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
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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

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
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

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 beta -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
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

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 [radical 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.


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Fig. 1.   Design of the study. ECG, electrocardiogram.

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
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

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).

                              
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Table 1.   Characteristics of the subjects and effect of an acute insulin load on sympathetic nerve activation


                              
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Table 2.   Responsiveness of an acute insulin load during the clamp study


                              
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Table 3.   Multiple regression analysis of clinical factors associated with R-%LF during the clamp study


                              
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Table 4.   Results of multiple regression analysis by the stepwise forward selection method


    DISCUSSION
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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

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.

                              
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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.


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DISCUSSION
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