after a 48 h fast. However, there were
no
changes in the cardiovascular
responses to adrenaline after the fast. Thus, there may be discrete activation of the SNS to
different tissues such that there is not an all-or-nothing whole-body response.
The main sex differences noted in the present study were the elevated plasma levels
of
adrenaline, noradrenaline, FT3 and FT4 in men compared with women. That RMR was
higher in men mainly reflects their larger size and greater fat-free mass. Although when
analysed by MANOVA there was
no
sex difference in the changes in RMR during
starvation, when the two groups were analysed separately there was
no
change in RMR in
men after 36 and 72 h, but
in
women RMR was increased at 36 h and then decreased after
72
h to a value not significantly different from that at
12
h. No differences in the hormonal
responses to starvation in the present study account for this disparity, but previous work
has noted higher levels of glucagon in women than men (Merimee
&
Fineberg, 1973), which
may perhaps enhance rates of gluconeogenesis
in
women compared with men. However,
in
that study plasma glucose fell to lower values in women than in men after 36 and 72 h of
446
J.
WEBBER
AND
I.
A.
MACDONALD
fasting
(so
accounting for the greater rise in glucagon), whereas the present study did not
show any difference in the pattern of fall of blood glucose. The explanation for this
disparity is not clear, but may include different ages of the experimental subjects and
differing degrees of physical fitness and activity during the study. The current study used
arterialized venous blood, whilst Merimee
&
Fineberg used venous plasma samples.
In
well-
insulinized subjects venous blood values may be lower than arterialized values, but in
fasting subjects there is unlikely to be any significant difference between the two sampling
sites. Moreover, values for whole-blood glucose are normally
10%
lower than those for
plasma glucose and, thus, lower values would be expected in the present study.
The only significant sex difference in the response to starvation was the greater FBF
increment in men which may reflect a greater proportion of muscle compared with adipose
tissue in the forearm of men. This argument implies that muscle blood flow increases more
than that of adipose tissue during starvation, but data to confirm this are lacking. Only one
study has examined adipose tissue blood flow in humans (four obese women) during acute
starvation and there was a doubling of flow after a 4 d fast from 1.3 to 2.4 m1/100 ml per
min (Nielson
et
al.
1968).
Basal blood flow, therefore, may be lower in subcutaneous
adipose tissue than
in
skeletal muscle and, hence, any increase in blood flow to this tissue
will have less overall effect
on
total limb blood flow than similar changes in the muscle
component.
In
the current study total FBF doubled after a 72 h fast (3.32-6.21 m1/100 ml
per min), but the separate contributions of muscle and adipose tissue were not assessed.
The overall pattern of changes is summarized in Table
1.
This shows that whilst RMR
is elevated at 36 h, there is
no
change in catecholamines at this time-point and FT3 is actually
reduced in comparison with 12 h. Then, after 72 h of fasting RMR is not significantly
different to the 12 h level, but noradrenaline (a marker of
SNS
activity) is increased.
Likewise, the elevation in HR is mostly complete at 36 h and does not seem to be directly
related to any
of
the hormonal changes observed. It is of note that the two variables which
continued to rise progressively throughout the period of starvation were FBF and blood
P-hydroxybutyrate levels. We have some data that infusion of /3-hydroxybutyrate can raise
FBF
(J.
Webber and I.
A.
Macdonald, unpublished results), although the mechanisms
behind this are unclear. The transient elevation
in
RMR is probably mediated by enhanced
rates of gluconeogenesis and ketogenesis, before the effect of these processes is overwhelmed
by the profound changes in thyroid status which contribute to the slowing of cellular
metabolism that predominates in more prolonged starvation.
In conclusion, the present study has shown that a 72 h fast in normal-weight subjects
causes marked cardiovascular, metabolic and hormonal changes. However, the pattern
of
changes observed does not readily allow a hormonal explanation of the phenomena.
In
particular, sympathetic activity (as assessed by plasma catecholamine levels) does not
correlate with elevations in RMR, HR or FBF. These data point to the need to measure
other indices of sympathetic activity both of the whole body and of individual organs, as
well as to look for other mediators of the adaptations which occur during starvation.
The authors are grateful to Mr
S.
Brown for measuring insulin, FT3 and FT4
concentrations,
to
Linda Ashworth for measuring intermediary metabolites, and to Ms
J.
Taylor and Mr
D.
Forster for catecholamine analyses. They are also grateful to all their
subjects for giving of their time and giving up their food. The study was supported by a
project grant from the Wellcome Trust.
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... The authors reported that fasting did not change blood pressure but increased heart rate at both the 36-and 72-hour timepoint. Forearm blood flow was significantly increased at the 36-and 72-hour time point and plasma epinephrine and norepinephrine increased at the 72 hours fasted (J.Webber & Macdonald, 1994). Webber and Macdonald repeated their fasting study and they again found that heart rate and forearm blood flow increased at 36 and 72 hours fasted compared to the 12 hour fasted timepoint(J Webber et al., 1995). ...
... glucagon continuously increases during 72 hours of fasting(Højlund et al., 2001). Both plasma epinephrine and norepinephrine concentrations fluctuate in a circadian rhythm during fasting. Studies have reported significant increases in plasma epinephrine and norepinephrine during fasting at the 24-, 48-, and 72-hour time points(Højlund et al., 2001;J. Webber & Macdonald, 1994). Plasma glucose steadily decreases until it plateaus after approximately 2 days of fasting(Haymond, Karl, Clarke, Pagliara, & Santiago, 1982;Højlund et al., 2001) Concurrently, ketones (β-hydroxybutyrate) progressively increase as fasting time continues(Haymond et al., 1982;J. Webber & Macdonald, 1994). ...
... and 72-hour time points(Højlund et al., 2001;J. Webber & Macdonald, 1994). Plasma glucose steadily decreases until it plateaus after approximately 2 days of fasting(Haymond, Karl, Clarke, Pagliara, & Santiago, 1982;Højlund et al., 2001) Concurrently, ketones (β-hydroxybutyrate) progressively increase as fasting time continues(Haymond et al., 1982;J. Webber & Macdonald, 1994). ...
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... Interestingly, despite an overall decrease in 24EE, during fasting spendthrift subjects actually increased SLEEP-a surrogate marker for RMR-while SLEEP decreased in thrifty subjects. The existing literature on this matter is inconclusive: in some studies, fasting was associated with a decreased RMR as a mechanism to conserve energy (14,58), while other studies have reported a fasting-induced increase in RMR by as much as to 14% (48,57,59,60). In one study, this increase was associated with an increased plasma norepinephrine secretion (while plasma epinephrine levels did not change during starvation) (48). ...
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