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(Circulation. 2001;103:513.)
© 2001 American Heart Association, Inc.
Clinical Investigation and Reports |
Hyperinsulinemia and Autonomic Nervous System Dysfunction in Obesity
Effects of Weight Loss
From the Metabolism Unit and Coronary Division, CNR Institute of Clinical Physiology, and Department of Internal Medicine, University of Pisa, Pisa, Italy.
Correspondence to E. Ferrannini, CNR Institute of Clinical Physiology, Via Savi 8, 56126 Pisa, Italy. E-mail ferranni{at}ifc.pi.cnr.it
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Abstract |
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 Top Abstract IntroductionMethodsResultsDiscussionReferences |
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Background—Because hyperinsulinemia acutely stimulates adrenergic activity, it has been postulated that chronic hyperinsulinemia may lead to enhanced sympathetic tone and cardiovascular risk.
Methods and Results—In 21 obese (body mass index, 35±1 kg/m2) and 17 lean subjects, we measured resting cardiac output (by 2-dimensional echocardiography), plasma concentrations and timed (diurnal versus nocturnal) urinary excretion of catecholamines, and 24-hour heart rate variability (by spectral analysis of ECG). In the obese versus lean subjects, cardiac output was increased by 22% (P<0.03), and the nocturnal drop in urinary norepinephrine output was blunted (P=0.01). Spectral power in the low-frequency range was depressed throughout 24 hours (P<0.04). During the afternoon and early night, ie, the postprandial phase, high-frequency power was lower, heart rate was higher; and the ratio of low to high frequency, an index of sympathovagal balance, was increased in direct proportion to the degree of hyperinsulinemia independent of body mass index (partial r=0.43, P=0.01). In 9 obese subjects who lost 10% to 18% of their body weight, cardiac output decreased and low-frequency power returned toward normal (P<0.05).
Conclusions—In free-living subjects with uncomplicated obesity, chronic hyperinsulinemia is associated with a high-output, low-resistance hemodynamic state, persistent baroreflex downregulation, and episodic (postprandial) sympathetic dominance. Reversal of these changes by weight loss suggests a causal role for insulin.
Key Words: obesity • heart rate • hyperinsulinemia • catecholamines • sympathetic activation
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Introduction |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Obesity, a condition characterized by hyperinsulinemia and insulin resistance,1 is associated with an increased incidence of hypertension2 and an enhanced risk for cardiovascular morbidity.3 Both complications have been attributed to chronic stimulation of sympathetic activity, imposing a functional overload on the heart and the vasculature.4 5 However, human studies examining adrenergic activity in obesity by whole-body methods (urinary excretion or plasma levels/turnover of catecholamines) have been inconclusive, with reports of normal, decreased, or increased sympathetic activity (see the work by Young and Macdonald6 for review). Regional studies of adrenergic activity have likewise yielded diverging results. For example, in obese men studied by the norepinephrine (NE) isotope dilution method, Rumantir et al7 found that, whereas total NE spillover was normal, renal NE spillover was increased and cardiac NE spillover was decreased. Clearly, these conclusions apply to the fasting, resting conditions under which NE spillover was measured. In contrast, studies using microneurography have reported increased muscle nerve sympathetic activity (MNSA) in obese subjects.5 8 This technique, however, records only regional neurosympathetic discharge over short time periods and under resting but not necessarily fasting5 conditions. Therefore, assessment of the whole-body autonomic activity prevailing under free-living conditions remains problematic, and the controversy continues.6
The hemodynamics of obesity also are incongruous with the presence of adrenergic overactivity alone. In fact, whereas cardiac output is increased, peripheral vascular resistances are generally reduced in the normotensive obese.9 Although this high-output, low-resistance state is partly the consequence of an expanded body mass,10 regional hemodynamic studies have confirmed that limb vascular resistances are either normal or decreased in normotensive obese individuals.10
A role for hyperinsulinemia in the sympathetic overactivity of obesity has been proposed. On the basis of studies in animals, Landsberg11 originally postulated that, during the development of obesity, hyperinsulinemia excites sympathetic activity, thereby increasing oxygen consumption and energy expenditure. This effect of insulin would, in the long term, be maladaptive because while limiting further weight gain it prepares the ground for the emergence of hypertension (and other metabolic abnormalities). Evidence for this phenomenon in humans is incomplete. In healthy volunteers, acute euglycemic hyperinsulinemia causes a dose-dependent increase in circulating NE concentrations.12 On the other hand, the sensitivity to insulin of cardiac activity has been found to be preserved in obese insulin-resistant subjects.13 It is therefore unclear whether the hemodynamic and autonomic nervous system (ANS) changes of the obese state are due to persistent hyperinsulinemia or insulin resistance.
To test this hypothesis, we explored ANS function in obesity by combining measurements of timed urinary catecholamine excretion with the monitoring of heart rate variability (HRV) during 24 hours of free living. Spectral analysis of beat-to-beat fluctuations in heart rate (HR) permits a dynamic evaluation of spontaneous autonomic control of cardiac activity.14 Weight reduction was used to test whether the ANS abnormalities found in the obese were reversible and therefore functional rather than structural in origin.
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Methods |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Study Population
Twenty-one obese subjects (body mass index [BMI] >30.5 kg/m2 in men and >27.3 kg/m2 in women, according to Italian Consensus Conference criteria15 ) and 17 lean subjects were studied. All had normal oral glucose tolerance16 and resting blood pressure levels (<140/90 mm Hg17 ); none were taking medications. All subjects had normal liver, renal, and endocrine function tests, and none had lost weight or changed dietary habits during the 6 months preceding the study. The investigation was approved by the Ethics Committee, and all subjects gave informed consent.
Experimental Protocol
Body composition was evaluated by electrical
bioimpedance.13 All subjects
received an oral glucose tolerance test (40
g/m2 glucose) with blood sampling at
30-minute intervals for 2 hours for plasma glucose and insulin
measurements. On a different day, cardiac output was determined by
2-dimensional
echocardiography,18 and
24-hour Holter recording of the ECG was begun with a bipolar lead
frequency-modulation system (Remco-Cardioline). A good-quality
recording and baseline sinus rhythm were prerequisites for entering the
study. Subjects were instructed to carry out their habitual activities
and record them in a diary. From a food questionnaire, diet was
ascertained to consist of 55% carbohydrate, 30% fat, and 15% protein
(ie, the standard Italian diet). As a rule, subjects consumed 20%,
20%, and 40% of total daily energy intake at breakfast (6:30 to 9:30
AM), lunch (1 to 2:30
PM), and dinner (7 to 9
PM), respectively. On the
same day as the Holter recording, an arterialized (by the hot-box
technique13 ) blood sample
was drawn for measurement of circulating catecholamine concentrations,
and separate urine samples were obtained during the daytime (6
AM to 10
PM) and nighttime (10
PM to 6
AM). To identify sleep
apnea/hypopnea,19 the
respiratory signal was simultaneously monitored through a piezoelectric
transducer as described20 ;
only 1 obese male patient had an apnea/hypopnea index
>5.19
After the initial set of studies, obese patients were
prescribed a hypocaloric diet (4.9±0.1 MJ/d; 55% carbohydrate, 25%
fat, and 20% protein). Over a period of 8±1 months, 9 patients (7
women and 2 men; age, 35±3 years) lost 8 to 12 kg (10% to 18% of
their initial weight). In these patients, studies were repeated when
their new weight had been stable for 
4 weeks.
Clinical Autonomic Function Tests
ANS was explored by means of the Valsalva maneuver,
the deep breathing test, and the lying-to-standing test, in that
sequence, following the method of
Ewing.21 All measurements
were made in the same room, which was maintained at a constant
temperature; 1 operator (M.E.) performed all
tests.
Frequency-Domain HRV
The ECG was digitized at 250 Hz. The time series of
RR intervals were computed throughout the 24-hour period and analyzed
in consecutive intervals of 256 data points by the autoregressive
technique as described.13
According to consensus
standards,14 3 major
frequency components were considered in the RR power spectrum: a
very-low-frequency (VLF) component (0.003 to 0.03 Hz), a low-frequency
(LF) component (0.03 to 0.15 Hz), and a high-frequency (HF) component
(0.15 to 0.40 Hz).22 For
each spectrum, the mean RR interval, total spectrum power, power of the
LF and HF components (in both absolute and normalized units, nu),
central frequency of the LF and HF bands, and LF/HF ratio were stored
for statistical analysis. Respiratory rate was obtained both from the
central frequency of the HF component and by separate spectral analysis
of R-wave amplitude variability (The latter is due to chest and heart
movements during respiration).
Analytical Procedures
Plasma glucose was measured by the glucose-oxidase
technique (Beckman Glucose Analyzer, Beckman). Plasma insulin
concentrations (InsKit, Sorin) were measured by radioimmunoassay,
whereas plasma and urine epinephrine and NE concentrations were assayed
by high-performance liquid chromatography (HLC 725 apparatus) with
electrochemical detection (Eurogenetics).
Data Analysis
Fat mass was calculated as the difference between
body weight and fat-free mass. Areas under the time-concentration
curves were calculated by the trapezium rule. All data are given as
mean±SEM. Because of their nonnormal distribution, plasma
concentrations of insulin and catecholamines, urine catecholamine
excretion values, and spectral parameters were log transformed for use
in statistical tests; these variables are summarized as geometric mean
[interquartile range]. Between-group comparison was carried out by
the Mann-Whitney U test; paired
comparisons were performed by the Wilcoxon signed-rank test. Two-way
ANOVA for repeated measures was used to compare group means over
different time periods. Regression analysis was performed by general
linear models including continuous and categorical
variables.
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Results |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Clinical, Metabolic, and Hemodynamic Characteristics
The excess weight of the obese group averaged 50% and consisted of both fat and lean mass (Table 1
). Although all subjects had normal glucose
tolerance by conventional criteria, the glucose area was significantly
higher in obese than lean subjects. In the fasting state and in
response to glucose, plasma insulin levels were 40% to 80% higher in
the obese and directly related to BMI
(r=0.48 and 0.65, respectively;
P<0.01). Cardiac output was
higher in the obese; because mean blood pressure was similar in obese
and control subjects, total peripheral vascular resistance (TPVR)
tended to be reduced in the obese.
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Basal arterialized plasma NE concentrations were similar in
the 2 groups. Basal epinephrine levels were lower in women than men (21
[interquartile range, 16] versus 44 [46] pg/mL;
P=0.01) and inversely related
to BMI (age- and sex-adjusted
r=0.44,
P=0.01). Urine flow did not
differ between the nocturnal and diurnal collection in either group
(Table 2). In the lean subjects, urinary output of
epinephrine and NE both dropped by 70% during the night compared
with day. In the obese group, 24-hour catecholamine output
(epinephrine, 8.2 [11.7] µg; NE, 41.0 [47.4] µg) was not
different from that of lean control subjects (epinephrine, 12.7
[18.0] µg; NE, 42.2 [27.3] µg;
P=NS for both). However, the
nocturnal decline in urinary NE excretion was blunted in the obese as
both total output and excretion rate. In the whole data set, the
difference in NE output between day and night was inversely related to
BMI (age- and sex-adjusted
r=0.53,
P=0.01).
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Clinical ANS Tests
The Valsalva ratio was 1.46±0.07 in obese subjects and
1.50±0.05 in control subjects
(P=NS). The ratio of maximum to
minimum RR calculated during deep breathing was 1.32±0.03 in the obese
and 1.39±0.04 in control subjects
(P=NS). The HR ratio in
response to standing averaged 1.26±0.03 in the obese and 1.31±0.05 in
control subjects
(P=NS).
Heart Rate Variability
To assess the influence of sex, age, and HR on HRV, a
preliminary analysis was performed on the 24-hour spectral parameters
for the whole data set
(Table 3). There were strong associations of all 3
physiological factors with most spectral parameters; in particular,
spectral indexes were reciprocally related to age and HR (data not
shown). Therefore, in comparisons of spectral variables between obese
and control subjects, simultaneous statistical adjustment for sex, age,
and HR was used in every case.
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In the whole data set, clock time was associated with marked changes in the autonomic control of HR. Thus, HR was higher during the day than at night (by 16 bpm on average, P<0.001). This physiological tachycardia was accompanied by a reduction in spectral powers, particularly marked within the VLF and HF bands, a left shift of the central VLF frequency, and a right shift of the central LF frequency. The proportion of total power in the LF band rose, and that in the HF band decreased, so the LF/HF ratio increased from a mean of 2.6 at night to a mean of 6.2 during the day (P<0.0001).
In the obese, the mean day/night HR excursion was significantly smaller than in control subjects (12 [10] versus 18 [9] bpm, P=0.05 after adjustment by age and sex). During both daytime and nighttime, LF power was significantly lower in the obese than in the lean group, the difference accounting for most of the observed decrease in total power.
Hourly analysis revealed that obese subjects had higher HRs
between 3 PM and 3
AM but lower HRs between 7
and 10 AM
(Figure 1). Whereas LF power was depressed essentially
throughout the 24-hour period, HF power was reduced during the late
afternoon through the first half of the night
(Figure 2). As a consequence, the LF/HF ratio was detectably
increased in the obese group at individual time points during the
afternoon.
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In the whole data set, higher daytime LF/HF ratios were
associated with higher fasting plasma insulin concentrations
independent of sex, age, HR, and BMI; quantitatively, a tripling of
fasting insulin predicted a doubling of the LF/HF ratio
(Figure 3).
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Effects of Weight Loss
In the weight-reduced patients, indexes of body mass
and fat distribution improved significantly, cardiac output decreased,
and TPVR rose
(Table 4). Urinary catecholamine excretion tended to
decrease (although the change was not statistically significant).
Baseline 24-hour LF power (608 [420] ms2)
returned toward the normal range (to 824 [799]
ms2;
P<0.05). The 24-hour hourly
profile of HR was generally decreased, whereas that of LF powers was
increased
(Figure 4); the LF/HF ratio was not significantly
changed.
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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In this study, obesity was of moderate to severe degree (BMI, 30 to 45 kg/m2), with all the metabolic changes typical of this condition. To avoid the confounding effects of structural vascular changes, the obese subjects were selected to have normal glucose tolerance and blood pressure levels. In addition, clinical tests of autonomic function were within normal limits. Our results therefore apply to uncomplicated obesity.
Sympathetic Activity
Adrenergic activity over 24 hours of free living was
inferred from timed urinary excretion of catecholamines. NE output was
not increased in the obese despite their expanded body mass, which per
se should augment NE
excretion23 ; likewise,
epinephrine output was similar in obese and lean subjects in absolute
terms. Furthermore, sex-adjusted plasma epinephrine concentrations were
lower in the obese group, in agreement with the previous
finding2 that 24-hour urinary
epinephrine excretion is reciprocally related to BMI. Thus, our obese
subjects under free-living conditions showed no absolute increase in
neuroadrenergic activity and a mild degree of adrenomedullary deficit.
Qualitatively, this result agrees with that of Narkiewicz et
al,19 who reported normal
MSNA in obese subjects without obstructive sleep apnea. After weight
loss, catecholamine output was, if anything, reduced. Although this may
represent a carryover from antecedent energy
restriction,24 the finding
is consistent with the
view11 that, at least in
some individuals, obesity may develop from an initially hypoadrenergic
state, which is partially compensated for by the enhancement in
sympathetic drive that accompanies weight gain. In support of this
possibility is the observation that in Pima Indian men a low
sympathetic nervous system activity predicts subsequent weight
gain.23
A further finding was that the normal nocturnal dip in urinary NE output was blunted in the obese. The time shift in NE output toward the late afternoon and early night clearly tracked with the time course of HR: The higher HR of the late evening extended into the early night, thereby overlapping with the nocturnal urine collection. Thus, the pattern of urinary NE excretion and the time course of HR coherently indicated episodic adrenergic activation and parasympathetic withdrawal in the obese in coincidence with the postprandial state.
ANS Function
HRV was larger in men than women, a consequence of the
constitutive bradycardia of men and the inverse relationship between HR
and HRV. Furthermore, age was associated with reduced
HRV.25 Finally, HRV was
lower during the daytime than nighttime, which represents the
adaptation of the baroreflex to the physiological tachycardia of the
awake state, characterized by increased sympathetic activity and vagal
withdrawal. After adjusting comparisons for sex, age, and HR, we found
that LF was generally reduced in the obese during the day and at night.
The LF power expresses the autonomic (sympathetic and parasympathetic)
control of HR
fluctuations.14 The lack of
a clear circadian LF cycle in the control group suggests that LF power
reflects peripheral modulation of baroreflex
activity,22 although central
components cannot be excluded. Accordingly, the flat LF profile of our
obese subjects indicates an impaired sensitivity of the sinus node to
spontaneous oscillations in blood pressure. This phenomenon, which we
observed under free-living conditions, likely is the equivalent of the
blunted baroreflex gain that has been documented in obese subjects
undergoing pharmacological modulation of baroreceptor
activity.5 26
After weight reduction, LF power returned toward normal
(Figure 4
), demonstrating that this abnormality is functional
in origin; ie, it is not due to structural damage within the baroreflex
pathway. In keeping with this conclusion, Grassi et
al27 reported decreased MSNA
and improved baroreflex sensitivity to pharmacological stimuli in
normotensive obese subjects after short-term (6-week) energy
restriction.
The circadian HR and HF oscillations were well evident in
the control group and were preserved in the obese; in the latter,
however, HF power was diminished in the late afternoon to early night
(Figure 2). As a result, the LF/HF ratio, an index of
sympathovagal balance,28
also was altered during this period of time, indicating a shift toward
sympathetic dominance. This finding may reflect a perturbation in the
central autonomic regulation of sinus node
activity.13
Interpretation
Hemodynamically, a hyporesponsive baroreflex may result
from baroreceptor downloading caused by chronic vasodilatation. In
keeping with this possibility, in our obese group, TPVR was lower than
in lean subjects and rose after weight loss in concomitance with the
recovery of baroreceptor sensitivity. A more general explanation calls
on hyperinsulinemia as the common mechanism underlying the hormonal,
hemodynamic, and HRV changes in the obese. Existing evidence indicates
that in humans acute physiological hyperinsulinemia simultaneously
increases systemic sympathetic activity (circulating NE
concentrations),12
desensitizes the
baroreflex,13 stimulates
MSNA,29 increases cardiac
output,13 and induces
peripheral vasodilatation.29
Experimentally, in dogs fed a high-fat diet, nyctohemeral HR rhythm
disappears and spontaneous baroreflex efficiency declines as the
animals gain weight and become
hypertensive.30 The present
results add to the existing evidence by showing the following. First,
in obese subjects, the periods of parasympathetic withdrawal and
sympathetic dominance coincided with the more hyperinsulinemic hours,
from the afternoon until late evening (breakfast being a small meal in
the Italian eating pattern). Second, the LF/HF ratio was increased in
proportion to the degree of hyperinsulinemia independent of BMI
(Figure 3). Third, the reduction in hyperinsulinemia that
accompanied weight loss reversed both the hemodynamic and HRV changes.
Thus, previous and present evidence converges on the conclusion that
the abnormal excursions in plasma insulin of the obese during
free-living conditions (as described by Polonski et
al31 ) elicit repeated
episodes of parasympathetic withdrawal, sympathetic dominance, and
baroreceptor downregulation. Thus, obesity can be viewed as the
extension into free living of the acute effects that insulin exerts on
the ANS and vasculature.
Conclusive proof of this interpretation can be derived only from the study of the preobese state; this, however, is defined only retrospectively. In a study analyzing HRV during short-term, small (10%) changes in body weight in healthy volunteers, Hirsch et al32 documented an increase in HR and a decline in spectral powers during weight gain and opposite changes during weight loss.
It should be pointed out that in our previous study13 we demonstrated that the acute effects of insulin on sinus node activity were similar between lean and obese insulin-resistant subjects; ie, they were unrelated to insulin resistance of glucose metabolism. Therefore, the ANS dysfunction of the obese appears to be the direct result of day-long hyperinsulinemia, unmitigated by insulin resistance. It should also be stressed that, although it can adequately explain the observed differences between obese and lean individuals, hyperinsulinemia need not be the sole determinant and may stand for underlying but unmeasured factors. Nevertheless, it is relevant that insulin is able to directly affect cell excitability (through its actions on transmembrane ion exchange33 ) and permeate the blood-brain barrier to modulate neuronal activities in the midbrain.34
Received July 10, 2000; revision received September 13, 2000; accepted September 14, 2000.
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M. R. Carnethon, D. R. Jacobs Jr., S. Sidney, and K. Liu Influence of Autonomic Nervous System Dysfunction on the Development of Type 2 Diabetes: The CARDIA study Diabetes Care, November 1, 2003; 26(11): 3035 - 3041. [Abstract] [Full Text] [PDF]
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I. C. Trombetta, L. T. Batalha, M. U. P. B. Rondon, M. C. Laterza, F. H. S. Kuniyoshi, M. M. G. Gowdak, A. C. P. Barretto, A. Halpern, S. M. F. Villares, and C. E. Negrao Weight loss improves neurovascular and muscle metaboreflex control in obesity Am J Physiol Heart Circ Physiol, August 7, 2003; 285(3): H974 - H982. [Abstract] [Full Text] [PDF]
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C. E. Negrao, I. C. Trombetta, L. T. Batalha, M. M. Ribeiro, M. U. P. B. Rondon, T. Tinucci, C. L. M. Forjaz, A. C. P. Barretto, A. Halpern, and S. M. F. Villares Muscle metaboreflex control is diminished in normotensive obese women Am J Physiol Heart Circ Physiol, August 1, 2001; 281(2): H469 - H475. [Abstract] [Full Text] [PDF]
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