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Original Studies |
Metabolism Unit (M.E., L.P., C.C., E.F.) and Coronary Division (E.M., A.N., S.C., A.G., S.B., E.F.), CNR Institute of Clinical Physiology, and the Department of Internal Medicine (E.F.), University of Pisa, Pisa, Italy
Address all correspondence and requests for reprints to: E. Ferrannini, CNR Institute of Clinical Physiology, Via Savi, 8, 56126 Pisa, Italy. E-mail: PISAMET{at}PO.IFC.PI.CNR.IT
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Abstract |
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We conclude that physiological hyperinsulinemia causes acute desensitization of sinus node activity to both sympathetic and parasympathetic stimuli, sympathetic shift of autonomic balance, and a high-output, low-resistance hemodynamic state. In the obese, these changes are already present in the basal state, and may therefore be linked with chronic hyperinsulinemia.
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Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Obesity is characterized by insulin resistance as well as hemodynamic abnormalities (9). The latter include increased cardiac output in the face of decreased total PVR (TPVR) and expanded blood volume. Whether obesity is also characterized by adrenergic activation has been controversial (10, 11). More recent data obtained in humans by microneurography have been concordant in finding that basal muscle nerve sympathetic activity is raised in direct proportion to body fat (12, 13). Landsberg (7) originally postulated that enhanced autonomic nervous activity in obese subjects is related to the hyperinsulinemia, and that the hypertension associated with obesity may be the maladaptive response to persistent sympathetic excitation. Moreover, the heart is a major target for damage in obesity, as documented by the increased cardiovascular morbidity and mortality that is associated with excess body weight (14, 15). Prolonged stimulation of the adrenergic system may be one of the mechanisms by which cardiovascular risk is enhanced in obesity (16). A further aim of the present study was to test whether the autonomic and hemodynamic responses to insulin are altered in obesity.
Sympathovagal control of cardiac activity was assessed with the use of spectral analysis of HRV. The study of beat-to-beat HRV, modulated by central (vasomotor and respiratory centers) and peripheral oscillators (afferent inputs derived from fluctuations in arterial pressure and respiratory movements), provides quantitative markers of autonomic activity (17). Whereas microneurography only measures regional sympathetic outflow, spectral analysis of spontaneous heart rate oscillations permits an accurate, dynamic, and noninvasive evaluation of sinoatrial node sensitivity to both sympathetic and vagal influences.
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Subjects and Methods |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Thirty-two subjects [18 of whom were obese, as defined by a
body mass index (BMI) 
30 kg·m-2) were studied. All
had normal glucose tolerance [on the oral glucose tolerance test
(OGTT) by the National Diabetes Data Group criteria (18)] and resting
arterial blood pressure levels; none were taking any medications. All
subjects had normal liver, renal, and endocrine function tests, and had
not lost weight or changed dietary habits during the 6 months preceding
the study. Their relevant clinical characteristics are given in Table 1
. Another group of 8 healthy subjects (5
female, 3 male, age 37 ± 3 yr, BMI of 22.0 ± 0.6
kg·m-2) volunteered for a time-control study (see
below). The investigation was approved by the Institutional Review
Board of the C.N.R. Institute of Clinical Physiology, and all subjects
gave informed consent before the study began.
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In all study subjects, body composition was evaluated by
electrical bioimpedance (19), and the waist and hip circumferences were
measured by the same physician. Each subject received an OGTT and a
euglycemic insulin clamp on different days approximately 1 week apart.
In the time-control experiments, a saline infusion replaced insulin
during the clamp study. For the OGTT, 40 g·m-2 of
glucose was ingested over 5 min, and venous blood was sampled at 30-min
intervals for 2 h for plasma glucose measurements. The clamp
study, which was carried out after an overnight (12–14 h) fast,
consisted of 2 h of euglycemic insulin infusion [at an insulin
infusion rate of 7 pmol·min-1·kg-1 (= 1
mU-min-1·kg-1) (20)]. A polyethylene,
20-gauge catheter was inserted into an antecubital vein for the
infusion of glucose and insulin. Another catheter was threaded into a
wrist vein retrogradely, and the hand placed in a heated box (
60 C)
for the sampling of arterialized blood (21). Following this procedure,
the patients rested at least 30 min in the supine position. The
following 2 h before the start of insulin infusion constituted the
basal period. During the basal period and the insulin clamp, the
following data were obtained: a) arterial blood pressure, which was
measured by mercury sphygmomanometry at 10-min intervals (in obese
individuals a large cuff was used); b) Holter recording of the
electrocardiogram (ECG) using a bipolar lead frequency-modulation
system (Remco-Cardioline, Milano, Italy) and both an inferior and a
precordial lead; c) circulating hormone (CRH, cortisol, GH, PRL, TSH,
epinephrine, and norepinephrine) concentrations, which were sampled
twice at the end of the 2 h of baseline and twice at the end of
the insulin clamp; and d) cardiac output, which was determined
noninvasively (in 21 of 32 study subjects) by two-dimensional
echocardiography (22) at the end of the basal and clamp periods by the
same physician (L.P.). Throughout the study protocol, patency of the
sampling catheter was maintained by injecting 1 mL saline after each
blood draw (no heparin was used). Furthermore, the blood loss caused by
the sampling was replaced by iv saline, whereas the urine loss was
empirically replaced by 150 mL of water ingested at the beginning of
the basal and the clamp periods. Urine was collected at the end of each
study period; in the whole group, urine output averaged 2.0 ± 0.2
[SEM ml·min-1 during the basal period, and
1.7 ± 0.2 ml·min-1 during the clamp;
P = not significant (NS) by Wilcoxon’s signed-rank
test].
ECG data processing
The ECG was digitized at 250 samples per sec with a 12-bit per sample precision, and stored in a binary format (2 bytes per sample) on digital tape for further computer analysis. The selected 250 Hz frequency allows detection of R-R oscillations up to 4 msec. The ECG was processed by using extensively tested algorithms (23) to detect the QRS complex and the R-wave reference point by a derivative/amplitude criterion, without interpolation of the original signal. To obtain a spectral representation of R-R, the autoregressive technique was found to be appropriate because of the nondeterministic behavior of the time series (24). The time series were analyzed in consecutive intervals of 256 data points. The intervals were processed by the Levinson-Durbin recursive algorithm (25) to generate the autoregressive coefficients. In the present analysis, the number of coefficients was set at 12. The goodness of the model was tested by evaluating the normality of the distribution of the resulting white noise. For each 256-data point interval, the power spectral function was evaluated, and the most significant spectral components were extracted according to a spectral decomposition algorithm (26, 27).
For the purpose of the present analysis, two major frequency components were considered in the R-R power spectrum: a low-frequency (LF) component (0.03–0.15 Hz, predominantly related to baroreflex control of arterial blood pressure by both sympathetic and vagal activity) and a high-frequency (HF) component (0.15–0.40 Hz, ascribed mostly to respiratory sinus arrhythmia) (28, 29, 30). The LF/HF ratio, which is regarded as an index of sympathovagal balance, was also computed from each LF and HF pair. The LF and HF components were expressed in absolute (msec2) as well as normalized units (i.e. as ratios to the total power minus the VLF component). When expressed in normalized units, LF is considered to be a quantitative index of sympathetic activity (31). From each spectrum, the mean R-R interval, the total spectrum power, the power and frequency of each component, and the LF/HF ratio were stored for statistical analysis. The 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 caused by chest and heart movements during respiration) (32).
Analytical procedures
Plasma glucose was measured by the glucose oxidase technique on a Beckman Glucose Analyzer (Beckman, Fullerton, CA). Plasma concentrations of insulin (InsKit, Sorin, Saluggia, Italy) and cortisol (Sorin, Saluggia) were measured by RIA, whereas GH (Hybritech), TSH (Sorin, Saluggia) and PRL (Hybritech) were measured by immunoradiometric assay (IRMA). Plasma catecholamine concentrations were assayed by high-performance liquid chromatography (HLC 725 apparatus) using electrochemical detection (Eurogenetics, Tessenderlo, Belgium). Serum CRH concentrations were measured by RIA, as previously described (33) (courtesy of Dr. F. Petraglia).
Data analysis
Fat-free mass (FFM) was calculated as the difference between body weight and fat mass. Whole-body glucose utilization (or the M value) was calculated from the infusion rate of exogenous glucose during the 2nd h of the insulin clamp period, after correction for changes in glucose levels in a distribution volume of 250 ml·kg-1. The M value was normalized by kilogram of FFM (µmol·min-1·kg FFM-1). Mean arterial blood pressure was calculated as the diastolic blood pressure plus one third of the pulse pressure. Cardiac output was estimated by measuring left ventricular outflow tract diameter by two-dimensional echocardiography in the parasternal long axis view and stroke volume by continuous-wave Doppler left ventricular outflow tract samples from the apical long-axis view. TPVR was calculated as the mean blood pressure divided by cardiac output. For statistical analysis, blood pressure values and spectral parameters were averaged over the final 60 min of the basal period and the 2nd hour of insulin administration.
Statistical analysis
All data are given as mean ± SEM. Because of
their nonnormal distribution, spectral parameters were transformed into
their natural logarithms. Paired means comparison was performed by the
Wilcoxon signed-rank test. Two-way ANOVA for repeated measures was used
to test for differences between lean and obese subjects and the effect
of insulin on the variable in question. Simple and multiple linear
regression analysis was carried out by standard techniques. A
P value 
0.05 was considered to be statistically
significant.
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Results |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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). In the whole data set, fasting plasma insulin
concentrations were directly related to both BMI (r = 0.56,
P < 0.001) and the waist/hip ratio (r = 0.43,
P < 0.02), whereas insulin sensitivity was inversely
related to BMI (r = 0.62, P < 0.0001) and the
waist/hip ratio (r = 0.63, P < 0.0001).
Heart rate variability (Table 2)
Preliminary analysis of the data was carried out to assess the influence of physiological determinants such as respiration, age, and heart rate (28, 29, 30). The central HF frequency (reflecting the respiratory rate) was stable both before and during insulin administration, in lean as well as obese subjects. Further proof that respiratory activity was unaltered during the clamp was obtained by spectral analysis of R-wave amplitudes, which retrieved mean frequencies [0.27 ± 0.005 Hz (= 16 ± 0.3 respirations per min) in the basal state, and 0.27 ± 0.01 Hz following insulin] that were similar to one another and superimposable on the central HF frequencies. Also the central frequency in the LF range was similar between groups, and was not affected by insulin. Both total spectral power and its components—LF and HF—were an inverse function of age (with r values of 0.41, 0.43, and 0.37, respectively, all P < 0.05 or less) and heart rate (r values of 0.43, 0.38, and 0.44, respectively, all P < 0.05 or less). In particular, the regressions predict that an increase in age of 10 yr and/or an increase in heart rate of 10 beats/min (bpm) are associated with an approximate 30% decrease in total spectral power.
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In the pooled data, euglycemic hyperinsulinemia reduced the mean
R-R interval (by 3% on average, P = 0.005), total
spectral power (by 21%, P < 0.001), and its LF
(-18%, P < 0.01) and HF component (-22%,
P < 0.01). These insulin-induced changes in spectral
powers were statistically significant in both groups, without
difference between obese and lean subjects. The time course of action
of insulin on total spectral power was rapid, reaching its maximum at a
time (20–40 min) when insulin-stimulated glucose uptake was only
approximately 60% of its steady state value (Fig. 1).
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). In the obese
group, the LF/HF ratio was higher than in the lean subjects (by 1.2
units on average, P < 0.03 after adjustment by age and
heart rate), but failed to be significantly stimulated by insulin (Fig. 2).
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)In the basal state, the obese subjects had higher cardiac output (P = 0.001) and stroke volume (P < 0.01), and lower TPVR (P = 0.002) in comparison with the lean group. In response to insulin, systolic blood pressure increased only in lean subjects (P < 0.01), diastolic blood pressure decreased in both lean (P < 0.05) and obese subjects (P < 0. 005), whereas mean blood pressure only decreased in the obese (P < 0.01). Cardiac output increased in both groups as a result of increments in both heart rate and stroke volume, whereas TPVR decreased significantly. None of the latter changes were different between lean and obese individuals.
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In the time-control (saline infusion) experiments, plasma glucose and
insulin concentrations declined slightly, and GH rose significantly as
fasting progressed; none of the other hormones nor any hemodynamic or
spectral parameter showed any significant change (Table 4).
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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In nonobese subjects, insulin exerted two distinct actions on HRV.
First, total spectral power was markedly reduced during euglycemic
hyperinsulinemia (Table 2). This change was at least twice as large as
that predicted (9%) from the concomitant increase in heart rate;
therefore, it represents a direct effect of insulin. Its time course
was somewhat more rapid than the stimulation of whole-body glucose
uptake (Fig. 1), and was unrelated to the level of insulin sensitivity.
More specifically, the insulin-induced decrease in total spectral power
resulted from a reduction in both the LF and HF component. This finding
demonstrates that acute hyperinsulinemia attenuates the variability of
sinoatrial node activity in response to both sympathetic and
parasympathetic influences. The mechanism of this generalized
desensitization is not known but may be linked with insulin-induced
stimulation of Na+-K+ exchange and the
attendant membrane hyperpolarization (34). In cultured baroreceptor
neurons, activation of Na+-K+ exchange reduces
baroreceptor excitability through hyperpolarization (35, 36). In dogs
with experimental heart failure, inhibition of the Na+ pump
by ouabain restores baroreceptor sensitivity (37). We have previously
shown that in human forearm skeletal muscle insulin effectively
stimulates K+ uptake in a manner that is inhibited by
ouabain and independent of forearm glucose uptake (38). Similarly, in
the current studies desensitization of sinoatrial node activity and
stimulation of peripheral glucose metabolism were parallel but
unrelated consequences of systemic insulinization. Thus, in addition to
paracrine agents (39), insulin is a previously unrecognized factor
modulating arterial baroreflex sensitivity. Of interest in this regard
is the circumstance that in vitro insulin can induce
membrane hyperpolarization also in central neurons (40).
The second specific action of insulin was to augment the fraction of
total power in the LF range (i.e. the normalized LF index)
as well as the ratio of LF/HF power (the LF/HF index, Fig. 2); the
latter change was caused by a simultaneous increase in normalized LF
and decrease in normalized HF (Table 2). Together, the normalized LF
and the LF/HF ratio reflect the strength of the sympathetic tone in
relation to the vagal tone (41). Thus, insulin acutely alters
sympathovagal control of cardiac activity both by enhancing sympathetic
outflow and by withdrawing vagal tone. The observed increases in heart
rate and circulating norepinephrine levels are coherent with
sympathetic activation. The fact that both arms of the autonomic
nervous system were affected in a reciprocal fashion supports the
interpretation that peripheral inputs (i.e. fluctuations in
blood pressure) are substantially integrated by direct central
influences.
Effect of insulin on hemodynamics
The systemic hemodynamic response to insulin consisted of small reductions in TPVR and diastolic blood pressure, and an increase in heart rate and cardiac output. The increase in cardiac output is similar in size to that measured by Baron and Brechtel (42) in clamp experiments in healthy volunteers with the use of a dye dilution technique. The decrease in TPVR has been attributed to limb vasodilatation (2, 42), mediated by the release of nitric oxide (3). An additional mechanism may be a contraction in blood volume, which we have recently reported to occur under experimental conditions similar to those of the present study (43). The increase in stroke volume, reflecting increased myocardial contractility, is further proof that sympathetic outflow to the heart was enhanced.
Effect of insulin on neurohormones
Insulin administration led to a rise in arterial norepinephrine, but not epinephrine, levels, as found by others (1). This was accompanied by increased cortisol [also previously reported during euglycemic hyperinsulinemia (44, 45)] and PRL, but decreased TSH and, to a lesser extent, GH concentrations. This pattern of hormonal responses is compatible with a moderate stress reaction (46). More specifically, these changes are the predicted consequence of an acute stimulation of the release of CRH, which exerts stimulatory influences on ACTH and SRIH, and inhibitory influences on GnRH, GHRH, and TRH (47). In agreement with this prediction, serum CRH levels rose detectably after insulin. Spillover from the hypothalamic-pituitary portal circulation into the systemic circulation is conceivable, because plasma CRH has been documented to increase after insulin-induced hypoglycemia (48, 49). This neurohormonal response thus indicates that circulating insulin acts directly on the brain also in the absence of hypoglycemia, thereby extending to humans the observations of Davis et al. (8) in the dog.
Taken together, the changes in systemic hemodynamics, autonomic activity, and neurohormones support the conclusion that the cardiac effects of insulin per se—consisting of increased contractility and heart rate, and reduced rate variability—are not only the reflex response to effects on the peripheral vasculature, but are part of a stress reaction directly elicited by insulin in the central nervous system. In support of this interpretation, recent evidence (50) has shown that in normal subjects 48 h of low-dose dexamethazone pretreatment abolished the increase in muscle sympathetic nerve activity, the rise in circulating norepinephrine, and the calf vasodilatation measured during euglycemic hyperinsulinemia, similar to the current experiments. As dexamethazone is a potent inhibitor of CRH release (47), a role for CRH as central transducer of the stress response to insulin appears likely.
Influence of obesity
Basal spectral powers were all lower (by 40%) in the obese group,
the reduction being proportional to BMI. Thus, independently of the
effect of age on HRV (51), obesity is a state of reduced sensitivity of
the sinoatrial node to both sympathetic and vagal influences. Before
insulin administration, the LF/HF ratio was slightly increased in obese
subjects, suggesting mild sympathetic overactivity. This finding is in
agreement with the microneurographic data of Vollenweider et
al. (52), who reported significantly increased MSNA in a small
group of obese patients in the basal, resting state. Although peroneal
microneurography records sympathetic traffic to the skeletal muscles of
the lower limb, whereas spectral analysis of heart rate explores an
integrated sympathovagal function, a recent study has shown that the
spectral parameters of both activities (including the LF/HF ratio) are
strongly correlated with one another over a range of heart rates
(55–81 bpm) (53). Following insulin, the LF/HF ratio failed to
increase in the obese group (Fig. 2); the difference from the lean
group was not dependent on the respective changes in heart rate. This
result suggests an inherent inability of insulin to shift the autonomic
control of heart rate in obesity. In accord with these spectral data,
Vollenweider et al. (52) found that in obese individuals
basal MSNA fails to be stimulated by insulin. Also coherent with our
result is the observation by Grassi et al. (13), that in
obese subjects the changes in MSNA elicited through pharmacological
modulation of blood pressure are blunted in comparison with those of
lean subjects. Because MSNA is sensitive to low doses of insulin
(52), it has been hypothesized that the chronic hyperinsulinemia of the
obese may be the signal that causes attenuation of baroreflex responses
and prevents enhancement of sympathetic tone by an acute insulin
increment.
In the fasting state, stroke volume was higher, and PVR was lower, in
the obese than the lean group. This high-output, low-resistance
hemodynamic pattern, which is characteristic of normotensive obesity
(9), is similar to that induced by insulin administration in the whole
group (Table 3). Thus, the obese basal state reproduces some of the
systemic hemodynamic effects of acute insulin administration. Notably,
however, the hemodynamic (heart rate, cardiac output, and PVR) and
hormonal (in particular, plasma norepinephrine levels) responses to
acute insulin administration were preserved in the obese group. Thus,
in obesity the stress response evoked by a standardized insulin
stimulus differs from the normal response in that it does not include
sympathovagal modulation of heart rate (the LF/HF ratio in the current
studies) or skeletal muscle sympathetic traffic [microneurographic
data (52)]. This finding resonates with the results of
Gudbjörnsdottir et al. (54), who reported increased
renal plasma flow and muscle sympathetic activity but unchanged renal
and total body norepinephrine spillover in obese men with
hypertension.
In summary, obesity is a state of chronic desensitization and impaired autonomic modulation of sinoatrial activity. As such, it recapitulates some features of the hemodynamic and heart rate response to acute insulin administration, suggesting a role for chronic hyperinsulinemia. These altered responses may be a substrate for both the increase in ischemic heart disease (55) and the higher incidence of arrhythmias and sudden death (56) that have been observed in obese subjects, and may be amenable to treatment through reduction of hyperinsulinemia.
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Footnotes |
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2 On leave from the Universidade Estadual de Campinas, S. Paulo,
Brasil.
Received January 22, 1998.
Revised February 24, 1998.
Accepted March 2, 1998.
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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