Departments of 1 Internal Medicine and 2 Pediatrics, and 3 The General Clinical Research Center, School of Medicine, and 4 School of Nursing, Yale University, New Haven, Connecticut 06520; and 5 Department of Internal Medicine, East Carolina University School of Medicine, Greenville, North Carolina 27858
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ABSTRACT |
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Insulin-induced
hypoglycemia occurs commonly in intensively treated patients with type
1 diabetes, but the cardiovascular consequences of hypoglycemia in
these patients are not known. We studied left ventricular systolic
[left ventricular ejection fraction (LVEF)] and diastolic [peak
filling rate (PFR)] function by equilibrium radionuclide angiography
during insulin infusion (12 pmol · kg1 · min
1) under
either hypoglycemic (~2.8 mmol/l) or euglycemic (~5 mmol/l) conditions in intensively treated patients with type 1 diabetes and
healthy nondiabetic subjects (n = 9 for each). During
hypoglycemic hyperinsulinemia, there were significant increases in LVEF
(
LVEF = 11 ± 2%) and PFR [
PFR = 0.88 ± 0.18 end diastolic volume (EDV)/s] in diabetic subjects as well as in
the nondiabetic group (
LVEF = 13 ± 2%;
PFR = 0.79 ± 0.17 EDV/s). The increases in LVEF and PFR were comparable
overall but occurred earlier in the nondiabetic group. A blunted
increase in plasma catecholamine, cortisol, and glucagon concentrations
occurred in response to hypoglycemia in the diabetic subjects. During
euglycemic hyperinsulinemia, LVEF also increased in both the diabetic
(
LVEF = 7 ± 1%) and nondiabetic (
LVEF = 4 ± 2%) groups, but PFR increased only in the diabetic group. In the
comparison of the responses to hypoglycemic and euglycemic
hyperinsulinemia, only the nondiabetic group had greater augmentation
of LVEF, PFR, and cardiac output in the hypoglycemic study
(P < 0.05 for each). Thus intensively treated type 1 diabetic patients demonstrate delayed augmentation of ventricular
function during moderate insulin-induced hypoglycemia. Although
diabetic subjects have a more pronounced cardiac response to
hyperinsulinemia per se than nondiabetic subjects, their response to
hypoglycemia is blunted.
left ventricular ejection fraction; diastolic function
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INTRODUCTION |
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INTENSIVE TREATMENT OF PATIENTS with type 1 diabetes slows the progression of microvascular complications but markedly increases the risk for insulin-induced hypoglycemia (11). Intensive treatment is also associated with blunted catecholamine responses to falling plasma glucose concentrations (1, 9, 20, 27), which might be expected to impair the cardiovascular response to hypoglycemia. Cardiac output normally increases with hypoglycemia (18), and diminished augmentation of cardiac output might impair the systemic delivery of glucose and other substrates.
The cardiovascular responses to hypoglycemia have been examined in healthy nondiabetic subjects after bolus intravenous administration of insulin (15, 16, 18). Severe insulin-induced hypoglycemia (1-2 mmol/l) leads to a transient increase in cardiac output, heart rate, and calculated left ventricular stroke volume, with an associated decrease in calculated systemic vascular resistance (18). Hypoglycemia also results in a significant increase in left ventricular ejection fraction (LVEF), indicating increased myocardial systolic function (15, 16). However, diabetic subjects were not included in those studies, so that the cardiac effects of insulin-induced hypoglycemia in this patient population remain unknown. In addition, these earlier studies did not assess the effects of hypoglycemia on diastolic function, which is an important component of cardiac performance (3).
Complicating the study of the cardiovascular effects of insulin-mediated hypoglycemia is the fact that cardiac function is also influenced by the effects of hyperinsulinemia per se. Even under euglycemic conditions, hyperinsulinemia increases cardiac output (4) through sympathetic activation (28, 29) and nitric oxide-mediated vasodilation in skeletal muscle (33). After an intravenous insulin bolus, LVEF increases before the onset of hypoglycemia in normal subjects (15). However, the non-steady-state conditions after bolus insulin injection make it difficult to determine the contribution of hyperinsulinemia to the hypoglycemic effects observed in these earlier studies. In addition, the contribution of hyperinsulinemia per se to the cardiac response to insulin-induced hypoglycemia in patients with diabetes is unknown.
The present studies were therefore undertaken to address the following questions concerning the cardiovascular effects of insulin-induced hypoglycemia. Do intensively treated type 1 diabetic patients augment their left ventricular function during moderate sustained insulin-induced hypoglycemia (glucose concentration ~2.8 mmol/l)? Is their response comparable to that of nondiabetic subjects? Do cardiac responses to hypoglycemia involve changes in both left ventricular systolic and diastolic function? Finally, what is the contribution of hyperinsulinemia per se to the hemodynamic responses to insulin-induced hypoglycemia in both diabetic and nondiabetic subjects?
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METHODS |
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Subjects.
Patients with intensively treated type 1 diabetes were recruited to
participate as subjects in this study. All had diabetes for >10 yr and
had achieved good glycemic control (hemoglobin A1c:
6.2 ± 1%). Of the nine diabetic subjects, seven were receiving treatment with a continuous-infusion insulin pump. The diabetic subjects had no other medical problems and were taking no medications (other than insulin) at the time of the study. Healthy, nondiabetic volunteers on no medications were also recruited to participate as
subjects in this study. All subjects refrained from vigorous exercise
and caffeine for 24 h before study. The clinical characteristics of the participants are summarized in Table
1. All diabetic subjects underwent
symptom-limited exercise treadmill testing with myocardial perfusion
imaging with the use of a 99mTc-sestamibi flowtracer (Du
Pont, N. Billerica, MA) to exclude the presence of occult myocardial
ischemia. Exclusion criteria included pregnancy, the
presence of significant systemic disease other than diabetes, and a
history of hypoglycemic seizures. The protocol was approved by the
Human Investigations Committee of the Yale University School of
Medicine and the Radiation Safety Committee of Yale-New Haven Hospital.
All participants gave informed, written consent before participating in
the study.
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Hyperinsulinemic clamps.
All subjects underwent two hyperinsulinemic clamp studies
(13) separated by 1 mo. The two studies consisted
of 1) a hyperinsulinemic (24 pmol · kg
1 · min
1 for 10 min
followed by 12 pmol · kg
1 · min
1 for 110 min) hypoglycemic (plasma glucose concentration ~2.8 mmol/l)
clamp study and 2) a hyperinsulinemic (24 pmol · kg
1 · min
1 for 10 min
followed by 12 pmol · kg
1 · min
1 for 110 min) euglycemic (plasma glucose concentration ~5 mmol/l) clamp study.
Subjects were fasted after midnight on the day before study. The
diabetic subjects were admitted to the Adult General Clinical Research
Center the evening before the study and received a low-dose intravenous
infusion of regular insulin (~3-12 nmol/h) to maintain a plasma
glucose concentration of 5-7.8 mmol/l until the start of the
experimental protocols. A retrograde catheter was inserted into a vein
in the dorsum of the right hand, which was positioned in a heated box,
for sampling of arterialized venous blood. A second intravenous
catheter was inserted in the right antecubital vein for the infusion of
insulin and glucose.
Analysis of baseline autonomic function. Baseline cardiac autonomic testing was performed at 7:30 AM before the clamp study. This included analysis of heart rate variability during deep breathing (26) and the Valsalva maneuver (23) as utilized by the Diabetes Control and Complications Trial study group (31). The standard deviation of the mean R-R interval and the circular mean resultant were calculated as indexes of parasympathetic cardiac function (17). The ratio of the longest interval after the performance of the Valsalva maneuver to the shortest interval during the maneuver was used as an index of overall autonomic function (23).
Assessment of left ventricular function. Left ventricular systolic and diastolic functions were quantified by serial equilibrium radionuclide angiography after in vitro red blood cell labeling with 925-1,110 MBq of 99mTc-pertechnetate (UltraTag, Mallinckrodt Medical, St. Louis, MO). Serial 5- to 7-min acquisitions were obtained in the left anterior oblique view. LVEF and peak diastolic filling rate (PFR) were computed using previously validated software (22). The end systolic and diastolic volumes (EDV) were determined using the Massardo count ratio method (24). Postacquisition processing of the scintigraphic data was performed in a blinded fashion. The coefficient of variation was 1.7% for the measurement of LVEF, 7.9% for PFR, and 12.8% for EDV.
Biochemical analysis. Plasma glucose concentrations were measured using an automated analyzer (Beckman Instruments, Fullerton, CA). Plasma concentrations of lactate and nonesterified fatty acids were measured by enzymatic analysis. Free plasma insulin was measured by a double-antibody radioimmunoassay (Diagnostic Systems Laboratories, Webster, TX). Plasma samples from diabetic patients were subjected to polyethylene glycol (PEG) precipitation before radioimmunoassay. Plasma epinephrine and norepinephrine were measured by high-performance liquid chromatography. Plasma cortisol and glucagon were measured by radioimmunoassay.
Statistical analysis.
All values are reported as means ± SE. Analyses of
2- and t-tests were used to compare baseline
data between the diabetic and nondiabetic groups. Analysis of variance
for repeated measures was used to determine differences in continuous
variables over the course of the experiment. After data were imported
into Statistical Analysis Software (SAS, Cary, NC), PROC MIXED was
used. For changes during euglycemia, three covariance structures were
tested: compound symmetric, autoregressive order 1, and unstructured.
Because of unevenly spaced data during hypoglycemia, spatial power law,
unstructured, and compound symmetric covariance structures were run.
The model with the covariance structure with the largest values of
Akaike's Information Criterion and Schwarz' Bayesian Criterion was
chosen to obtain estimates of the effects of patient group, time, and the interaction of patient group and time. A value for
P < 0.05 was considered statistically significant.
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RESULTS |
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Subject characteristics. The subjects with and without diabetes were well matched with respect to age, sex, body mass index, heart rate, blood pressure, resting LVEF, and resting PFR (Table 1). Although there was a trend toward a higher baseline cardiac output in the nondiabetic group, the difference was not statistically significant (P = 0.08). There were no significant differences in the baseline (resting) values for LVEF, PFR, or cardiac output between the hypoglycemic and euglycemic studies in either group. There were no differences in baseline autonomic function, as evidenced by similar standard deviations and variations in the R-R interval and a similar Valsalva ratio in the diabetic and nondiabetic groups (Table 1).
Responses to hyperinsulinemic hypoglycemia.
During hyperinsulinemic hypoglycemia, insulin infusion (12 pmol · kg1 · min
1)
increased the plasma insulin concentration from 76 ± 15 to
589 ± 92 pmol/l in the diabetic group and from 58 ± 8 to
947 ± 82 pmol/l in the nondiabetic group (P < 0.05 vs. diabetic group). The lower free insulin concentrations in the
diabetic subjects may reflect insulin binding by insulin antibodies and
the PEG plasma precipitation. The plasma glucose concentration profiles were nearly identical during the hypoglycemia protocol in both groups
(Fig. 1). However, the steady-state
glucose infusion rate required to maintain hypoglycemia during the last
30 min of the study was 14.8 ± 4.0 µmol · kg
1 · min
1 in the
diabetic group and only 7.7 ± 1.7 µmol · kg
1 · min
1 in the
nondiabetic group (P < 0.05, Fig. 1). Hyperinsulinemic hypoglycemia increased the plasma lactate concentration in both diabetic and nondiabetic subjects (Fig. 1), although to a lesser extent
in the diabetic group (P < 0.05). Skeletal muscle
glycogen is mobilized during hypoglycemia (7), and the
smaller increase in the lactate concentration in the diabetic group may
reflect decreased epinephrine-stimulated glycogenolysis. In addition, the plasma nonesterified fatty acid concentration decreased in both
groups during hyperinsulinemic hypoglycemia (Fig. 1).
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Responses to hyperinsulinemic euglycemia.
To determine the contribution of hyperinsulinemia per se to the
increases in systolic and diastolic cardiac function observed during
hypoglycemia, left ventricular function was also examined during a
hyperinsulinemic euglycemic clamp in the same subjects. As in the
hypoglycemic clamps, despite identical insulin infusions, the plasma
free insulin concentration increased less in the diabetic group (from
64 ± 7 to 504 ± 93 pmol/l) than in the nondiabetic group
(from 56 ± 5 to 905 ± 65 pmol/l) (P < 0.05 vs. diabetic group). The steady-state glucose infusion rate at the end
of the study was 34.4 ± 3.5 µmol · kg1 · min
1 in the
diabetic group and 43.8 ± 3.5 µmol · kg
1 · min
1 in the
nondiabetic group (P < 0.05, Fig. 1). The lower
requirement for exogenous glucose in the diabetic group primarily
reflected the relative insulin resistance observed in type 1 diabetic
subjects (12). Hyperinsulinemia in the setting of
euglycemia did not significantly affect the plasma concentrations of
epinephrine, norepinephrine, cortisol, or glucagon in either group
(Fig. 2).
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DISCUSSION |
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The present study is the first to assess the cardiovascular responses to insulin-induced hypoglycemia in type 1 diabetic subjects and contains several novel observations. The diabetic subjects had a significant augmentation of systolic and diastolic left ventricular function during hyperinsulinemic hypoglycemia, which together with an increase in heart rate resulted in a substantial increase in cardiac output. Overall, the changes in cardiac function during hypoglycemia were similar in magnitude but were delayed compared with those observed in nondiabetic subjects. However, in the case of the diabetic subjects, the response to insulin-induced hypoglycemia largely reflected the effects of hyperinsulinemia per se on cardiac function. In contrast, in the nondiabetic subjects, although hyperinsulinemic euglycemia modestly increased LVEF, there was significant further augmentation of LVEF and other cardiac parameters during hyperinsulinemic hypoglycemia. Thus these results suggest that the cardiac responses to hypoglycemia per se are diminished in intensively treated patients with type 1 diabetes.
The current studies examined the effects of steady-state moderate hypoglycemia during continuous infusions of insulin and glucose in both diabetic and nondiabetic subjects. In contrast, previous studies have analyzed the cardiovascular responses following the bolus administration of insulin and did so only in nondiabetic subjects (15, 16, 18). Coincident with the nadir of the blood glucose concentration in the earlier studies was a transient 25% increase in the LVEF (15, 16), which is twofold greater than that seen in the present study but occurred at a much more extreme degree of hypoglycemia (~1 mmol/l).
Recent studies have also documented an increase in LVEF during euglycemic insulin administration in nondiabetic subjects (25). In the current study, there were statistically significant increases in LVEF in the diabetic and nondiabetic groups during euglycemic hyperinsulinemia. Interestingly, the insulin-induced change in LVEF tended to be lower in the nondiabetic subjects, despite higher plasma insulin concentrations in that group. It is possible that the differences in the hemodynamic response to insulin between the diabetic and nondiabetic groups might have been even more pronounced if the insulin concentrations had been identical during the infusions.
Diastolic performance was not assessed during hypoglycemia in previous studies. The PFR is an index of left ventricular filling during diastole and is an important determinant of cardiac performance (3). The PFR reflects not only the rate of active myocardial relaxation, which is increased by adrenergic stimulation, but is also influenced by preload, heart rate, afterload, and the intrinsic compliance of the left ventricle (5, 6). Although patients with diabetes mellitus may have diastolic dysfunction (10, 14, 19), the subjects included in the present study had normal baseline values for PFR and were able to increase their PFR during hypoglycemia, although the increase was somewhat delayed in the diabetic group. This augmentation in diastolic filling enhances the ability of the left ventricle to fill more rapidly at higher heart rates, thereby maintaining left ventricular end diastolic volume and enabling the heart to increase the stroke volume and cardiac output during hyperinsulinemic hypoglycemia. In contrast to the augmentation of PFR during hypoglycemia, euglycemic hyperinsulinemia caused a significant increase in PFR only in the diabetic group.
In this study, we utilized a moderate insulin dose (12 pmol · kg1 · min
1) to
ensure that hypoglycemia would be sustained during the study, particularly in the young, healthy nondiabetic subjects, who have a
more pronounced counterregulatory response to hypoglycemia. However,
because this dose of insulin augmented cardiac function, the specific
effect of hypoglycemia per se could only be defined by comparing the
results of the hypoglycemic and euglycemic hyperinsulinemic studies
performed in the same individual. When the results of these studies are
compared (Table 2; Fig. 5), it is evident that the specific responses
to hypoglycemia are different in the diabetic and nondiabetic groups.
In the diabetic subjects, the effects of insulin-induced hypoglycemia
can be attributed largely to the effects of hyperinsulinemia per se,
because there was no significantly greater augmentation of function
during the hypoglycemic clamp compared with the euglycemic clamp. In
contrast, in the nondiabetic group, there were significantly greater
increases in LVEF, PFR, stroke volume, and cardiac output in the
hypoglycemic compared with the euglycemic study. Thus the augmentation
of cardiac function in response to hypoglycemia per se appears to be
blunted in diabetic subjects.
Previous studies have demonstrated that adrenal catecholamine release is blunted specifically during recurrent hypoglycemia (1, 8, 9, 20, 27). As expected, the intensively treated diabetic subjects in the present study had impaired counterregulatory responses to hypoglycemia, as reflected by the blunted rise in the plasma epinephrine, norepinephrine, cortisol, and glucagon concentrations. This impaired counterregulatory response accounts for the greater amount of exogenous glucose required during hyperinsulinemic hypoglycemia in the diabetic group and most likely results from decreased stimulation of hepatic gluconeogenesis and muscle glycogenolysis. On the basis of our findings, a diminished adrenomedullary response also delayed and attenuated the augmentation of cardiac function during hypoglycemia in the diabetic group.
The increase in cardiac function observed during euglycemic hyperinsulinemia likely reflects both insulin-mediated sympathetic activation (2, 28) and peripheral vasodilation (2, 21). The former mechanism increases cardiac contractility and heart rate, whereas the latter decreases left ventricular afterload, and both increase ejection phase indexes and cardiac output. Sympathetic activation leads to adrenomedullary epinephrine release and increased local cardiac sympathetic activity. However, as in previous studies, there was no change in the epinephrine concentration during euglycemic insulin infusions (28), suggesting that the increase in left ventricular contractile function during hyperinsulinemic euglycemia was not due to adrenomedullary release of epinephrine. Although the norepinephrine concentration tended to increase during euglycemic hyperinsulinemia in the present study, as in previous studies (28), changes in the plasma norepinephrine concentration provide only an indirect marker for cardiac sympathetic activation. Although direct measurement of neurosympathetic cardiac activity is not possible, it is likely that the increase in cardiac function during euglycemic hyperinsulinemia also reflects neurocardiac sympathetic activation.
The subjects in the present study had no evidence of coronary artery disease, hypertension, or autonomic neuropathy, all of which can affect left ventricular function and cardiac sympathetic function. Previous studies have demonstrated that type 1 diabetic patients have scintigraphic evidence of cardiac sympathetic dysinnervation based on altered 123I-labeled metaiodobenzylguanidine or [11C]hydroxyephedrine uptake, even in the absence of changes in standard autonomic testing (30, 32, 34). Although there was no evidence of cardiac autonomic neuropathy in the diabetic group on the basis of heart rate variability and standard autonomic testing, we cannot exclude the possibility that the diabetic patients in this study may have had early cardiac sympathetic dysinnervation. If present, dysinnervation might be responsible, in part, for the trend toward lower baseline hemodynamic parameters observed in the diabetic group. It is also possible that some degree of regional hyperinnervation (34) or denervation hypersensitivity might amplify the cardiac sympathetic response to hyperinsulinemia, contributing the more dramatic cardiac effects of hyperinsulinemic euglycemia observed in the diabetic group.
In clinical practice, diabetic patients may experience hypoglycemia at plasma concentrations of insulin that are lower than those used in the present study and have less cardiovascular effect than the dose utilized in our study. However, it is difficult experimentally to mimic the development of hypoglycemia seen in clinical practice, which is often unpredictable and involves a complex combination of excessive insulin administration (for the amount of food intake) and exercise. Nonetheless, the current study indicates that the response to hypoglycemia per se is diminished in intensively treated subjects with diabetes, and it is likely that the cardiac response of patients with diabetes to hypoglycemia would also be considerably less in the clinical setting.
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ACKNOWLEDGEMENTS |
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We gratefully acknowledge the contributions of Drs. David Maggs and Lee Marcus, as well as Edward Etkind, Patricia Gatcomb and the staff of the General Clinical Research Center, Yale University School of Medicine/Yale-New Haven Hospital, to the study.
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FOOTNOTES |
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This study was supported by a Clinical Research Award from the American Diabetes Association (L. H. Young) and by Grants DK-20495, RR-06022, R-1200, and M01-RR-00125 (General Clinical Research Center) from the National Institutes of Health.
Address for reprint requests and other correspondence: L. H. Young, Div. of Cardiovascular Medicine, Yale University School of Medicine, 333 Cedar St., 3 FMP, New Haven, CT 06520 (E-mail: lawrence.young{at}yale.edu).
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.
Received 23 March 2001; accepted in final form 10 July 2001.
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