Responsiveness of insulin-induced cardiac sympathetic nerve
activation associates with blood pressure regulation in
diabetics
Miki
Takagi1,
Yasushi
Tanaka1,
Yoshimitsu
Yamasaki2,
Masahiko
Yamamoto2,
Masatsugu
Hori2,
Tomiko
Nakaniwa1,
Masataka
Niwa1,
Hiroshi
Uchino1,
Yoshifumi
Tamura1,
Takashi
Nomiyama1,
Hirotaka
Watada1, and
Ryuzo
Kawamori1
1 Department of Medicine, Metabolism, and
Endocrinology, Juntendo University School of Medicine, Tokyo
113 - 8421; and 2 First Department of Medicine, Osaka
University, Osaka 565-0871, Japan
 |
ABSTRACT |
To
quantitatively evaluate the effect of insulin on cardiac sympathetic
nerve activity (SNA) and analyze clinical factors associated with
insulin sensitivity for the regulation of SNA in diabetics, 29 Japanese
type 2 diabetics without neuropathy were recruited. A 2-h control study
and a 2-h hyperinsulinemic euglycemic glucose clamp study were
performed. From the power spectral analysis of R-R intervals on ECG
during both studies, two major components, the low-frequency (LF) and
the high-frequency component (HF), were obtained. Then %LF was
calculated as LF/(LF +HF), and the ratio of the average %LF during the
last 30 min of the clamp or the control to the average %LF for the
entire time for clamp or control (R-%LF) was used as a marker of
changes in SNA. R-%LF was significantly higher during the clamp than
in the control (1.07 ± 0.04 vs. 1.03 ± 0.03, P < 0.05). High responders (individual R-%LF during
clamp
mean + 2SD in control) showed a higher basal mean
blood pressure (BP) before the clamp (89 ± 3 vs. 82 ± 2, P < 0.03) but not a higher glucose infusion rate (GIR)
compared with low responders (<mean + 2SD). Furthermore, R-%LF
showed a positive correlation with basal mean BP (P < 0.02) but not with GIR. These data demonstrate that an acute insulin load stimulates cardiac SNA, and insulin sensitivity in the regulation of SNA may be associated with BP regulation independently of peripheral insulin sensitivity.
insulin action; type 2 diabetes; blood pressure; power spectral
analysis
 |
INTRODUCTION |
INFUSION OF
INSULIN during hyperinsulinemic euglycemic glucose clamp studies
can enhance sympathetic nerve activity (SNA), as detected by monitoring
muscle microelectrodes, but this phenomenon is not observed when
glucose or fructose is infused without insulin, suggesting an
insulin-specific effect on SNA (20). Although the
mechanism of this insulin-induced increase in SNA remains unclear,
insulin receptors are expressed in the hypothalamus (7, 11), and direct intraventricular infusion of insulin increases SNA in rats (12). Thus it has been hypothesized that
insulin may physiologically enhance SNA, at least partly, via
hypothalamic regulation (16). Previous studies have shown
that the action of insulin on SNA, as monitored by plasma catecholamine
levels or muscle SNA, is not correlated with the glucose infusion rate (GIR), a marker of insulin sensitivity for peripheral glucose uptake
during hyperinsulinemic euglycemic glucose clamp studies (14,
19). These results suggest that compensatory hyperinsulinemia secondary to peripheral insulin resistance may decrease the GIR and
enhance SNA, which in turn may be a possible cause of hypertension through an increment of cardiovascular SNA (16). However,
there was no increase of plasma catecholamines during euglycemic
hyperinsulinemic clamping, according to another study
(20). Furthermore, a previous study showed a significant
correlation between the responsiveness of muscle SNA and GIR during a
hyperinsulinemic euglycemic clamp study in patients with essential
hypertension (2). Therefore, it is still unclear whether
or not the insulin responsiveness of SNA is independent of the
peripheral insulin sensitivity for the regulation of glucose uptake.
Direct microelectrode recording can assess muscle SNA precisely, but it
is invasive and requires a special environment to enhance the
signal-to-noise ratio. Moreover, this method is limited to muscle SNA
and cannot evaluate cardiovascular SNA. Thus it remains difficult to
quantitatively assess the insulin-regulated enhancement of
cardiovascular SNA by a noninvasive method without specialized monitoring.
To assess cardiac autonomic nerve activity quantitatively, we
(22) previously devised computer software that can
evaluate diurnal heart rate (HR) variability by power spectral analysis of the R-wave-R-wave (R-R) interval on 24-h Holter electrocardiogram (ECG) records. Two major frequency components can be detected, i.e., a
low-frequency component (LF, 0.03-0.15 Hz) that represents both
cardiac
-adrenergic and parasympathetic activity and is relatively
higher in the daytime (15) and a high-frequency component (HF, 0.15-0.4 Hz) that represents almost pure parasympathetic activity (8) and is relatively higher at night. Although
the LF-to-HF ratio has been suggested as a marker of SNA, we have shown
that the LF/(LF + HF) ratio is an alternative marker
(22). We have also reported that type 2 diabetics with
symptomatic autonomic or peripheral neuropathy, but not diabetics
without neuropathy, show a decrease of both the LF and HF components
and loss of the normal circadian rhythm of heart variability
(21).
The effect of acute insulin infusion during hyperinsulinemic euglycemic
glucose clamp on cardiac SNA has not been evaluated by power spectral
analysis of the R-R interval in subjects without neuropathy by
comparison with the spontaneous changes on another day. Therefore, we
performed such a study and assessed the clinical factors associated
with the responsiveness of cardiac SNA to insulin in Japanese type 2 diabetic subjects.
 |
METHODS |
Subjects.
Twenty-nine Japanese patients aged 27-69 yr with type 2 diabetes
who had a fasting plasma glucose level <120 mg/dl were recruited. None
of the subjects was taking antihypertensive agents, and none had
cardiac arrhythmia or diabetic neuropathy. We excluded patients showing
signs and symptoms of peripheral neuropathy or autonomic neuropathy
such as paresthesia, numbness, pain, decreased vibration sensation,
loss of ankle reflexes, delayed peroneal nerve conduction velocity,
orthostatic hypotension, loss of sweating on the feet, impotence,
persistent diarrhea, and bladder dysfunction. To exclude subjects with
cardiac autonomic neuropathy, we used two criteria: one was the
coefficient variable (CV) of R-R interval on the resting ECG (CV-RR),
and the other was the mean total frequency (TF: LF + HF) obtained
by analysis of the 24-h ECG record. Our previous study of TF in healthy
subjects (22) showed that it decreases age dependently
[
TF = 42.50548
0.354887 × age (yr)] and allowed us to calculate the lower limit of the 75% confidence interval of TF
values. Patients showing a CV-RR <2% or a TF value below the lower
limit were excluded from the study even if they did not have any of the
aforementioned signs and symptoms.
Hyperinsulinemic euglycemic glucose clamp study.
After an overnight fast, a 2-h hyperinsulinemic euglycemic glucose
clamp study was performed in each subject by use of an artificial
pancreas (STG22; Nikiso, Shizuoka, Japan) and a modified method of
DeFronzo et al. (6). Briefly, regular human insulin and
glucose were infused intraveneously according to an algorithm that
maintained the plasma insulin level at 200 mU/l (1,200 pmol/l) and the
plasma glucose level at 95 mg/dl (5.3 mmol/l). The mean glucose
infusion rate (GIR) from 1.5 to 2 h after the clamp study was
started was used as a marker of peripheral insulin sensitivity.
Noninvasive hemodynamic monitoring.
From 20 min before the start to the end of the clamp study, hemodynamic
parameters [blood pressure (BP), pulse rate (PR), cardiac output (CO),
and total peripheral vascular resistance (TPR)] were monitored every 5 min (before clamping) or every 15 min (after clamping) using a
noninvasive monitor (GP-303S; Paramatech, Fukuoka, Japan), which was
equipped with both a mercury sphygmomanometer for BP monitoring and a
brachial artery pulse wave analyzer to estimate CO (10,
18). The CO values estimated by this method showed a significant
positive correlation with the CO values measured by the impedance
method (13). TPR was automatically calculated from the
mean BP and CO, and the cardiac index (CI) was also automatically calculated from CO, height, and weight. The mean value before clamping
and the mean value from 1 to 2 h were used as the baseline and 2-h
values of the hemodynamic parameters, respectively. The ratio of the
mean CI (or TPR) from 1 to 2 h during the clamp study to the mean
CI (or TPR) before clamping was calculated as R-CI (R-TPR), and this
value was used as a marker of changes in CI (or TPR) due to acute
insulin infusion during the clamp study.
Holter ECG recording.
As shown in Fig. 1, Holter ECG recordings
were performed from 1600 on day 1 to 1600 on day
3 (48 h) to compare the acute response of SNA to insulin with the
spontaneous changes occurring in daily life. For the control study, the
subjects were fasted and rested on a bed for 2 h at the same clock
time as during the clamp study (on the day before the clamp study).
Holter tapes were analyzed using a Marquette Laser SXP Holter analysis
system (Marquette Electronics, Milwaukee, WI) to identify and label
each QRS complex. After the computer had automatically detected and
labeled each QRS complex, all of the data files were reviewed and
edited by the same physician (M. Takagi), who was blinded to the
clinical characteristics of the subjects. Then, the labeled QRS data
were moved via high-speed transfer to a computer, after which the data were analyzed and additional editing was done. Measurements of HR
variability were calculated and printed out for the entire 24-h period.
Each printout that included an R-R interval was selected and measured.
Power spectral analysis of R-R intervals.
The method of analysis was described in our previous report
(21). Briefly, to subtract the R-R interval from the
Holter ECG record, 512 consecutive normal-normal intervals were
identified for each 15-min period (0800-0815, 0815-0830,
etc.). An autoregressive algorithm, which was described previously
(22), was used for power spectral analysis and was
selected to minimize Akaike's (1) final prediction error
figure of merit after several iterations were performed and the order
was increased. The program determined the individual power and central
frequency of each spectral component. Then the sum of the powers with a
central frequency at 0.15-0.4 Hz was defined as the HF component,
and the sum of powers with a central frequency at 0.03-0.15 Hz was
defined as the LF component. Next, the total frequency (TF) was
calculated as the sum of HF and LF, and the percent LF (%LF) was
calculated as the LF-to-TF ratio. When one 15-min period had two or
more runs of 512 consecutive normal-normal intervals, the LF and HF
components were averaged separately. The %LF value was averaged for
the full study period (2 h) and for the last 30 min each of the control
and clamp studies. Then the ratio of mean %LF during the last 30-min
period to mean %LF for the entire 2-h period (R-%LF) was used as a
marker of SNA changes in the control and clamp studies. Although this
derivation of R-%LF may seem rather complex, it has the advantage of
correcting intra- and interstudy variations. Similarly, the ratio of
mean HR during the last 30-min period to mean HR for the entire 2-h period (R-HR) was used as a marker of the change in HR.
Statistical analysis.
Data are expressed as means ± SE. Statistical significance was
determined by the paired t-test or one-way ANOVA. Multiple regression analysis was used to evaluate the clinical factors associated with R-%LF.
 |
RESULTS |
The clinical profile of the subjects and the effect of acute
insulin infusion on SNA during the clamp study compared with those
during the control study are shown in Table
1. Although both R-HR and R-CI were
>1.0, R-TPR was <1.0, reflecting the insulin-stimulated increase of
CO and HR as well as insulin-induced vasodilation. R-%LF was
significantly higher in the clamp study than in the control study. As
shown in Table 2, the subjects were
divided into two groups based on the value of R-%LF in the clamp
study. A high responder was defined as having an R-%LF in the clamp
study that was equal to or greater than the mean + 2SD of R-%LF
calculated from the results of all subjects in the control
study. The R-%LF value of the high-responder group was
significantly higher than that of the low-responder group (1.36 ± 0.06 vs. 0.97 ± 0.02, P < 0.01). As shown in
Table 2, basal mean BP (MBP) before start of the clamp study and R-HR
were significantly higher in the high-responder group than in the
low-responder group (basal MBP 89 ± 3 vs. 82 ± 2, P < 0.03; R-HR 1.09 ± 0.04 vs. 1.03 ± 0.01, P < 0.01), whereas the other clinical factors
did not differ between the two groups. Furthermore, multiple regression
analysis showed that basal MBP, but not GIR, was positively correlated
with R-%LF in the clamp study (Table
3). Likewise, basal MBP and R-CI were
positively correlated with R-%LF in the clamp study (Table
4).
 |
DISCUSSION |
Previous studies evaluating the effect of acute insulin infusion
on muscle SNA by electrophysiological methods examined used a 2-h
glucose infusion without insulin as the control and found no increase
of SNA (4), suggesting that the increase of SNA during the
2-h euglycemic hyperinsulinemic clamp study may have been a direct
effect of insulin. However, SNA increases physiologically from the
early morning, reflecting the circadian rhythm of the autonomic nervous
system. We previously observed a spontaneous increase of LF and %LF
from the morning by diurnal R-R power spectral analysis of 24-h Holter
ECG records (22). Thus, to properly evaluate the acute
effect of insulin on cardiac SNA, we performed a separate control study
and compared the results with those of the clamp study. We showed that
acute insulin infusion during the hyperinsulinemic euglycemic glucose
clamp study caused a significant increase of R-%LF compared with the
change at the same clock time during daily life in type 2 diabetic
subjects. As shown in Table 1, there was a 4% increase of R-%LF after
acute insulin infusion. This may seem a small change, but we previously
found that the relative increase of mean %LF between 0800 and 1200 compared with the daily mean %LF (0800-0800) was 4-6%,
whereas no significant increase was detected in subjects with diabetic
autonomic neuropathy (21). Accordingly, the modest
increase of R-%LF observed in the present study may be physiologically
meaningful. A preliminary study showed that there was no effect of an
acute insulin load on the increment of R-%LF in nine subjects with
diabetic autonomic neuropathy during both control and clamp studies
(0.97 ± 0.06 vs. 0.97 ± 0.08). Thus acute insulin infusion
may directly increase cardiac SNA in diabetic subjects without
neuropathy. However, further evaluation of subjects with autonomic
neuropathy is required to confirm this point.
We used the R-%LF value in the clamp study (more or less than the
mean + 2SD of the control study) to separate the subjects, but
this criterion may not have any pathophysiological basis. Because there
have been no previous reports about the responsiveness of R-%LF to an
acute insulin load, we used this value as a tentative criterion, but
further studies should be performed to determine the optimal value. It
would be interesting to assess whether R-%LF is associated with
changes of plasma catecholamine, especially norepinephrine
(NE), during the clamp study. We checked plasma NE levels
before clamping and at 2 h after start of the clamp study, and the
relative increase of NE from baseline was greater in the high-responder
group than in the low-responder group, but the difference was not
significant (1.36 ± 0.16 vs. 1.06 ± 0.07, P = 0.06). Thus detailed evaluation of the changes of NE by measurement at multiple points during the clamp study may clarify the relationship between R-%LF and NE.
It is important to examine whether the physiological and clinical
significance of the cardiac sympathetic response to hyperinsulinemia is
similar in diabetic and nondiabetic subjects. Accordingly, we also
performed the same study in 10 healthy, nondiabetic subjects aged
23-38 yr (29 ± 1 yr, 9 males, 1 female, all nonsmokers) who showed normal glucose tolerance in a 75-g oral glucose tolerance test.
They did not have any signs or symptoms of peripheral neuropathy and
showed normal CV-RR and TF values. R-%LF was significantly higher
during the clamp study than in the control study (1.09 ± 0.04 vs.
1.01 ± 0.07, P < 0.01) and was not significantly
different from the value in diabetic subjects. As shown in Table
5, univariate regression analysis
indicated that basal MBP, but not GIR, was positively correlated with
R-%LF in these healthy individuals as well as in the diabetic
subjects. Previous reports have indicated that an acute insulin load
during the clamp study induces the activation of muscle SNA and the HR
in nondiabetic subjects (4, 17). Taken together, the
enhancement of cardiac SNA by acute hyperinsulinemia and the
association between BP and the responsiveness of cardiac SNA to insulin
may be common to diabetic and nondiabetic subjects.
View this table:
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|
Table 5.
Univariate regression analysis of clinical factors associated with
R-%LF during the clamp study in nondiabetic subjects
|
|
The present study also showed that the responsiveness of SNA to insulin
was not associated with GIR in either diabetic or nondiabetic
subjects. Thus the effect of insulin on glucose uptake may not parallel
the response of SNA to insulin, suggesting that compensatory
hyperinsulinemia due to peripheral insulin resistance-impaired glucose
uptake potentiates the increase of SNA. It has been suggested that
insulin may contribute to BP regulation through the balance between
insulin-induced direct vasodilation and insulin-mediated cardiovascular
sympathetic nerve activation (16). We (9) previously evaluated the hemodynamic effect of acute insulin infusion during a clamp study and found that the insulin-induced decrease of
peripheral vascular resistance was impaired in patients with peripheral
insulin resistance on glucose uptake. Thus compensatory hyperinsulinemia due to insulin resistance may potentiate SNA but not
vasodilation, leading to an imbalance between these actions of insulin
and, consequently, an increase of BP (3), and our data
seem to be consistent with such a hypothesis.
Interestingly, the present study showed that R-%LF was correlated with
basal MBP, suggesting an association between BP control and the insulin
sensitivity of SNA. Although no one has evaluated the physiological
significance of insulin sensitivity in such a context, our results
suggest the possibility that the sensitivity of SNA may be associated
with BP regulation independently of the influence of peripheral insulin
sensitivity. However, the mechanism regulating individual variations in
the sensitivity of SNA to insulin and the mechanism underlying the
linkage of SNA responsiveness with BP regulation are still unclear.
Recently, an animal model, i.e., a neuron-specific insulin receptor
knockout mouse, was developed to evaluate the physiological role of
insulin in the central nervous system (CNS) (5). These
mice show normal brain development and neuron survival, diet-sensitive
obesity with an increase of body fat and plasma leptin levels, mild
insulin resistance, and impaired spermatogenesis in males and impaired
ovarian follicle maturation in females because of hypothalamic
dysregulation of luteinizing hormone, suggesting an important role of
the CNS actions of insulin in the regulation of energy storage,
metabolism, and reproduction (5). Although neither the BP
profile nor the regulation of cardiac SNA in these mice was described,
this animal model may be useful to elucidate the main site of action by
insulin in the regulation of SNA. It is also necessary to evaluate the molecular mechanisms regulating insulin sensitivity itself and to study
the clinical meaning of the influence of insulin on SNA.
In conclusion, an acute insulin load can enhance cardiac SNA, and the
extent of this response to insulin is not associated with GIR but with
basal MBP in both nondiabetic and diabetic subjects. These results
demonstrate an influence of insulin on cardiac autonomic function, so
future studies should elucidate the mechanism and the role of insulin
in BP regulation.
 |
ACKNOWLEDGEMENTS |
Some of the data in this manuscript were presented at the 60th
Annual Meeting and Scientific Sessions of the American Diabetes Association (San Antonio, Texas, 9-13 June, 2000).
 |
FOOTNOTES |
Address for reprint requests and other correspondence: Y. Tanaka, Dept. of Medicine, Metabolism, and Endocrinology, Juntendo Univ. School of Medicine, 2-1-1, Hongo, Bunkyo-ku, Tokyo
113-8421 Japan (E-mail:
y-tanaka{at}med.juntendo.ac.jp).
The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement"
in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
First published February 4, 2003;10.1152/ajpendo.00169.2002
Received 22 April 2002; accepted in final form 13 January 2003.
 |
REFERENCES |
1.
Akaike, H.
Statistical predictor identification.
Ann Inst Stat Math
22:
203-217,
1970[ISI].
2.
Anderson, EA,
Balon TW,
Hoffman RP,
Sinskey CA,
and
Mark AL.
Insulin increases sympathetic activity but not blood pressure in borderline hypertensive humans.
Hypertension
19:
621-627,
1992[Abstract].
3.
Baron, AD,
Brechtel-Hook G,
Johnson A,
and
Haedin D.
Skeletal muscle blood flow: a possible link between insulin resistance and blood pressure.
Hypertension
21:
129-135,
1993[Abstract].
4.
Berne, C,
Fagius J,
Pollare T,
and
Hjemdahl P.
The sympathetic response to euglycaemic hyperinsulinaemia: evidence from microelectode nerve recordings in healthy subjects.
Diabetologia
35:
873-879,
1992[ISI][Medline].
5.
Brünig, JC,
Gautam D,
Burks DJ,
Gillette J,
Schubert M,
Orban PC,
Klein R,
Krone W,
Müller-Wieland D,
and
Kahn CR.
Role of brain insulin receptor in control of body weight and reproduction.
Science
289:
2122-2125,
2000[Abstract/Free Full Text].
6.
DeFronzo, RA,
Tobin JD,
and
Andres R.
Glucose clamp technique: a method for quantifying insulin secretion and resistance.
Am J Physiol Endocrinol Metab Gastrointest Physiol
237:
E214-E223,
1979[Abstract/Free Full Text].
7.
Havrankova, J,
Roth J,
and
Brownstein M.
Insulin receptors are widely distributed in the central nervous system of the rat.
Nature
272:
827-829,
1978[ISI][Medline].
8.
Hirsch, JA,
and
Bishop B.
Respiratory sinus arrhythmia in humans: how breathing pattern modulates heart rate.
Am J Physiol Heart Circ Physiol
241:
H620-H646,
1981[Abstract/Free Full Text].
9.
Kinoshita, J,
Tanaka Y,
Niwa M,
Yoshii H,
Takagi M,
and
Kawamori R.
Impairment of insulin-induced vasodilation is associated with muscle insulin resistance in type 2 diabetes.
Diabetes Res Clin Pract
47:
185-190,
2000[ISI][Medline].
10.
Kouchoukos, NT,
Sheppard LC,
and
McDonald DA.
Estimation of stroke volume in the dog by a pulse contour method.
Circ Res
26:
611-623,
1970[ISI][Medline].
11.
Landau, BR,
Abrams MA,
White RJ,
Takaoka Y,
Taslitz N,
Austin P,
Austin J,
and
Chernicky C.
Insulin action on the primate hypothalamus.
Diabetes
25, Suppl 1:
322,
1976.
12.
Muntzel, MS,
Morgan DA,
Mark AL,
and
Johnson AK.
Intracerebroventricular insulin produces nonuniform regional increases in sympathetic nerve activity.
Am J Physiol Regul Integr Comp Physiol
267:
R1350-R1355,
1994[Abstract/Free Full Text].
13.
Nagata, K,
Okamoto A,
Kamano Y,
Kubota K,
Kamano S,
Honda R,
Yamasaki M,
and
Okuaki A.
Noninvasive measurement of hemodynamics.
Jpn J Clin Monitor
2:
151-156,
1991.
14.
O'Hara, JA,
Minaker KL,
Meneilly GS,
Rowe JW,
Pallotta JA,
and
Young JB.
Effect of insulin on plasma norepinephrine and 3,4-dihydroxyphenylalanine in obese men.
Metabolism
38:
322-329,
1989[ISI][Medline].
15.
Preiss, G,
and
Polasa C.
Patterns of sympathetic neuron activity associated with Meyer waves.
Am J Physiol
226:
724-730,
1974[Free Full Text].
16.
Reaven, GM,
Lithell H,
and
Landsberg L.
Hypertension and associated metabolic abnormalities: the role of insulin resistance and the sympathoadrenal system.
N Engl J Med
334:
374-381,
1996[Free Full Text].
17.
Rowe, JW,
Young JB,
Minaker KL,
Stevens AL,
Pallota J,
and
Landsberg L.
Effect of insulin and glucose infusions on sympathetic nervous system activity in normal man.
Diabetes
30:
219-225,
1981[ISI][Medline].
18.
Schwid, HA,
Taylor LA,
and
Smith NT.
Computer model analysis of the radial artery pressure waveform.
J Clin Monit
3:
220-228,
1987[ISI][Medline].
19.
Spraul, M,
Ravussin E,
and
Baron AD.
Lack of relationship between muscle sympathetic nerve activity and skeletal muscle vasodilation in response to insulin infusion.
Diabetologia
39:
91-96,
1996[ISI][Medline].
20.
Vollenweider, P,
Tappy L,
Randin D,
Schneiter P,
Jequier E,
Nicod P,
and
Scherrer U.
Differential effects of hyperinsulinemia and carbohydrate metabolism on sympathetic nerve activity and muscle blood flow in humans.
J Clin Invest
92:
147-154,
1993[ISI][Medline].
21.
Yamamoto, M,
Yamasaki Y,
Kodama M,
Matsuhisa M,
Kishimoto M,
Ozaki H,
Tani A,
Ueda N,
Iwasaki M,
and
Hori M.
Impaired diurnal cardiac autonomic function in subjects with type 2 diabetes.
Diabetes Care
22:
2072-2077,
1999[Abstract].
22.
Yamasaki, Y,
Kodama M,
Matsuhisa M,
Kishimoto M,
Ozaki H,
Tani A,
Ueda N,
Ishida Y,
and
Kamada T.
Diurnal heart rate variability in healthy subjects: effects of aging and sex difference.
Am J Physiol Heart Circ Physiol
271:
H303-H310,
1996[Abstract/Free Full Text].
Am J Physiol Endocrinol Metab 284(5):E1022-E1026
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