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Original Studies |
Department of Medicine, Divisions of Endocrinology and Diabetology (S.M., A.S., H.Y.-J.) and Ophthalmology (P.S.), Helsinki University Central Hospital; and Research Institute of Military Medicine (M.M.), Helsinki, Finland
Address all correspondence and requests for reprints to: Hannele Yki-Järvinen, M.D., University of Helsinki, Department of Medicine, Division of Endocrinology and Diabetology, Haartmaninkatu 4, FIN-00290 Helsinki, Finland. E-mail: ykijarvi{at}helsinki.fi
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Abstract |
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Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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In patients with insulin-dependent diabetes mellitus (IDDM) and autonomic neuropathy, various abnormalities in the hemodynamic effects of insulin, independent of changes in blood glucose concentrations, have been described. These include description of a hypotensive effect of insulin, but not saline, in IDDM patients with autonomic neuropathy (10), a case report of provocation of postural hypotension by insulin (11), and three more detailed descriptions of the hemodynamic responses to insulin in IDDM patients with autonomic neuropathy (4, 12, 13). Takata et al. (12) found no hemodynamic effects of 4 IU insulin in IDDM patients with neuropathy, but observed a decrease in mean arterial blood pressure and forearm vascular resistance in patients with autonomic neuropathy. Heart rate responses to insulin were similar in both groups. Scott et al. (4) compared a group of 50-yr-old, hypertensive IDDM patients to nondiabetic, normotensive, 23- to 32-old subjects and found blunted heart rate, peripheral blood flow, and blood pressure responses to insulin in the IDDM patients. However, as both aging (14) and hypertension (15) impair blood flow responses to insulin, the contribution of autonomic neuropathy to these changes remained unclear. Finally, Porcellati et al. (13) found insulin to decrease blood pressure in IDDM patients with autonomic neuropathy, but not in those without, primarily by decreasing arterial vascular resistance. The heart rate responses were greater in patients with than in those without autonomic neuropathy, whereas the increases in plasma norepinephrine concentrations caused by insulin were similar in both groups of patients.
Theoretically, autonomic dysfunction could impair insulin-induced hemodynamic changes via at least two mechanisms. First, sympathetic denervation might impede insulin-induced sympathetic activation and consequent vasoconstriction, and thereby lower peripheral vascular resistance excessively during hyperinsulinemia. Second, defects in vagal control of heart rate might impair baroreflex control of the heart rate response to changes in blood pressure, but evidence for the contribution of this defect to abnormal insulin-induced hemodynamic responses is currently lacking. We hypothesized that both sympathetic denervation and defects in vagal control of heart rate contribute to abnormal hemodynamic changes in patients with autonomic neuropathy. This hypothesis was tested by quantitating separately sympathetic and parasympathetic autonomic function by tests such as frequency domain analysis of heart rate variability in patients with IDDM and relating the results of these function tests to the hemodynamic responses of a standardized increment in the circulating insulin concentration. As insulin-induced vasodilation has been suggested to contribute to the ability of insulin to promote glucose uptake (1), and as sympathetic denervation might exaggerate insulin-induced vasodilation in patients with autonomic dysfunction, we also quantitated the impact of autonomic dysfunction on whole body and forearm insulin-mediated glucose uptake.
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Subjects and Methods |
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Twenty-eight men with IDDM and seven normal men volunteered for
the studies. The diabetic patients were recruited from the out-patient
clinic based on the following criteria: 1) age between 18–50 yr, 2)
age at diagnosis of diabetes less than 30 yr, and 3) undetectable
fasting C peptide concentration (<0.1 nmol/L). A history, physical
examination, and standard laboratory tests were performed in all
subjects to exclude diseases other than IDDM. The patients and normal
subjects had normal blood counts, electrolyte and liver enzyme
concentrations, and thyroid function tests (data not shown). The IDDM
patients and normal subjects were matched for age, blood pressure, body
mass index, and composition (Table 1
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The diabetic patients were treated with two (n = 2), three (n
= 2), or four (n = 23) injections of a combination of intermediate
and short acting insulins. One patient was using continuous sc insulin
infusion therapy. Their mean insulin dose was 56 ± 2 IU/day
(0.71 ± 0.03 IU/kg·day). Symptoms or signs of neuropathy are
described in Results and in Table 1. Informed written
consent was obtained after the purpose, nature, and potential risks
were explained to the subjects. The experimental protocol was designed
and performed according to the principles of the Helsinki Declaration
and was approved by the ethical committee of the Helsinki University
Central Hospital.
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All subjects were studied on two separate occasions with at least a 1-week interval between the studies. On one occasion, two sequential doses of insulin were infused iv in a primed continuous manner for 4 h (insulin infusion study). Before and during hyperinsulinemia, forearm blood flow and glucose uptake as well as blood pressure were recorded at 30-min intervals, and heart rate was recorded continuously, as detailed below. On the other occasion, a set of autonomic function tests was performed to assess autonomic dysfunction as described in detail below. For 2 days before the studies, the subjects ingested a weight-maintaining diet containing at least 200 g carbohydrate/day, with 15–20%, 45–50%, and 35–40% of calories from protein, carbohydrate, and fat, respectively.
Insulin infusion study
The study was begun after a 10- to 12-h fast at 0730 h. Three 18-gauge catheters (Venflon, Viggo-Spectramed, Helsingborg, Sweden) were inserted as previously described (16). Insulin and glucose were infused in a catheter inserted in the left antecubital vein. The left hand was kept in a heated chamber (65 C), and arterialized venous blood was withdrawn from a heated dorsal hand vein. The deep branch of the right medial cubital vein draining forearm muscles was cannulated retrogradely to obtain blood samples from venous blood draining forearm muscle tissue (16).
Before the start of the insulin and glucose infusions, basal heart
rate, blood pressure, blood flow, and the glucose arterio-venous (AV)
difference were measured at -60, -30, and -10 min. At 0 min, a
primed continuous infusion of insulin was started. During the first 120
min, the continuous insulin infusion rate was 1 mU/kg·min, which
corresponds to 4.2 IU insulin/h for a 70-kg person. At 120 min, a
second dose of insulin was infused in a primed continuous manner for
another 120 min; the rate of the continuous infusion was 5 mU/kg·min.
Normoglycemia was maintained by adjusting the rate of a 20% glucose
infusion based on plasma glucose measurements performed at 5-min
intervals from arterialized venous blood (17). The rate of glucose
infusion needed to maintain normoglycemia provides a measure of whole
body insulin sensitivity (17). In the IDDM patients, plasma glucose was
allowed to fall to 
5 mmol/L during infusion of the first insulin
dose. Normoglycemia was thereafter maintained using a variable rate
infusion of glucose. During the second hour of the 1 mU/kg·min
insulin dose, plasma glucose averaged 5.2 ± 0.1 and 5.7 ±
0.2 mmol/L in the normal subjects and the patients with IDDM (P= NS). During the higher dose insulin infusion, plasma glucose
averaged 5.2 ± 0.03 and 5.2 ± 0.02 mmol/L, respectively.
Fasting serum free insulin concentrations averaged 42 ± 7 and
52 ± 5 pmol/L in the normal subjects and the patients with IDDM.
During the low and high dose insulin infusions, serum free insulin
averaged 401 ± 15 and 2857 ± 101 in the normal subjects and
370 ± 18 and 2421 ± 100 pmol/L in the patients with
IDDM.
Forearm blood flow and glucose uptake measurements were performed at 30-min intervals during the insulin infusion study. Forearm blood flow was measured with venous occlusion plethysmography using mercury in rubber strain gauges (EC4 Strain Gauge Pletysmograph, Hokanson, Bellevue, WA). The gauge was attached around the widest, most muscular segment of the forearm (3). Two minutes before measurement of the glucose AV difference and blood flow, circulation to the hand was interrupted by inflating a pediatric blood pressure cuff around the wrist to above the systolic blood pressure. Blood samples were withdrawn simultaneously from arterialized venous and deep venous blood-draining forearm tissues to calculate the glucose AV difference. Venous return was then occluded by a rapid cuff inflator (E20 Rapid Cuff Inflator, Hokanson) by inflating a sphygmomanometer cuff around the upper arm to 50 mm Hg. An analog to digital converter (McLab/4e, AD Instruments, Castle Hill, Australia) connected to personal computer was used for recording blood flow. Calibration was performed using a built-in electronic calibration signal for a 1% volume change, the height of which was used for blood flow calculations. Forearm glucose uptake was calculated according to the Fick principle by multiplying the AV difference for glucose times forearm blood flow (3).
Blood pressure was recorded using an automatic sphygmomanometer (Datascope Accutor, Datascope Corp., Paramus, Japan). Pulse pressure was calculated from the difference between systolic and diastolic blood pressures, and mean arterial pressure was determined by adding one third of the pulse pressure to the diastolic blood pressure. Forearm vascular resistance was calculated by dividing mean blood pressure by forearm blood flow.
Autonomic function tests
Reflex forearm blood flow response to cold immersion. To assess thermoregulatory reflex sympathetic vasomotor function, the forearm blood flow response to a standardized cold stimulus was measured (18). The subjects were supine during the test. The right forearm was immersed in a container containing iced water for 30 s. Forearm blood flow was measured in the left forearm before cold immersion and immediately after the 30-s cold immersion period for a total of 5 min using venous occlusion plethysmography as described above. The reproducibility of the cold pressor test performed on 2 consecutive days in 10 normal subjects on 2 separate occasions was 4 ± 3%.
Cardiovascular autonomic function tests. These tests were performed in the supine position, except for the orthostatic test and the controlled breathing test, which were performed in the head-up position. The tests were performed in the following order: controlled and deep breathing test, Valsalva test, isometric handgrip test, and orthostatic test. In the controlled breathing test, a measure of both parasympathetic and sympathetic inputs into heart rate control (19), a quiet sound signal was given to pace the inspiration and expiration for 2 s each. This pattern was maintained for 5 min, during which the R-R intervals were measured from the electrocardiogram. The square root of the mean of the square of successive R-R interval differences (RMSSD) was calculated. The frequency domain analysis of heart rate variability was performed using spectral analysis of R-R interval variability using the CAFTS system (Medicro Oy, Kuopio, Finland). After detrending the R-R interval signal, a least mean square autoregressive model with a model order of 14 was used to obtain the power spectral estimate of R-R interval variability. The total power (TP) was determined in the frequency range from 0 Hz to 0.5 times the heart rate in Hz. Low frequency power (LF) was determined in the frequency range from 0.04–0.15 Hz, and it is thought to be mediated by both parasympathetic and sympathetic pathways (20). High frequency power (HF) was determined in the frequency range from 0.15–0.40 Hz, and it is thought to be mediated by parasympathetic pathways (20). The signal powers were calculated as integrals under the respective part of the power spectral density function and were expressed in absolute units (milliseconds2) and as a ratio (LF/HF) as a measure of sympathovagal balance (21). In the deep breathing test, a test of vagal heart rate control (19), the durations of inspiration and expiration were both 5 s over a 40-s period (four respiratory cycles). The ratio of the longest and shortest R-R intervals was determined from the electrocardiogram for each respiratory cycle, and the mean of the four ratios was taken as the expiration to inspiration ratio (E/I ratio). In the Valsalva test, a measure of both parasympathetic and sympathetic function (19), the subjects blew into a manometer, thereby maintaining an intrathoracic pressure of 40 mm Hg for 15 s. The ratio of the shortest R-R interval during the expiratory strain and the longest R-R interval during the 20 s after the end of the strain was calculated (Valsalva ratio). In the isometric handgrip test, the subjects squeezed a dynamometer in their dominant hand for 3 min at a force corresponding to 30% of their maximal squeezing force. Heart rate and blood pressure were measured at rest before the test and at the end of the handgrip. In the orthostatic test, the subjects actively stood up after resting quietly supine for 5 min. Heart rate and blood pressure were measured at rest and 1, 3, 5, and 7 min after standing up. We have recently determined the reproducibility and impact of ambient glycemia and insulinemia on autonomic function tests (22). The intraindividual coefficients of variation of two tests performed under hyper- and normoglycemic conditions were: E/I ratio, 3.7%; Valsalva ratio, 4.7%; hand grip test, 14%; orthostatic test, 25%; RMSSD, 16%; LF, 25%; HF, 34%; LF/HF, 19%; and TP, 18%. These coefficients of variation are lower than those previously reported for nondiabetic subjects (23) and can be classified as very good for all except the HF test according to the French Group for Research and Study of Diabetic Neuropathy (24).
Other measurements
Plasma glucose concentrations were measured in duplicate with
the glucose oxidase method, using the Beckman Glucose Analyzer II
(Beckman Instruments, Fullerton, CA). Hemoglobin A1c was
measured by high performance liquid chromatography using the fully
automated Glycosylated Hemoglobin Analyzer System (Bio-Rad, Richmond,
CA). Three timed overnight urine collections were performed to classify
the patients according to their urinary albumin excretion rate (Table 1
) (25). Urinary albumin was measured by an immunoturbidimetric
(Hitachi, Tokyo, Japan) method, using an antiserum against human
albumin (Orion Diagnostica, Espoo, Finland). To grade diabetic
retinopathy (Table 1), two 45° fundus color slides of macular and
disc/nasal field were taken of each eye through dilated pupils and
scored by an ophthalmologist (P.S.) in a masked fashion using modified
Early Treatment of Diabetic Retinopathy Study scoring (26, 27).
Fat-free mass was measured by a single frequency bioelectrical
impedance device (model BIA-101A, Bio-Electrical Impedance Analyzer
System, Mt. Clemens, MI).
Statistical methods
Data from the study groups were analyzed using Student’s t test. HF and LF were log-transformed because of their nonnormal distribution before analysis. Simple correlations between selected study variables were calculated using Spearman’s rank correlation coefficient. Multivariate linear regression analysis was used to analyze the causes of variation in hemodynamic parameters and selected study variables. All calculations were made using the Systat statistical package (Systat, Evanston, IL). The insulin response denotes a change in a given parameter under normoglycemic conditions in both groups, i.e. a change between the mean value during the high dose compared to that during the second hour of the low dose insulin infusion. All data are expressed as the mean ± SEM.
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Results |
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In the normal subjects, insulin increased the heart rate
significantly more than in the patients with IDDM (Fig. 1). Within the patients with IDDM, the
change in heart rate was inversely related to the resting heart rate
(r = -0.59; P < 0.01). Systolic blood pressure
increased significantly in the normal subjects, but remained unchanged
in the IDDM patients (Fig. 1). Diastolic blood pressure remained
unchanged in the normal subjects, but decreased significantly in the
patients with IDDM (Fig. 1). Mean arterial blood pressure changed
significantly less in the IDDM patients than in the normal subjects
(Fig. 1).
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). Forearm vascular resistance decreased
significantly in the patients with IDDM, but not in the normal subjects
(Fig. 2). The decrease in forearm vascular resistance was significantly
(P < 0.05) greater in the IDDM patients than in the
normal subjects (Fig. 2).
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The IDDM patients exhibited significant defects in several
autonomic function tests, as shown in Table 2. Abnormal test results were far more
common than symptoms of autonomic neuropathy (Table 1). Using the
classification scheme of Ewing et al. (28), 5 of 28 subjects
(18%) had an abnormal Valsalva ratio (<1.20), 5 of 28 (18%) had a
blunted (<10 mm Hg) increase in diastolic blood pressure during
sustained handgrip, and 2 of 28 (7%) had an excessive postural fall in
systolic blood pressure (more than -30 mm Hg). A positive history of
symptomatic autonomic neuropathy was, within the group of IDDM
patients, significantly correlated with the Valsalva ratio, the
increase in diastolic pressure during the handgrip test, LF, TP, and
RMSSD (P < 0.05 or less for each test).
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The various autonomic function tests were grouped based on
knowledge of what aspect of autonomic function they are predominantly
thought to reflect (19) (Table 3). The
tests measuring vagal control of heart rate variability, such as the
E/I and HF (Fig. 3), were significantly
correlated with the change in heart rate induced by the high compared
to the low dose insulin infusion both in the entire group and within
the patients with IDDM, but not with changes in systolic or diastolic
blood pressure (data not shown) or forearm vascular resistance (Table 3).
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), but not with the change in heart rate
by insulin (Table 3). The decrease in blood pressure in response to
standing and handgrip, tests that primarily reflect sympathetic
function, was also significantly correlated with the change in forearm
vascular resistance by insulin, but not with changes in heart rate
(Table 3).
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These correlations remained significant even after adjusting for age
and baseline blood pressure using multivariate analysis with the
insulin-induced change in the hemodynamic parameter as the dependent
variable and the autonomic function test, age, and systolic or
diastolic blood pressure as the independent variables (data not
shown). Insulin action on glucose uptake
The rate of whole body glucose uptake was 52% lower in the IDDM patients (21 ± 2 µmol/kg·min) than in the normal subjects (43 ± 5 µmol/kg·min; P < 0.001) during the second hour of the low dose insulin infusion and 29% lower during the high dose insulin infusion (48 ± 2 vs. 67 ± 5 µmol/kg·min, respectively; P < 0.005). Forearm glucose uptake was 51% lower in the IDDM patients than in the normal subjects during the low dose insulin infusion (25 ± 4 vs. 51 ± 6 µmol/kg·min; P < 0.005, IDDM vs. normal subjects) and 34% lower during the high dose insulin infusion (44 ± 4 vs. 67 ± 8, respectively; P < 0.05). The latter decrease was due to a lower glucose AV difference across the forearm in the patients with IDDM [1.1 ± 0.1 vs. 1.8 ± 0.1 mmol/L during low dose insulin infusion (P < 0.001 in IDDM vs. normal subjects); 1.5 ± 0.1 vs. 2.2 ± 0.2 mmol/L during the high dose insulin infusion (P < 0.01), respectively]. The rate of whole body glucose uptake was inversely correlated with the fasting plasma glucose concentration (r = -0.47; P < 0.01) and the body mass index (r = - 0.40; P < 0.05) within the group of IDDM patients, but not with parameters such as age (r = -0.33; P = NS) or mean arterial blood pressure (r = -0.23; P = NS).
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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In previous studies addressing the impact of autonomic neuropathy on hemodynamic responses to insulin, patients with IDDM were classified based on symptoms of autonomic neuropathy (4, 12, 13). In the present study we examined autonomic function as a continuous variable, which also enabled detailed analysis of the sympathetic and parasympathetic components of autonomic function. With respect to the ability of the various autonomic function tests to measure sympathetic vs. vagal influences on hemodynamic parameters, it is generally agreed that efferent vagal activity is the major contributor to the HF component (29) and to the E/I ratio (30). The HF component specifically responds to stimuli such as vagotomy, muscarinic receptor blockade, and electrical vagal stimulation (31, 32, 33). Interpretation of the LF component is more controversial, which is why we classified LF as well as the Valsalva ratio (19) as mixed tests, measuring both sympathetic and vagal influences on heart rate control (29). The integrity of the forearm vasoconstrictive response to cold immersion of the contralateral forearm is dependent upon a reflex arc. The latter consists of cold-induced afferent nerve impulses, which are transmitted via small myelinated and unmyelinated sensory fibers involved in exteroception to the thermotactic center in the hypothalamus (34), and of efferent stimuli transmitted along sympathetic fibers, which cause vasoconstriction (35). Thus, this test may not purely reflect the degree of sympathetic denervation, but has the advantage of providing a direct and insulin-independent measure of the impact of peripheral (sensory and autonomic) neuropathy on vascular function. The changes in blood pressure induced by orthostasis and handgrip represent classic measures of sympathetic function, but suffer from poorer sensitivity than the E/I ratio or the cold pressor test (19). This was also evident in the present study, in which the IDDM patients had an abnormal result in cold pressor test, but did not differ significantly from the normal subjects with respect to the results of the handgrip or orthostasis tests.
The finding of significant inverse correlations between measures of sympathetic nervous function and forearm vascular resistance with the insulin-induced hemodynamic responses represents the first demonstration of a direct association between sympathetic function and a hemodynamic response to insulin in patients with IDDM. As discussed above, insulin has two seemingly opposite hemodynamic effects, one of which involves sympathetic activation and another that can be blocked by inhibiting NO synthesis in normal subjects. Patients with IDDM are characterized by impaired, rather than enhanced, endothelium-dependent vasodilation (22, 36, 37). It is therefore unlikely that the significantly greater fall in forearm vascular resistance in response to insulin in the IDDM than the normal subjects can be attributed to the NO-dependent component in insulininduced vasodilation. Consequently, we interpret the excessive insulin-induced fall in forearm vascular resistance to reflect the lack of a sympathetic counteractive response in IDDM patients with autonomic neuropathy.
Regarding changes in heart rate in previous studies, Takata et al. (12) found no change in heart rate by insulin and no differences in either resting heart rates or heart rates during hyperinsulinemia between patients with and without autonomic neuropathy, whereas Porcellati et al. (13) found greater increases in patients with than in those without autonomic neuropathy. In the present study, resting heart rate was increased, in keeping with a defect in vagal heart rate control (38). We found an insulin-induced increase in heart rate in normal subjects and significant blunting of this response in the patients with IDDM. Use of a low (4 IU) insulin dose, perhaps insufficient to increase heart rate significantly (3), in the studies of Takata et al. (12) and Porcellati et al. (13) might explain the lack of an insulin effect on heart rate. Alternatively, the lack of an increase in heart rate might have been due to diabetes, as no normal subjects were included in the latter two studies (12, 13). The blunting of the heart rate response to insulin in the IDDM patients correlated with measures of vagal heart rate control, including the E/I ratio and HF, but not with measures of sympathetic nervous function. These data suggest that failure of the heart rate to increase after insulin administration was a consequence of defective baroreflex function rather than of blunted stimulation of the sympathetic nervous system by insulin.
The IDDM patients exhibited significant resistance to insulin stimulation of glucose uptake at the level of the whole body and across forearm tissues. This defect was unrelated to the abnormal hemodynamic responses to insulin or to the degree of autonomic dysfunction. Although it has been suggested that defects in insulin’s hemodynamic effects might per se cause insulin resistance, studies directly testing this hypothesis have not supported the idea that a change in blood flow per se can alter glucose uptake. Thus, increases in limb blood flow induced by adenosine (39) or bradykinin (40) during hyperinsulinemia do not change glucose uptake. Although a decrease in leg blood flow caused by NG-monomethyl-L-arginine has been reported to decrease glucose uptake, this result may be questioned because NG-monomethyl-L-arginine does itself decrease glucose uptake in muscle tissue under in vitro conditions (41, 42).
We conclude that patients with IDDM and autonomic dysfunction are characterized by alterations in the hemodynamic effects of insulin. These include blunted changes in heart rate and blood pressure and an excessive fall in forearm vascular resistance. Both impaired vagal heart rate control and sympathetic denervation seem to contribute to these defects and may explain why hypotension after an insulin injection may be a symptom of autonomic neuropathy. Impaired hemodynamic regulation of insulin cannot account for resistance to insulin stimulation of glucose uptake, which can be attributed to a defect in cellular glucose extraction. As both autonomic neuropathy (43) and cellular insulin resistance (44, 45) appear to be causally linked to chronic hyperglycemia, improvement of glycemic control might reverse both problems.
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Acknowledgments |
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Footnotes |
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Received June 11, 1997.
Revised September 11, 1997.
Accepted October 10, 1997.
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References |
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) and patients with IDDM (•).