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The Journal of Clinical Endocrinology & Metabolism Vol. 83, No. 9 3190-3193
Copyright © 1998 by The Endocrine Society

Original Studies

Nocturnal Blood Pressure Elevation in Patients with Type 1 Diabetes Receiving Intensive Insulin Therapy Compared with that in Patients Receiving Conventional Insulin Therapy1

Sami T. Azar and Adel Birbari

Department of Internal Medicine, Divisions of Endocrinology (S.T.A.) and Nephrology (A.B.), American University Hospital-Medical Center and Chronic Care Center for Diabetes, New York, New York 10022

Address all correspondence and requests for reprints to: Sami T. Azar, M.D., F.A.C.P., Division of Endocrinology, American University Hospital, 850 3rd Avenue, 18th Floor, New York, New York 10022.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Studies have shown that type 1 diabetic patients may suffer from nocturnal elevation in blood pressure and that this elevation may be related to hyperinsulinemia. In this study we tested the hypothesis that tight type 1 diabetes control, which is usually accompanied by hyperinsulinemia and subclinical nocturnal hypoglycemia, may result in a higher rise in nocturnal blood pressure compared with conventional type 1 diabetes control. Eighteen patients treated with intensive insulin therapy (multiple daily injections; IIT) were compared with 18 patients treated with conventional insulin regimens (twice daily injections of regular and intermediate acting insulin; CIT). Both groups were matched for age, sex, duration of diabetes, body weight, body mass index, baseline daytime blood pressure, and microalbuminuria levels. Hemoglobin A1c was lower in the IIT group compared with that in the CIT group (8.1 ± 1.2% vs. 11.0 ± 3.2%; P < 0.01). The amount of insulin/body weight (units per kg) was higher in the IIT group than that in the CIT group (1.0 ± 0.2 vs. 0.7 ± 0.2 U/kg; P < 0.05). In all patients, a 24-h ambulatory blood pressure was recorded. The nocturnal diastolic blood pressure was higher in the IIT group (66 ± 9 mm Hg) than in the CIT group (55 ± 4 mm Hg; P < 0.01). The nocturnal decline in both systolic and diastolic blood pressure was lower in the IIT group (7 ± 5 and 6 ± 4 mm Hg, respectively) compared with that in the CIT group (13 ± 6 and 16 ± 6 mm Hg, respectively; P < 0.01). The nocturnal heart rate was higher in IIT group than in the CIT group (81 ± 12 vs. 67 ± 9/min; P < 0.05). These findings show that the intensive insulin therapy regimen may have a more deleterious effect than the conventional insulin therapy regimen on the nocturnal blood pressure of patients with type 1 diabetes.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
THE REPORT of the Diabetes Control and Complication Trial Research Group (1) has established the long term benefits of intensive insulin therapy aimed at near normalization of glucose levels in insulin-dependent diabetes mellitus (IDDM). To prevent or delay microvascular and neuropathic complications of diabetes, this therapeutic approach has been recommended for (2) and is instituted in the management of a number of patients with IDDM. Unfortunately, the frequency and the severity of hypoglycemia are increased in such regimens (1, 3). Intensified insulin treatment aimed at restoring glycemia as close to normal as possible was found to lead to further deterioration of hypoglycemic counterregulation and sympathetic unawareness of hypoglycemia (4, 5, 6, 7). In both healthy subjects and IDDM patients, a brief period of moderate hypoglycemia reduces hormonal responses and symptoms during experimentally induced hypoglycemia the following day (8, 9). A recent study concluded that intensively treated IDDM patients are resistant to changes in cortical-evoked potentials induced by mild hypoglycemia (10). This may explain why intensively treated IDDM counterregulate and experience hypoglycemic symptoms at a lower glucose level than conventionally treated patients.

IDDM and elevated blood pressure have been found to be associated in several clinical studies, and hyperinsulinemia was believed to be the cause of the hypertension (11, 12, 13, 14, 15). However, some studies have demonstrated that the apparent correlation between hyperinsulinemia and elevated blood pressure was actually nonsignificant. Peters et al. (16) have shown that type 1 diabetic patients may suffer from nocturnal elevation in blood pressure and that this elevation is not related to hyperinsulinemia but to high serum catecholamines. The Diabetes Control and Complication Trial Research Group study concluded that tight diabetes control with intensive insulin treatment (more than three injections per day) reduced the incidence of most complications of diabetes (1), and in its primary prevention cohort, it showed a slightly higher daytime systolic blood pressure in the intensively treated group (17).

We hypothesize that tight diabetes control, which may be accompanied by subclinical nocturnal hypoglycemias and a high serum catecholamine level, may result in a rise in nocturnal blood pressure in type 1 diabetics on intensive insulin therapy. We studied 24-h ambulatory blood pressure (AMBP) in nonobese normoalbuminuric IDDM patients treated with the twice a day conventional insulin therapy (CIT) and those treated with intensive insulin therapy (IIT).


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Subjects

A total of 36 IDDM patients were studied. Eighteen patients were treated with intensive insulin therapy (multiple daily injections) for at least 6 months, and 18 patients were treated with conventional insulin regimens (twice daily injections of regular and intermediate acting insulin) for at least 6 months. They were eligible for study if their disease duration was more than 1 yr, they were not hypertensive (morning blood pressure <130 mm Hg systolic and <80 mm Hg diastolic), they had no symptoms or physical signs of autonomic neuropathy, they were receiving no medications other than insulin, and they had no acute illness. The clinical characteristics of the patients are shown in Table 1Go. All subjects gave consent to the study.


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  		Table 1. Clinical characteristics of study subjects

 
Methods

All patients had an AMBP recorded over a period of 24 h. AMBP was recorded at 30-min intervals from 0900–0900 h by means of an oscillometric AMBP recorder (SPACELABS 90202, Redmond, WA). Daytime and nighttime blood pressures were computed. Daytime included values between 0600–2200 h. Nighttime included values between 2200–0600 h.

All patients followed their usual insulin regimen. Blood glucose levels were determined four times during the 24-h AMBP (before each meal and at bedtime). None of the patients had symptoms suggestive of hypoglycemia or had a blood glucose level lower than 50 mg/dL during the 24-h AMBP.

Statistical analysis

Data are reported as the mean ± SD. Scheffe’s multiple comparison test was used for analysis. P < 0.05 was accepted as statistically significant. The sample size of our study was sufficiently large to detect a 6-mm Hg difference in blood pressure at a power of 0.8.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Diabetes control results

Hemoglobin A1c was lower in the IIT group compared with the CIT group (8.1 ± 1.2% vs. 11.0 ± 3.2%). The amount of insulin per body weight (units per kg) was higher in the IIT group than in the CIT group (1.0 ± 0.2 vs. 0.7 ± 0.2 U/kg). The frequency of reported weekly hypoglycemias was significantly higher in the ITT group than in the CIT group (3.0 ± 1.8 vs. 0.7 ± 0.8; P < 0.01; Table 2Go).


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  		Table 2. Diabetes control, daily insulin requirement, and frequency of hypoglycemia

 
AMBP results

The nocturnal diastolic blood pressure was higher in the IIT group (66 ± 9 mm Hg) than in the CIT group (55 ± 4 mm Hg). The nocturnal systolic blood pressure was not significantly higher in the IIT group. The nocturnal decline in both systolic and diastolic blood pressure was lower in IIT group (7 ± 5 and 6 ± 4 mm Hg, respectively) than that in the CIT group (13 ± 6 and 16 ± 6 mm Hg, respectively). The nocturnal mean arterial blood pressure was also higher in the IIT group compared with the CIT group (82 ± 11 vs. 72 ± 5). The nocturnal heart rate was higher in IIT group compared with CIT group (81 ± 12 vs. 67 ± 9/min). The daytime systolic blood pressure, diastolic blood pressure, and heart rate were similar in both groups (Table 3Go).


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  		Table 3. Ambulatory blood pressure monitoring

 

   Discussion
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 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
These results provide clear evidence that AMBP was different between IDDM patients receiving IIT and those receiving CIT. In the patients undergoing the IIT regimen, the physiological nocturnal decline in systolic and dystolic blood pressure was diminished and less than that in the patients undergoing the CIT regimen. There was, however, no difference between the mean AMBP of both groups during the day.

In normal individuals, one of the important findings of AMBP is the pronounced diurnal rhythm. Blood pressure tends to be higher in the morning, lower at night, and at its nadir during sleep, when there is more than a 10% dip in both systolic and diastolic blood pressure. A blunted nocturnal decline in arterial blood pressure has been demonstrated both in type 1 (18, 19) and type 2 diabetes (20). However, this is the first report that looks at the behavior of the diurnal changes in blood pressure in the type 1 diabetics receiving IIT compared with those in the type 1 diabetics receiving CIT. In nondiabetic subjects, the lack of nocturnal dip of blood pressure is associated with left ventricular hypertrophy (21, 22), enhanced cardiovascular complications, and retinopathy (22, 23). Hypertensive patients lacking this decline are also at increased risk of cardiovascular morbidity (24). This indicates that a diminished nocturnal fall in blood pressure in type 1 diabetics receiving intensive insulin therapy is a critical clinical finding. Previous studies established not only a blunted nocturnal blood pressure decline (18, 19), but also AMBP elevations during the day in normoalbuminuric type 1 diabetics (25). In this study we did not find any statistical difference in the daytime blood pressure between the two groups, which implies that the lack of the nocturnal dip in blood pressure may be independent of an overall tendency toward hypertension in these patients. These changes in AMBP seem to be consistent and reproducible with minimal intraindividual variability (19, 21, 22, 24). For instance, four of our patients had a repeat 24-h AMBP with essentially no change in daytime and nighttime BP readings.

Obesity is a known independent risk factor for hypertension in diabetic and nondiabetic patients of all ages (26, 27, 28, 29, 30). In our study, the two groups of patients were matched with respect to body mass index. Multivariate analysis revealed no correlation between the daytime blood pressure or nocturnal blood pressure and the body mass index.

One may speculate that in the IIT group, with or without a relative state of nocturnal hyperinsulinemia, a relative state of hypoglycemia could have occurred that resulted in alterations of sleep and consequently affected the nocturnal blood pressure. However, this possibility is unlikely because none of the patients in either group reported being awakened by hypoglycemia or by any other event during the night of AMBP. In this study, a relationship between the nocturnal drop in blood glucose and the nocturnal drop in blood pressure was not assessed, as this would have involved blood glucose monitoring during sleeping hours, which could have awakened the patients and subsequently altered the blood pressure determination.

A recent study demonstrated a higher nocturnal blood pressure in NIDDM patients with microalbuminuria (31). However, in our study, there was no significant difference in the amount of 24-h microalbuminuria in both groups of patients.

Many studies have demonstrated that the apparent correlation between hyperinsulinemia and elevated blood pressure was actually nonsignificant. Peters et al. (16) have shown that this elevation in nocturnal blood pressure is not related to hyperinsulinemia but, rather, to high serum catecholamines. Moreover, several studies emerged, challenging the hypothesis of hyperinsulinemia as an independent risk factor for hypertension. Data from a population-based study in Pima Indians do not support a major role for insulin in determining the occurrence of hypertension or the regulation of blood pressure (30). Another strong evidence against a role of insulin in hypertension is made by a population-based study in the Pacific (26). A further argument against the role of insulin comes from data of insulinoma patients (32, 33). Like insulinoma patients and unlike type 2 diabetics, type 1 diabetics have hyperinsulinemia that is not primarily caused by an underlying state of insulin resistance (34, 35). We believe that at this stage the hyperinsulinemia-hypertension hypothesis is not yet confirmed.

Finally, we speculate that with or without a relative state of nocturnal hyperinsulinemia in the IIT group, a relative state of hypoglycemia may occur that results in a relative hypercatecholaminic state. This nocturnal rise in catecholamine levels may be the cause of this alteration in nocturnal blood pressure. The fact that both a higher nocturnal blood pressure and a higher nocturnal heart rate are present in the IIT group speaks for a higher nocturnal catecholamine level in this group of patients compared with that in the CIT group of patients. Several studies have been reported on catecholamine levels in diabetics. Del Rio et al. (36, 37) found increased 24-h urinary epinephrine in patients with uncomplicated IDDM. They proposed that adrenomedullary hyperactivity may be a compensatory reaction to a blunted norepinephrine response to stimuli that normally increase sympathetic outflow. Zadic et al. (38) showed increased catecholamine concentrations in the 24-h plasma pool of IDDM patients without diabetic complications. Nevertheless, all of these findings need further metabolic studies to explain them.


   Footnotes
 
1 This work was supported by Lebanese National Council for Scientific Research Grant 32411032319. Back

Received January 26, 1998.

Revised May 22, 1998.

Accepted June 1, 1998.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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