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Ambulatory and exercise-induced blood pressure responses in type I diabetic patients and normal subjects
Diabetes Research and Clinical Practice, 3 (1987) 125-134
Elsevier
125
DRC 00120
Ambulatory and exercise-induced blood pressure responses in type I diabetic patients and normal subjects K w a m e Osei Department of Medicine, Division of Endocrinology, The Ohio State University, Columbus, OH 43210, U.S.A.
(Received 27 March 1986, revised received 20 June 1986, accepted 13 September 1986)
Key words: Blood pressure; Exercise;Ambulation;Type I diabetics
Summary We evaluated the ambulatory blood pressure (BP) readings during daily activities and compared the values with the casual office BPs in 12 type I diabetic patients and 12 age-matched, non-diabetic normal controls. The BP responses to 750 kpm/min exercise work load on bicycle ergometer were also evaluated in all the subjects. The mean ambulatory BPs were significantly higher in the diabetic patients compared with nondiabetic subjects. However, the ambulatory and casual office BPs were remarkably similar in each group. Mean peak exercise BPs were higher in the diabetics, but significantly so for diastolic BP (P < 0.05) and mean arterial pressure (MAP) (P < 0.01). The mean ambulatory MAP significantly correlated with the casual office MAP in both the diabetics (r = 0.75, P < 0.005) and non-diabetics (r = 0.58, P < 0.02). A significantly positive relationship (r = 0.87, P < 0.001) existed between the ambulatory and peak exercise MAP in the diabetics, but not in the non-diabetic subjects. The mean peak exercise BP responses were significantly (P < 0.01) higher in the diabetic patients with proliferative retinopathy vs. those with nonproliferative retinopathy. We conclude that casual office BPs reflect the ambulatory values in both diabetics and non-diabetics. Exaggerated BP responses to exercise are found in diabetic patients, especially in the presence of proliferative retinopathy. These findings are suggestive of possible defects in the cardiovascular, autonomic and autoregulatory mechanisms that maintain a normal MAP during daily stresses and exercise in the diabetic patients.
Introduction Diabetic nephropathy and retinopathy constitute the major chronic complications in type I diabetic Address for correspondence: Kwame Osei, M.D., N-If20 Doan Hall, 410 W. 10th Avenue,Columbus,OH 43210, U.S.A.
patients. Both are associated with high morbidity [1-3]. Even though the actual pathogenesis of diabetic microangiopathy is unknown, several factors such as diabetic control, hypertension and genetics have been implicated. Recent evidence indicates that hypertension (BP > 140/90 mm Hg) is a major risk factor in the pathogenesis of diabetic nephro-
0168-8227/87/$03.50 O 1987 ElsevierScience Publishers B.V. (Biomedical Division)
126
pathy since aggressive antihypertensive therapy has been reported to delay the progression of diabetic nephropathy [4-6]. However, it is uncertain whether reduction in elevated BP would result in similar delay in the progression of diabetic retinopathy. The interrelationships between hypertension and microangiopathy are more complex since the temporal relationships between these various parameters are ill-defined [7-12]. Several investigators have reported elevated basal BP (albeit subhypertensive) in type I diabetic patients when compared with age-matched controls [8,9,13]. In addition, type I diabetic patients have exaggerated BP responses to exercise compared with normal controls [8,13]. The latter findings have led to the speculation that these patients may have elevated BP under 'stresses' of daily activities. However, there is little data in the literature regarding the value of ambulatory BP recordings during daily activities in type I diabetic patients. It is also unknown whether the elevated ambulatory BP and/or episodic responses to stress have any relationships with the chronic diabetic complications. The purposes of the present study were 3-fold: (a) to document the ambulatory BP profile during normal daily activities and 'stresses', (b) to determine the relationship between ambulatory BP and casual office BP, and (c) to determine the association, if any, of ambulatory BP with diabetic complications in type I diabetic patients. We found that both ambulatory and casual office BPs were significantly higher in the type I diabetic patients compared with age-matched non-diabetic controls. In addition, exaggerated BP responses to exercise were found in diabetic patients with proliferative retinopathy when compared to those with non-proliferative retinopathy.
Patients, materials and methods Twelve type I diabetic patients (7 females, 5 males, age range 26-54 years) as defined by the National Diabetes Data Group Criteria [14] were studied. Twelve age-matched non-diabetic controls (10 females, 2 males, age range 22-53 years) with no fam-
ily history of diabetes in the first-degree relatives were recruited. The clinical characteristics of the subjects are shown in Table 1. All the subjects had direct fundoscopic examination with dilated pupils by an experienced ophthalmologist. An informed written consent approved by the Human Research Review Committee of the University was obtained from each subject after the risk entailed in the protocol had been thoroughly explained. Blood samples were obtained for measurements of glucose, glycosylated hemoglobin (HbA1), creatinine, BUN and electrolytes. 24 h urine samples were collected for protein and creatinine. Also, urine specimens were examined microscopically for sediments and casts and cultured for bacteria. They were all unremarkable. Renal biopsies were not done to rule out non-diabetic causes of renal disease. However, patients with heart disease, liver disease and history of renal disease not associated with diabetes were excluded from the study.
Study protocol Each subject was instructed to measure his/her BP and pulse rate (PR) at least 8 times during normal daily activities between 6 a.m. and 12 a.m. on 2 separate days using a semi-automated, patient-activated, digital BP monitor (Tycos R, model 7052-08) in the sitting position. These are subsequently designated ambulatory BP or pulse rates. The clock time was divided into 2 h segments, e.g. 6-8 a.m., 8-10 a.m., 10-12 a.m., etc. and a single reading was obtained in each time segment during the day. The digital BP readings by the monitor were compared to those of the conventional mercury sphygmomanometer using a standard (13 x 35 cm) cuff for adults. The difference between 10 separate readings using the 2 procedures (performed by the same person) was + 2 mm Hg. The phase V Korotkoff sounds - disappearance of sounds - was taken as the diastolic pressure. On a separate day, subjects were admitted to the clinical research center at 7 a.m. Electrocardiogram was obtained to rule out any cardiac arrhythmia or ischemic cardiac disease. After 30 min of rest in the sitting position, 3 baseline BP and PR were obtained at 10 min intervals. Each subject then in-
127 gested 250 ml of water starting at 8 a.m. at 1 h intervals for 4 h to ensure adequate hydration and diuresis. Subjects then performed a 20 min exercise in a sitting position on a bicycle ergometer at a work load of 750 kpm/min. BP and PR were recorded at 5 min intervals during the exercise. Subjects continued to ingest the measured volume of water hourly for the next 4 h. Urine samples for protein and creatinine were obtained at hourly intervals throughout the study period of 8 h. Serum and urine creatinine concentrations were measured by the Technicon Autoanalyser. Glycosylated hemoglobin (HbA~) was determined by the microcolumn chromatographic technique (Isolabs, Akron, OH). Urine protein was measured by the Coomassie brilliant blue method [15]. All values are presented as mean + SEM unless otherwise stated. The mean BP and PR readings were taken as the mean of 16 recordings. Mean arterial pressure (MAP) was calculated as diastolic BP and ]/3 pulse pressure. The diabetic patients with non-proliferative retinopathy were compared with those with proliferative retinopathy. Since fluorescein angiography was not performed in our study, diabetic patients with either background retinopathy or normal fundoscopic examination were categorized as the non-proliferative retinopathy group in the present study. The glomerular filtration rate (GFR) was calculated by the standard formula for endogenous creatinine clearance (UV/P). The functional G F R reserve was estimated as the difference between the mean baseline pre-exercise and post-exercise GFR values over the two 4 h periods. Statistical analyses were performed by two-tailed Student's paired and unpaired t-test, and analyses of variance where appropriate. Linear regression analyses and correlation coefficients were calculated by the least-squares method. A P value of less than 0.05 was considered statistically significant.
Table 1. The mean age, body weight, height and serum creatinine were similar in both groups. However, as expected, the mean 24 h urinary protein and HbA1 values were significantly higher in the diabetics compared with the non-diabetic subjects. The 24 h urinary protein exceeded the clinical nephropathic range in 3 diabetic patients (Nos. 3, 4, 6) and was within normal limits in the rest. The mean GFR values were significantly lower in the diabetic patients vs. non-diabetic subjects (77 + 8.8. vs. I07 + 9 ml/min, P < 0.05). Diabetic patients with non-proliferative retinopathy had GFR values similar to those with proliferative retinopathy. The ambulatory BP profiles during the daytime in both the diabetics and non-diabetics are shown in Fig. 1. Clearly, the diabetics had elevated mean systolic and diastolic BP values during the daily activities compared with the non-diabetics. Between 8 p.m. and 12 a.m., the systolic BP in the diabetics approached those of the non-diabetics, while the diastolic BP remained significantly different. The mean systolic BP, diastolic BP and MAP in both groups during the visit to office (casual) and am-
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129 TABLE 2 COMPARISON OF CASUAL OFFICE AND AMBULATORY BP A N D P U L S E R A T E IN T H E S I T T I N G POSITION IN D I A B E T I C P A T I E N T S A N D N O N - D I A B E T I C C O N TROLS" Diabetics (n = 12)
Non-diabetics (n = 12)
Casual Systolic BP ( m m Hg) 121 + 4.6(110-150)* Diastolic BP ( m m Hg) 82 4- 4 (60-98)** MAP ( m m Hg) 96 + 4 (77-110)*** Pulse rate (beats/min) 80 4- 5 (62-112)***
111 4- 3.4(110-140) 74 4- 2 (60-80) 87 4- 2 (73-100) 73 + 3 (64-100)
Ambulatory Systolic (mm Hg) 125 4- 5 (98-149)* Diastolic ( m m Hg) 82 4- 3 (62-99)** MAP (mm Hg) 96 4- 3 (74-115)*** Pulse rate (beats/min) 84 4- 3 (71-96)***
II0 4- 3 (96-136) 70 4- 3 (59-96) 83 4- 3 (71-102) 73 4- 2 (62-81)
Values are means 4- SEM, (range) o f 16 readings between 6 a.m. and 12 a.m. on 2 separate days. No significant differences were seen between the ambulatory and casual office BP and PR recordings. * P < 0.025, diabetics vs. non-diabetic controls; ** P < 0.01, diabetics vs. non-diabetic controls: *** P < 0.005, diabetics vs. non-diabetic controls.
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bulation are shown in Table 2. Mean ambulatory and casual office systolic BP, diastolic BP and MAP were significantly higher in the diabetic patients compared with those of the non-diabetic subjects. Similarly, the ambulatory PR were higher in the diabetic vs. non-diabetic subjects (80 + 4.8 vs. 73 + 3, P < 0.05). However, when the ambulatory and casual office BP and PR readings were compared in each group, values were remarkably identical (Table 2). During the 20 min exercise period, the mean peak systolic BP increased significantly (P < 0.01) in both the diabetic and non-diabetic subjects when compared with the baseline pre-exercise values (Fig. 2A). Even though the peak exercise systolic BP values were higher in the diabetics vs. non-diabetics, the differences were not statistically significant. In contrast, the mean diastolic BP significantly (P < 0.05) increased in the diabetic patients when compared with the baseline and those of the non-diabetic subjects (Fig. 2B). In fact, except in one subject whose diastolic BP slightly increased, the diastolic BPs either decreased or remained unchanged during the exercise in the non-diabetic group. Consequently, the calculated MAP values were higher (P < 0.01) in the diabetic patients when compared with the pre-exercise values and those of the nondiabetic subjects (Fig. 2C). In 4/12 diabetic patients (Nos. 7, 8, I0, 12), the absolute BP responses were
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BLOOD PRESSURE RESPONSES D U R I N G EXERCISE IN TYPE I DIABETIC PATIENTS W I T H A N D W I T H O U T P R O L I F E R A T I V E RET1NOPATHY"
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Fig. 3. Correlations between ambulatory mean arterial pressure (MAP) and casual office and peak exercise-induced MAPs in diabetic patients and non-diabetic subjects.
similar to those of the non-diabetic controls. Mean peak PR during the exercise were similar in both groups despite significantly higher pre-exercise values in the diabetic patients (Fig. 2D). The relationships between ambulatory MAP and casual office and peak, exercise-induced MAP are shown in Fig. 3. Significant correlations existed between ambulatory and casual MAP values in both the non-diabetlc subjects (r = 0.58, P < 0.02, Fig. 3A) and diabetic patients (r = 0.75, P < 0.005, Fig. 3B). No relationship was found between the ambulatory MAP and peak exercise MAP values (r = 0.04, P = NS, Fig. 3C) in the non-diabetic subjects. In contrast, a highly significant correlation (r = 0.85, P < 0.001, Fig. 3D) existed between the ambulatory MAP and peak exercise MAP in the diabetic patients. Also, a significant relationship existed between the ambulatory MAP and proteinuria (r = 0.77, P < 0.005) in the diabetic patients as a group, but
not in the non-diabetic subjects. However, when the 3 patients with clinical nephropathic range of proteinuria (greater than 500 mg) were excluded, the significant correlation disappeared. We did not find any correlation between ambulatory BPs (systolic, diastolic and MAP) and G F R , HbA1, duration of diabetes, age of onset of diabetes and daily insulin dosage in the diabetic patients. Mean basal BP responses were slightly higher in patients with proliferative retinopathy vs. non-proliferative retinopathy, but values were not statistically different (Table 3). However, during exercise, significantly higher diastolic (P < 0.025) and MAP (P < 0.025) peak responses were seen in diabetic patients with proliferative retinopathy compared with patients with non-proliferative retinopathy, irrespective of the presence or absence of clinical proteinuria (Table 3). The systolic BP differences were not statistically significant. The mean functional G F R reserve estimated as the increments or decrements from the baseline values after the exercise were similar between the diabetic patients and non-diabetic subjects (data not shown).
131 Discussion
The role of hypertension in both diabetic nephropathy and retinopathy is now well established [2,3,9,15-17]. In the initial phase of microangiopathy, hemodynamic alterations seem to feature prominently in the genesis of these complications [11,12]. Indeed, Hostetter et al. [16] have demonstrated an increased renal plasma flow, GFR and intraglomerular capillary pressure using a single nephron micropuncture technique in early diabetic nephropathy. Likewise, some investigators have demonstrated increased retinal blood flow in early diabetic retinopathy. Even though the specific etiologies of various lesions in different target organs remain elusive, the concomitant occurrence of both diabetic retinopathy and nephropathy, in part, supports a common pathogenetic mechanism. Indeed, diabetic nephropathy is almost invariably associated with retinopathy and the absence of the latter makes the diagnosis of the former less likely. Recent attention has focused on the temporal relationship between hemodynamic changes and diabetic microangiopathy [18-20]. Mogensen et al. [7] have observed that patients with incipient nephropathy who progress to clinical nephropathy have elevated diastolic BP at the initial presentation in addition to higher microalbuminuria (greater than 15/~g/min). Knowler et al. [20] have reported higher incidence of retinal hemorrhages and exudates in diabetic Pima Indians with elevated blood pressure. Similarly, we have recently demonstrated a significant association between elevated brachial and retinal MAP to stress in type I diabetic patients but not in the age-matched, normal controls [21]. Furthermore, Berkman and Rifkin [22] have demonstrated that renal artery stenosis rendered protection from diabetic glomerulosclerotic lesions in the ipsilateral kidney at autopsy in a diabetic patient. Similarly, Slusher et al. [23] observed a partial protection from diabetic retinopathy by ipsilateral carotid artery stenosis in a diabetic patient as assessed by fluorescein angiography. Whether these associations are related to the pressure head and/or toxic factors circulating in the plasma of diabetic patients has not been resolved.
Availability of a simple, non-invasive, digital BP monitor to measure frequent BPs as an outpatient would be invaluable in the care of diabetic patients. This is important since casual office BP readings have been reported to be elevated in diabetic patients compared with the age-matched controls [8,13] and is in agreement with the present findings. In addition, there is controversy regarding the use of casual office BP as a true reflection of daily BP in both diabetic and non-diabetic populations [24-27]. It is believed by most investigators that the mere office visit and presence of the doctor may induce anxiety with an associated elevation in BP which has been previously referred to as 'white coat' or 'doctors office' hypertension [26]. However, recent studies by Drayer et al. [27] using an expensive Del Mar Avionic (Irvine, CA) ambulatory BP monitor in normotensive non-diabetics demonstrated a significant relationship between casual office and ambulatory BPs. Of great importance is that Perloffet al. [25] have reported that the ambulatory BP is a better predictor of risk of cardiovascular and cerebrovascular events compared with the casual office BP. We are not aware of similar studies in the diabetic patients. This issue is noteworthy since long-term diabetic complications may be associated with higher mean perfusion pressures (albeit within normal range) during the daily stresses in type I diabetic patients and the latter may play a role in the accelerated cardiovascular and cerebrovascular events found in diabetics. Using a simple, inexpensive, ambulatory, digital BP monitoring system, we have demonstrated that ambulatory BPs correlate significantly with the casual office readings in both diabetic and non-diabetic subjects. However, the association was much stronger in the diabetic patients. Furthermore, the diabetic patients had significantly higher ambulatory and casual BPs compared with those of the non-diabetic subjects. Indeed, the ambulatory and casual BP values were similar in each group. By the current classification of the National Committee on Detection, Evaluation and Treatment of High Blood Pressure [28], the mean ambulatory BPs of 121/82 mm Hg and 111/74 mm Hg attained in both the diabetics and non-diabetics, respectively, are
132 considered to be within normal limits. However, whether the current recommendation with upper cut-off limits of 140/90 mm Hg for normal BP should be applied to diabetic patients with abnormal capillary basement membrane thickness and increased leakiness of plasma proteins [17,29], has not been satisfactorily addressed. It should be noted that, according to the Framingham studies [30], there is a continuum of increasing cardiovascular and cerebrovascular morbidity and mortality associated with BP and these are accelerated in diabetics. Thus, the significantly higher BPs noted in the diabetic patients compared with the agematched controls may be biologically significant and require further elucidation. In this regard, we found a significantly positive relationship between the ambulatory MAP and proteinuria in the diabetic patients taken as a group while no such association existed in non-diabetic subjects, which is in agreement with previous reports [4]. In addition, diabetic patients with proliferative retinopathy had higher mean ambulatory and basal BP recordings compared with those with non-proliferative retinopathy. Several reports have suggested that type I diabetic patients have exaggerated BP responses to stress and exercise [8,10,13]. This was confirmed in our study. During the submaximal exercise, the peak systolic BP was higher in the diabetic patients vs. the non-diabetic subjects, but mean values were not statistically different. However, the diastolic BP and MAP were significantly higher in the diabetic patients. Of great interest is that the ambulatory MAP correlated significantly with the peak exercise MAP only in the diabetic patients but not in the non-diabetic subjects. It is noteworthy to mention that these findings are similar to the retinal artery MAP responses to cold pressor test in diabetic and non-diabetic subjects we reported previously [21]. Furthermore, the presence of proliferative retinopathy was associated with significantly higher BP responses compared with patients with non-proliferative retinopathy. Thus, it appears that some type I diabetic patients have lost the cardiovascular, autonomic and autoregulatory mechanisms required to maintain a normal mean perfusion pres-
sure in the target organs. These abnormalities may play a role or may be associated with the macroand microangiopathy found in diabetes [31,32]. The exact cause of these abnormal BP responses in the type I diabetic patients is unknown but several possibilities should be considered. Firstly, it may be due to the abnormal metabolic state found in diabetes per se. However, we did not find any relationship between serum glucose, HbA~, and ambulatory BP or peak BP responses to exercise in our study. Secondly, increased basement membrane thickness and vascular wall changes such as arteriolar hyalinosis may be involved [32]. Thirdly, hypersensitivity to various pressor hormones has been reported in some diabetic patients. Indeed, Rhie et al. [33] and Christlieb et al. [34] have reported abnormal retinal and brachial artery responses, respectively, to i.v. infusions of norepinephrine and angiotensin II especially in patients with diabetic retinopathy and nephropathy. In addition, autonomic nervous derangement is not uncommon in type I diabetic patients with and without microangiopathy. Similar to our previous report [21], we observed that 4 of our diabetic patients (Nos. 7, 8, 10 and 12) in the present study with minimal increases in their MAP during the exercise, had either mild or no background retinopathy. In contrast, significantly higher mean peak MAP responses occurred in the diabetic patients with proliferative retinopathy irrespective of the presence or absence of clinical nephropathy. It is, therefore, tempting to postulate that episodic or sustained increases in BP such as during hypoglycemic reaction, strenuous exercise and other sympathetic stimulation may be associated with diabetic microangiopathy. Finally, it is also possible that the exaggerated BP responses in some of these patients may, in part, be secondary to the severity of the microangiopathy per se. Our subjects found the frequent ambulatory BP recordings acceptable and non-intrusive. We should note that patient-recorded BPs have several advantages over doctor-recorded measurements, among the most important being greater diagnostic accuracy. The closer correlations of ambulatory BP with left ventricular hypertrophy and those between stress and cardiovascular events argue strongly in
133 favor of such non-invasive ambulatory BP recordings as suggested by Perloff and his associates [25]. The ambulatory BP may also prove to be a valuable tool in the early detection of labile hypertension and in judging the effects of antihypertensive therapy especially in diabetic patients. We found both the a m b u l a t o r y and casual office BPs to be similar in each group during our study which is in agreement with some previous studies [24] but not others [35]. We believe both approaches should be complementary. Even though an inherent error may occur during the positioning of the microphone of the Tycos BP cuff, our subjects had no difficulty in palpating the pulsations of the brachial artery when reexamined by the investigators. Furthermore, we excluded patients with cardiac arrhythmia which may cause inaccurate readings. O f practical value is that this non-invasive approach eliminates the interindividual variations in BP endpoints that occur when a standard mercury s p h y g m o m a n o m e t e r is used to measure BPs in population studies. In summary, a m b u l a t o r y BPs are elevated in type I diabetic patients compared with the non-diabetic subjects. The mean a m b u l a t o r y BP correlated positively with the casual office BPs in both groups. However, while a m b u l a t o r y M A P correlated significantly with the peak, exercise-induced M A P in the diabetic patients, no such relationship existed in non-diabetic patients. Furthermore, diabetic patienJ;s with proliferative retinopathy with or without clinical nephropathy had exaggerated BP responses to exercise. In conclusion, the ambulatory BPs recorded by the Tycos Digital BP Monitor are reliable and agree with the casual office BP readings. The a m b u l a t o r y BPs are elevated in some type I diabetic patients and m a y predict the BP responses to peak exercise especially in the presence of proliferative retinopathy. Whether early treatment of the elevated BP (albeit subhypertensive) to achieve values similar to that of the age-matched controls and/or reduction of exaggerated responses to stress may prevent the development or progression of diabetic microangiopathy is yet to be determined in a larger prospective study. Finally, in the light of current national enthusiasm for intense exercise to improve
physical fitness and insulin sensitivity of the peripheral tissues in diabetics, caution should be exercised in the prescription of various exercise modalities until their safety can be established in type I diabetic patients.
Acknowledgements We thank Elizabeth A. Robinson for her secretarial assistance, the nurses at the clinical research center for taking care of the patients, and G.CRC RR-34, N I H . Supported in part by the Veterans Administration.
References I Andersen, A.R., Christiansen, J.S., Andersen, J.K., Driener, S. and Deckert, T., Diabetic nephropathy in type I (insulin-dependent) diabetes: an epidemiological study, Diabetologia, 25: 495-501, 1983. 2 Deckert, T., Andersen, A.R., Christiansen, J.S. and Andersen, J.K., Course of diabetic nephropathy. Factors related to development, Acta Endocrinol., 97 (Suppl 242): 14-15, 1981. 3 Andersen, A.R., Andersen, J.K., Christiansen, J.S. and Deckert, T., Prognosis for juvenile diabetics with nephropathy and failing renal function, Acta Med. Scand., 203: 131-134, 1978. 4 Parving, H.H., Andersen, A.R., Smidt, U., Friisberg, B. and Svensen, P.A., Reduced albuminuria during early and aggressive antihypertensive treatment of insulin-dependent diabetic patients with diabetic nephropathy, Diabetes Care, 4: 459-463, 1981. 5 Mogensen, C.E., Antihypertensive treatment inhibits the progression of diabetic nephropathy, Acta Endocrinol., 238: 103-11 I, 1980. 6 Cataland, S. and O'Dorisio, T.M., Diabetic nephropathy: clinical course in patients treated with the subcutaneous insulin pump, J. Am. Med. Assoc., 249: 2059-2061, 1983. 7 Mogensen, C.E. and Christiansen, C.K., Predicting diabetic nephropathy in insulin-dependent patients, N. Engl. J. Med., 31 I: 356-360, 1984. 8 Parving, H.H., Oxenbou, B., Svensen, P.A., Christiansen, J.S. and Andersen, A.R., Early detection of patients at risk of developing diabetic nephropathy. A longitudinal study of urinary albumin excretion, Acta Endocrinol., 100: 550-555, 1982. 9 Parving, H.H., Smidt, U.M., Friisberg, B., Bonnevie-Nielsen, V. and Andersen, A.R., A prospective study of glomerular filtration rate and arterial blood pressure in insulin-
134
10
11
12
13 14
15
16
17
18 19
20
21
dependent diabetics with diabetic nephropathy, Diabetologia, 20:457-461, 198 I. Wiseman, M., Viberti, G., Mackintosh, D., Jarrett, R.J. and Keen, H., Glycemia, arterial pressure and microalbuminuria in type I (insulin-dependent) diabetes mellitus, Diabetologia, 26: 401-405, 1984. Viberti, G., Pickup. J.C., Bilous, R.W., Keen, H. and Mackintosh, D., Correlation of exercise-induced microalbuminuria in insulin-dependent diabetics after 3 weeks of subcutaneous insulin infusion, Diabetes. 30: 818-823, 1981. The Kroc Collaborative Study Group. Blood glucose control and the evolution of diabetic retinopathy and albuminuria: a preliminary multicenter trial, N. Engl. J. Med., 311: 376382, 1984. Karlefors, J.T., Hemodynamic studies in male diabetics, Aeta Med. Stand.. 180: 45-80, 1966. National Diabetes Data Group. Classification and diagnosis of diabetes mellitus and other categories of glucose intolerance, Diabetes, 29: 1039-1057, 1979. Lott, J.A., Stephen, V.A. and Pritchard. K.A., Evaluation of the Coomassie brilliant blue G-250 method for urinary protein, Clin. Chem., 29: 1946-1950, 1983. Hostetter, T.H., Rennke, H.G. and Brenner, B.M., The case for intrarenal hypertension in the initiation and progression of diabetic and other glomerulopathies, Am. J. Med., 72: 375-380, 1982. O'Hare, J.A., Ferriss, J.B., Twomey, B. and O'Sullivan, D.J., Poor metabolic control, hypertension and microangiopathy independently increase the transcapillary escape rate of albumin in diabetes, Diabetologio, 25: 260-263, 1983. Christlieb, A.R., The hypertensions of diabetes, Diabetes Care, 5: 50-58, 1982. Parving, H.H., Andersen, A.R., Smidt, U.M., Oxenbou, B., Edsberg, B. and Christiansen, J.S., Diabetic nephropathy and arterial hypertension, Diabetologia, 24: 10-12, 1983. Knowler, W.C., Bennett, P.H. and Ballintine, E.J., Increased incidence of retinopathy in diabetes with elevated blood pressure. N. Engl. J. Med., 302: 645-650, 1980. Osei, K., Fields, P.G., Cataland, S., Craig, E.L., George, J.M. and O'Dorisio, T.M., Abnormal retinal artery responses to stress in type I diabetic patients, Am. J. Med., 78: 595-601, 1985.
22 Berkman, J. and Rifkin, H., Unilateral nodular diabetic glomerulosclerosis (Kimmelsiel-Wilson): report of a case, Metabolism, 22: 717-721, 1973. 23 Slusher, M. M., Retinal sparing in diabetic retinopathy, South. Med. J., 68: 665-667, 1975. 24 Vondan, S., Mookherjee, S., Warner, R. and Smulyan, H., Systolic hypertension; direct and indirect BP requirements, Arch. hit. Med., 143: 935-938, 1983. 25 Perloff, D., Sokolow, M. and Cowan, R., The prognostic value of ambulatory blood pressure, J. Am. Med. Assoc., 249: 2792-2798, 1983. 26 Mancia, G., Grassi, G., Ponidossi, G. et al., Effects of blood pressure measurement by the doctor on patient's blood pressure and heart rate, Lancet ii: 695-697, 1983. 27 Drayer, J.I.M., Weber, M.A. and Hoeger, W.J., Whole-day BP monitoring in ambulatory normotensive men, Arch. Int. Med., 145: 271-274, 1985. 28 The 1984 Report of the Joint National Committee on Detection, Evaluation and Treatment of High Blood Pressure, Arch. hit. Med., 144: 1045-1057, 1984. 29 Parving, H.H., Microvascular permeability to plasma proteins in hypertension and diabetes mellitus in man: on pathogenesis of hypertensive and diabetic microangiopathy, Dan. Med. Bull.. 22: 217-233, 1975. 30 Kannel, W.B., Some lessons in cardiovascular epidemiology from Framingham, Am. J. Cardiol.. 37: 269-282, 1976. 31 Wieling, W., Bmst, C., Van Dangen Torman, M.A. et al., Relationship between impaired parasympathetic and sympathetic cardiovascular control in diabetes mellitus, Diahetologia, 24: 422-427, 1983. 32 Parving, H.H., Viberti, G.C., Keen, H., Christensen, J.S. and Lassen, N.A., Hemodynamic factors in the genesis of diabetic microangiopathy, Metabolism, 32: 943-949, 1983. 33 Rhie, P.H., Christlieb, A.R., Sender, T. et al., Retinal vascular reactivity to norepinephrinc and angiotensin il in normals and diabetics, Diabetes. 31: 1056-1060, 1982. 34 Christlieb, A.R., Janker, H.-U., Kraus, B. et al., Vascular reactivity to angiotensin II and to norepinephrine in diabetic subjects, Diabetes. 25: 268-274, 1976. 35 O'Brien, E., Fitzgerald, D. and O'Malley, K., Blood pressure measurement: current practice and future trends, Br. Med. J.. 290: 729-734, 1985.
Elsevier
125
DRC 00120
Ambulatory and exercise-induced blood pressure responses in type I diabetic patients and normal subjects K w a m e Osei Department of Medicine, Division of Endocrinology, The Ohio State University, Columbus, OH 43210, U.S.A.
(Received 27 March 1986, revised received 20 June 1986, accepted 13 September 1986)
Key words: Blood pressure; Exercise;Ambulation;Type I diabetics
Summary We evaluated the ambulatory blood pressure (BP) readings during daily activities and compared the values with the casual office BPs in 12 type I diabetic patients and 12 age-matched, non-diabetic normal controls. The BP responses to 750 kpm/min exercise work load on bicycle ergometer were also evaluated in all the subjects. The mean ambulatory BPs were significantly higher in the diabetic patients compared with nondiabetic subjects. However, the ambulatory and casual office BPs were remarkably similar in each group. Mean peak exercise BPs were higher in the diabetics, but significantly so for diastolic BP (P < 0.05) and mean arterial pressure (MAP) (P < 0.01). The mean ambulatory MAP significantly correlated with the casual office MAP in both the diabetics (r = 0.75, P < 0.005) and non-diabetics (r = 0.58, P < 0.02). A significantly positive relationship (r = 0.87, P < 0.001) existed between the ambulatory and peak exercise MAP in the diabetics, but not in the non-diabetic subjects. The mean peak exercise BP responses were significantly (P < 0.01) higher in the diabetic patients with proliferative retinopathy vs. those with nonproliferative retinopathy. We conclude that casual office BPs reflect the ambulatory values in both diabetics and non-diabetics. Exaggerated BP responses to exercise are found in diabetic patients, especially in the presence of proliferative retinopathy. These findings are suggestive of possible defects in the cardiovascular, autonomic and autoregulatory mechanisms that maintain a normal MAP during daily stresses and exercise in the diabetic patients.
Introduction Diabetic nephropathy and retinopathy constitute the major chronic complications in type I diabetic Address for correspondence: Kwame Osei, M.D., N-If20 Doan Hall, 410 W. 10th Avenue,Columbus,OH 43210, U.S.A.
patients. Both are associated with high morbidity [1-3]. Even though the actual pathogenesis of diabetic microangiopathy is unknown, several factors such as diabetic control, hypertension and genetics have been implicated. Recent evidence indicates that hypertension (BP > 140/90 mm Hg) is a major risk factor in the pathogenesis of diabetic nephro-
0168-8227/87/$03.50 O 1987 ElsevierScience Publishers B.V. (Biomedical Division)
126
pathy since aggressive antihypertensive therapy has been reported to delay the progression of diabetic nephropathy [4-6]. However, it is uncertain whether reduction in elevated BP would result in similar delay in the progression of diabetic retinopathy. The interrelationships between hypertension and microangiopathy are more complex since the temporal relationships between these various parameters are ill-defined [7-12]. Several investigators have reported elevated basal BP (albeit subhypertensive) in type I diabetic patients when compared with age-matched controls [8,9,13]. In addition, type I diabetic patients have exaggerated BP responses to exercise compared with normal controls [8,13]. The latter findings have led to the speculation that these patients may have elevated BP under 'stresses' of daily activities. However, there is little data in the literature regarding the value of ambulatory BP recordings during daily activities in type I diabetic patients. It is also unknown whether the elevated ambulatory BP and/or episodic responses to stress have any relationships with the chronic diabetic complications. The purposes of the present study were 3-fold: (a) to document the ambulatory BP profile during normal daily activities and 'stresses', (b) to determine the relationship between ambulatory BP and casual office BP, and (c) to determine the association, if any, of ambulatory BP with diabetic complications in type I diabetic patients. We found that both ambulatory and casual office BPs were significantly higher in the type I diabetic patients compared with age-matched non-diabetic controls. In addition, exaggerated BP responses to exercise were found in diabetic patients with proliferative retinopathy when compared to those with non-proliferative retinopathy.
Patients, materials and methods Twelve type I diabetic patients (7 females, 5 males, age range 26-54 years) as defined by the National Diabetes Data Group Criteria [14] were studied. Twelve age-matched non-diabetic controls (10 females, 2 males, age range 22-53 years) with no fam-
ily history of diabetes in the first-degree relatives were recruited. The clinical characteristics of the subjects are shown in Table 1. All the subjects had direct fundoscopic examination with dilated pupils by an experienced ophthalmologist. An informed written consent approved by the Human Research Review Committee of the University was obtained from each subject after the risk entailed in the protocol had been thoroughly explained. Blood samples were obtained for measurements of glucose, glycosylated hemoglobin (HbA1), creatinine, BUN and electrolytes. 24 h urine samples were collected for protein and creatinine. Also, urine specimens were examined microscopically for sediments and casts and cultured for bacteria. They were all unremarkable. Renal biopsies were not done to rule out non-diabetic causes of renal disease. However, patients with heart disease, liver disease and history of renal disease not associated with diabetes were excluded from the study.
Study protocol Each subject was instructed to measure his/her BP and pulse rate (PR) at least 8 times during normal daily activities between 6 a.m. and 12 a.m. on 2 separate days using a semi-automated, patient-activated, digital BP monitor (Tycos R, model 7052-08) in the sitting position. These are subsequently designated ambulatory BP or pulse rates. The clock time was divided into 2 h segments, e.g. 6-8 a.m., 8-10 a.m., 10-12 a.m., etc. and a single reading was obtained in each time segment during the day. The digital BP readings by the monitor were compared to those of the conventional mercury sphygmomanometer using a standard (13 x 35 cm) cuff for adults. The difference between 10 separate readings using the 2 procedures (performed by the same person) was + 2 mm Hg. The phase V Korotkoff sounds - disappearance of sounds - was taken as the diastolic pressure. On a separate day, subjects were admitted to the clinical research center at 7 a.m. Electrocardiogram was obtained to rule out any cardiac arrhythmia or ischemic cardiac disease. After 30 min of rest in the sitting position, 3 baseline BP and PR were obtained at 10 min intervals. Each subject then in-
127 gested 250 ml of water starting at 8 a.m. at 1 h intervals for 4 h to ensure adequate hydration and diuresis. Subjects then performed a 20 min exercise in a sitting position on a bicycle ergometer at a work load of 750 kpm/min. BP and PR were recorded at 5 min intervals during the exercise. Subjects continued to ingest the measured volume of water hourly for the next 4 h. Urine samples for protein and creatinine were obtained at hourly intervals throughout the study period of 8 h. Serum and urine creatinine concentrations were measured by the Technicon Autoanalyser. Glycosylated hemoglobin (HbA~) was determined by the microcolumn chromatographic technique (Isolabs, Akron, OH). Urine protein was measured by the Coomassie brilliant blue method [15]. All values are presented as mean + SEM unless otherwise stated. The mean BP and PR readings were taken as the mean of 16 recordings. Mean arterial pressure (MAP) was calculated as diastolic BP and ]/3 pulse pressure. The diabetic patients with non-proliferative retinopathy were compared with those with proliferative retinopathy. Since fluorescein angiography was not performed in our study, diabetic patients with either background retinopathy or normal fundoscopic examination were categorized as the non-proliferative retinopathy group in the present study. The glomerular filtration rate (GFR) was calculated by the standard formula for endogenous creatinine clearance (UV/P). The functional G F R reserve was estimated as the difference between the mean baseline pre-exercise and post-exercise GFR values over the two 4 h periods. Statistical analyses were performed by two-tailed Student's paired and unpaired t-test, and analyses of variance where appropriate. Linear regression analyses and correlation coefficients were calculated by the least-squares method. A P value of less than 0.05 was considered statistically significant.
Table 1. The mean age, body weight, height and serum creatinine were similar in both groups. However, as expected, the mean 24 h urinary protein and HbA1 values were significantly higher in the diabetics compared with the non-diabetic subjects. The 24 h urinary protein exceeded the clinical nephropathic range in 3 diabetic patients (Nos. 3, 4, 6) and was within normal limits in the rest. The mean GFR values were significantly lower in the diabetic patients vs. non-diabetic subjects (77 + 8.8. vs. I07 + 9 ml/min, P < 0.05). Diabetic patients with non-proliferative retinopathy had GFR values similar to those with proliferative retinopathy. The ambulatory BP profiles during the daytime in both the diabetics and non-diabetics are shown in Fig. 1. Clearly, the diabetics had elevated mean systolic and diastolic BP values during the daily activities compared with the non-diabetics. Between 8 p.m. and 12 a.m., the systolic BP in the diabetics approached those of the non-diabetics, while the diastolic BP remained significantly different. The mean systolic BP, diastolic BP and MAP in both groups during the visit to office (casual) and am-
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129 TABLE 2 COMPARISON OF CASUAL OFFICE AND AMBULATORY BP A N D P U L S E R A T E IN T H E S I T T I N G POSITION IN D I A B E T I C P A T I E N T S A N D N O N - D I A B E T I C C O N TROLS" Diabetics (n = 12)
Non-diabetics (n = 12)
Casual Systolic BP ( m m Hg) 121 + 4.6(110-150)* Diastolic BP ( m m Hg) 82 4- 4 (60-98)** MAP ( m m Hg) 96 + 4 (77-110)*** Pulse rate (beats/min) 80 4- 5 (62-112)***
111 4- 3.4(110-140) 74 4- 2 (60-80) 87 4- 2 (73-100) 73 + 3 (64-100)
Ambulatory Systolic (mm Hg) 125 4- 5 (98-149)* Diastolic ( m m Hg) 82 4- 3 (62-99)** MAP (mm Hg) 96 4- 3 (74-115)*** Pulse rate (beats/min) 84 4- 3 (71-96)***
II0 4- 3 (96-136) 70 4- 3 (59-96) 83 4- 3 (71-102) 73 4- 2 (62-81)
Values are means 4- SEM, (range) o f 16 readings between 6 a.m. and 12 a.m. on 2 separate days. No significant differences were seen between the ambulatory and casual office BP and PR recordings. * P < 0.025, diabetics vs. non-diabetic controls; ** P < 0.01, diabetics vs. non-diabetic controls: *** P < 0.005, diabetics vs. non-diabetic controls.
A
bulation are shown in Table 2. Mean ambulatory and casual office systolic BP, diastolic BP and MAP were significantly higher in the diabetic patients compared with those of the non-diabetic subjects. Similarly, the ambulatory PR were higher in the diabetic vs. non-diabetic subjects (80 + 4.8 vs. 73 + 3, P < 0.05). However, when the ambulatory and casual office BP and PR readings were compared in each group, values were remarkably identical (Table 2). During the 20 min exercise period, the mean peak systolic BP increased significantly (P < 0.01) in both the diabetic and non-diabetic subjects when compared with the baseline pre-exercise values (Fig. 2A). Even though the peak exercise systolic BP values were higher in the diabetics vs. non-diabetics, the differences were not statistically significant. In contrast, the mean diastolic BP significantly (P < 0.05) increased in the diabetic patients when compared with the baseline and those of the non-diabetic subjects (Fig. 2B). In fact, except in one subject whose diastolic BP slightly increased, the diastolic BPs either decreased or remained unchanged during the exercise in the non-diabetic group. Consequently, the calculated MAP values were higher (P < 0.01) in the diabetic patients when compared with the pre-exercise values and those of the nondiabetic subjects (Fig. 2C). In 4/12 diabetic patients (Nos. 7, 8, I0, 12), the absolute BP responses were
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BLOOD PRESSURE RESPONSES D U R I N G EXERCISE IN TYPE I DIABETIC PATIENTS W I T H A N D W I T H O U T P R O L I F E R A T I V E RET1NOPATHY"
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140
Fig. 3. Correlations between ambulatory mean arterial pressure (MAP) and casual office and peak exercise-induced MAPs in diabetic patients and non-diabetic subjects.
similar to those of the non-diabetic controls. Mean peak PR during the exercise were similar in both groups despite significantly higher pre-exercise values in the diabetic patients (Fig. 2D). The relationships between ambulatory MAP and casual office and peak, exercise-induced MAP are shown in Fig. 3. Significant correlations existed between ambulatory and casual MAP values in both the non-diabetlc subjects (r = 0.58, P < 0.02, Fig. 3A) and diabetic patients (r = 0.75, P < 0.005, Fig. 3B). No relationship was found between the ambulatory MAP and peak exercise MAP values (r = 0.04, P = NS, Fig. 3C) in the non-diabetic subjects. In contrast, a highly significant correlation (r = 0.85, P < 0.001, Fig. 3D) existed between the ambulatory MAP and peak exercise MAP in the diabetic patients. Also, a significant relationship existed between the ambulatory MAP and proteinuria (r = 0.77, P < 0.005) in the diabetic patients as a group, but
not in the non-diabetic subjects. However, when the 3 patients with clinical nephropathic range of proteinuria (greater than 500 mg) were excluded, the significant correlation disappeared. We did not find any correlation between ambulatory BPs (systolic, diastolic and MAP) and G F R , HbA1, duration of diabetes, age of onset of diabetes and daily insulin dosage in the diabetic patients. Mean basal BP responses were slightly higher in patients with proliferative retinopathy vs. non-proliferative retinopathy, but values were not statistically different (Table 3). However, during exercise, significantly higher diastolic (P < 0.025) and MAP (P < 0.025) peak responses were seen in diabetic patients with proliferative retinopathy compared with patients with non-proliferative retinopathy, irrespective of the presence or absence of clinical proteinuria (Table 3). The systolic BP differences were not statistically significant. The mean functional G F R reserve estimated as the increments or decrements from the baseline values after the exercise were similar between the diabetic patients and non-diabetic subjects (data not shown).
131 Discussion
The role of hypertension in both diabetic nephropathy and retinopathy is now well established [2,3,9,15-17]. In the initial phase of microangiopathy, hemodynamic alterations seem to feature prominently in the genesis of these complications [11,12]. Indeed, Hostetter et al. [16] have demonstrated an increased renal plasma flow, GFR and intraglomerular capillary pressure using a single nephron micropuncture technique in early diabetic nephropathy. Likewise, some investigators have demonstrated increased retinal blood flow in early diabetic retinopathy. Even though the specific etiologies of various lesions in different target organs remain elusive, the concomitant occurrence of both diabetic retinopathy and nephropathy, in part, supports a common pathogenetic mechanism. Indeed, diabetic nephropathy is almost invariably associated with retinopathy and the absence of the latter makes the diagnosis of the former less likely. Recent attention has focused on the temporal relationship between hemodynamic changes and diabetic microangiopathy [18-20]. Mogensen et al. [7] have observed that patients with incipient nephropathy who progress to clinical nephropathy have elevated diastolic BP at the initial presentation in addition to higher microalbuminuria (greater than 15/~g/min). Knowler et al. [20] have reported higher incidence of retinal hemorrhages and exudates in diabetic Pima Indians with elevated blood pressure. Similarly, we have recently demonstrated a significant association between elevated brachial and retinal MAP to stress in type I diabetic patients but not in the age-matched, normal controls [21]. Furthermore, Berkman and Rifkin [22] have demonstrated that renal artery stenosis rendered protection from diabetic glomerulosclerotic lesions in the ipsilateral kidney at autopsy in a diabetic patient. Similarly, Slusher et al. [23] observed a partial protection from diabetic retinopathy by ipsilateral carotid artery stenosis in a diabetic patient as assessed by fluorescein angiography. Whether these associations are related to the pressure head and/or toxic factors circulating in the plasma of diabetic patients has not been resolved.
Availability of a simple, non-invasive, digital BP monitor to measure frequent BPs as an outpatient would be invaluable in the care of diabetic patients. This is important since casual office BP readings have been reported to be elevated in diabetic patients compared with the age-matched controls [8,13] and is in agreement with the present findings. In addition, there is controversy regarding the use of casual office BP as a true reflection of daily BP in both diabetic and non-diabetic populations [24-27]. It is believed by most investigators that the mere office visit and presence of the doctor may induce anxiety with an associated elevation in BP which has been previously referred to as 'white coat' or 'doctors office' hypertension [26]. However, recent studies by Drayer et al. [27] using an expensive Del Mar Avionic (Irvine, CA) ambulatory BP monitor in normotensive non-diabetics demonstrated a significant relationship between casual office and ambulatory BPs. Of great importance is that Perloffet al. [25] have reported that the ambulatory BP is a better predictor of risk of cardiovascular and cerebrovascular events compared with the casual office BP. We are not aware of similar studies in the diabetic patients. This issue is noteworthy since long-term diabetic complications may be associated with higher mean perfusion pressures (albeit within normal range) during the daily stresses in type I diabetic patients and the latter may play a role in the accelerated cardiovascular and cerebrovascular events found in diabetics. Using a simple, inexpensive, ambulatory, digital BP monitoring system, we have demonstrated that ambulatory BPs correlate significantly with the casual office readings in both diabetic and non-diabetic subjects. However, the association was much stronger in the diabetic patients. Furthermore, the diabetic patients had significantly higher ambulatory and casual BPs compared with those of the non-diabetic subjects. Indeed, the ambulatory and casual BP values were similar in each group. By the current classification of the National Committee on Detection, Evaluation and Treatment of High Blood Pressure [28], the mean ambulatory BPs of 121/82 mm Hg and 111/74 mm Hg attained in both the diabetics and non-diabetics, respectively, are
132 considered to be within normal limits. However, whether the current recommendation with upper cut-off limits of 140/90 mm Hg for normal BP should be applied to diabetic patients with abnormal capillary basement membrane thickness and increased leakiness of plasma proteins [17,29], has not been satisfactorily addressed. It should be noted that, according to the Framingham studies [30], there is a continuum of increasing cardiovascular and cerebrovascular morbidity and mortality associated with BP and these are accelerated in diabetics. Thus, the significantly higher BPs noted in the diabetic patients compared with the agematched controls may be biologically significant and require further elucidation. In this regard, we found a significantly positive relationship between the ambulatory MAP and proteinuria in the diabetic patients taken as a group while no such association existed in non-diabetic subjects, which is in agreement with previous reports [4]. In addition, diabetic patients with proliferative retinopathy had higher mean ambulatory and basal BP recordings compared with those with non-proliferative retinopathy. Several reports have suggested that type I diabetic patients have exaggerated BP responses to stress and exercise [8,10,13]. This was confirmed in our study. During the submaximal exercise, the peak systolic BP was higher in the diabetic patients vs. the non-diabetic subjects, but mean values were not statistically different. However, the diastolic BP and MAP were significantly higher in the diabetic patients. Of great interest is that the ambulatory MAP correlated significantly with the peak exercise MAP only in the diabetic patients but not in the non-diabetic subjects. It is noteworthy to mention that these findings are similar to the retinal artery MAP responses to cold pressor test in diabetic and non-diabetic subjects we reported previously [21]. Furthermore, the presence of proliferative retinopathy was associated with significantly higher BP responses compared with patients with non-proliferative retinopathy. Thus, it appears that some type I diabetic patients have lost the cardiovascular, autonomic and autoregulatory mechanisms required to maintain a normal mean perfusion pres-
sure in the target organs. These abnormalities may play a role or may be associated with the macroand microangiopathy found in diabetes [31,32]. The exact cause of these abnormal BP responses in the type I diabetic patients is unknown but several possibilities should be considered. Firstly, it may be due to the abnormal metabolic state found in diabetes per se. However, we did not find any relationship between serum glucose, HbA~, and ambulatory BP or peak BP responses to exercise in our study. Secondly, increased basement membrane thickness and vascular wall changes such as arteriolar hyalinosis may be involved [32]. Thirdly, hypersensitivity to various pressor hormones has been reported in some diabetic patients. Indeed, Rhie et al. [33] and Christlieb et al. [34] have reported abnormal retinal and brachial artery responses, respectively, to i.v. infusions of norepinephrine and angiotensin II especially in patients with diabetic retinopathy and nephropathy. In addition, autonomic nervous derangement is not uncommon in type I diabetic patients with and without microangiopathy. Similar to our previous report [21], we observed that 4 of our diabetic patients (Nos. 7, 8, 10 and 12) in the present study with minimal increases in their MAP during the exercise, had either mild or no background retinopathy. In contrast, significantly higher mean peak MAP responses occurred in the diabetic patients with proliferative retinopathy irrespective of the presence or absence of clinical nephropathy. It is, therefore, tempting to postulate that episodic or sustained increases in BP such as during hypoglycemic reaction, strenuous exercise and other sympathetic stimulation may be associated with diabetic microangiopathy. Finally, it is also possible that the exaggerated BP responses in some of these patients may, in part, be secondary to the severity of the microangiopathy per se. Our subjects found the frequent ambulatory BP recordings acceptable and non-intrusive. We should note that patient-recorded BPs have several advantages over doctor-recorded measurements, among the most important being greater diagnostic accuracy. The closer correlations of ambulatory BP with left ventricular hypertrophy and those between stress and cardiovascular events argue strongly in
133 favor of such non-invasive ambulatory BP recordings as suggested by Perloff and his associates [25]. The ambulatory BP may also prove to be a valuable tool in the early detection of labile hypertension and in judging the effects of antihypertensive therapy especially in diabetic patients. We found both the a m b u l a t o r y and casual office BPs to be similar in each group during our study which is in agreement with some previous studies [24] but not others [35]. We believe both approaches should be complementary. Even though an inherent error may occur during the positioning of the microphone of the Tycos BP cuff, our subjects had no difficulty in palpating the pulsations of the brachial artery when reexamined by the investigators. Furthermore, we excluded patients with cardiac arrhythmia which may cause inaccurate readings. O f practical value is that this non-invasive approach eliminates the interindividual variations in BP endpoints that occur when a standard mercury s p h y g m o m a n o m e t e r is used to measure BPs in population studies. In summary, a m b u l a t o r y BPs are elevated in type I diabetic patients compared with the non-diabetic subjects. The mean a m b u l a t o r y BP correlated positively with the casual office BPs in both groups. However, while a m b u l a t o r y M A P correlated significantly with the peak, exercise-induced M A P in the diabetic patients, no such relationship existed in non-diabetic patients. Furthermore, diabetic patienJ;s with proliferative retinopathy with or without clinical nephropathy had exaggerated BP responses to exercise. In conclusion, the ambulatory BPs recorded by the Tycos Digital BP Monitor are reliable and agree with the casual office BP readings. The a m b u l a t o r y BPs are elevated in some type I diabetic patients and m a y predict the BP responses to peak exercise especially in the presence of proliferative retinopathy. Whether early treatment of the elevated BP (albeit subhypertensive) to achieve values similar to that of the age-matched controls and/or reduction of exaggerated responses to stress may prevent the development or progression of diabetic microangiopathy is yet to be determined in a larger prospective study. Finally, in the light of current national enthusiasm for intense exercise to improve
physical fitness and insulin sensitivity of the peripheral tissues in diabetics, caution should be exercised in the prescription of various exercise modalities until their safety can be established in type I diabetic patients.
Acknowledgements We thank Elizabeth A. Robinson for her secretarial assistance, the nurses at the clinical research center for taking care of the patients, and G.CRC RR-34, N I H . Supported in part by the Veterans Administration.
References I Andersen, A.R., Christiansen, J.S., Andersen, J.K., Driener, S. and Deckert, T., Diabetic nephropathy in type I (insulin-dependent) diabetes: an epidemiological study, Diabetologia, 25: 495-501, 1983. 2 Deckert, T., Andersen, A.R., Christiansen, J.S. and Andersen, J.K., Course of diabetic nephropathy. Factors related to development, Acta Endocrinol., 97 (Suppl 242): 14-15, 1981. 3 Andersen, A.R., Andersen, J.K., Christiansen, J.S. and Deckert, T., Prognosis for juvenile diabetics with nephropathy and failing renal function, Acta Med. Scand., 203: 131-134, 1978. 4 Parving, H.H., Andersen, A.R., Smidt, U., Friisberg, B. and Svensen, P.A., Reduced albuminuria during early and aggressive antihypertensive treatment of insulin-dependent diabetic patients with diabetic nephropathy, Diabetes Care, 4: 459-463, 1981. 5 Mogensen, C.E., Antihypertensive treatment inhibits the progression of diabetic nephropathy, Acta Endocrinol., 238: 103-11 I, 1980. 6 Cataland, S. and O'Dorisio, T.M., Diabetic nephropathy: clinical course in patients treated with the subcutaneous insulin pump, J. Am. Med. Assoc., 249: 2059-2061, 1983. 7 Mogensen, C.E. and Christiansen, C.K., Predicting diabetic nephropathy in insulin-dependent patients, N. Engl. J. Med., 31 I: 356-360, 1984. 8 Parving, H.H., Oxenbou, B., Svensen, P.A., Christiansen, J.S. and Andersen, A.R., Early detection of patients at risk of developing diabetic nephropathy. A longitudinal study of urinary albumin excretion, Acta Endocrinol., 100: 550-555, 1982. 9 Parving, H.H., Smidt, U.M., Friisberg, B., Bonnevie-Nielsen, V. and Andersen, A.R., A prospective study of glomerular filtration rate and arterial blood pressure in insulin-
134
10
11
12
13 14
15
16
17
18 19
20
21
dependent diabetics with diabetic nephropathy, Diabetologia, 20:457-461, 198 I. Wiseman, M., Viberti, G., Mackintosh, D., Jarrett, R.J. and Keen, H., Glycemia, arterial pressure and microalbuminuria in type I (insulin-dependent) diabetes mellitus, Diabetologia, 26: 401-405, 1984. Viberti, G., Pickup. J.C., Bilous, R.W., Keen, H. and Mackintosh, D., Correlation of exercise-induced microalbuminuria in insulin-dependent diabetics after 3 weeks of subcutaneous insulin infusion, Diabetes. 30: 818-823, 1981. The Kroc Collaborative Study Group. Blood glucose control and the evolution of diabetic retinopathy and albuminuria: a preliminary multicenter trial, N. Engl. J. Med., 311: 376382, 1984. Karlefors, J.T., Hemodynamic studies in male diabetics, Aeta Med. Stand.. 180: 45-80, 1966. National Diabetes Data Group. Classification and diagnosis of diabetes mellitus and other categories of glucose intolerance, Diabetes, 29: 1039-1057, 1979. Lott, J.A., Stephen, V.A. and Pritchard. K.A., Evaluation of the Coomassie brilliant blue G-250 method for urinary protein, Clin. Chem., 29: 1946-1950, 1983. Hostetter, T.H., Rennke, H.G. and Brenner, B.M., The case for intrarenal hypertension in the initiation and progression of diabetic and other glomerulopathies, Am. J. Med., 72: 375-380, 1982. O'Hare, J.A., Ferriss, J.B., Twomey, B. and O'Sullivan, D.J., Poor metabolic control, hypertension and microangiopathy independently increase the transcapillary escape rate of albumin in diabetes, Diabetologio, 25: 260-263, 1983. Christlieb, A.R., The hypertensions of diabetes, Diabetes Care, 5: 50-58, 1982. Parving, H.H., Andersen, A.R., Smidt, U.M., Oxenbou, B., Edsberg, B. and Christiansen, J.S., Diabetic nephropathy and arterial hypertension, Diabetologia, 24: 10-12, 1983. Knowler, W.C., Bennett, P.H. and Ballintine, E.J., Increased incidence of retinopathy in diabetes with elevated blood pressure. N. Engl. J. Med., 302: 645-650, 1980. Osei, K., Fields, P.G., Cataland, S., Craig, E.L., George, J.M. and O'Dorisio, T.M., Abnormal retinal artery responses to stress in type I diabetic patients, Am. J. Med., 78: 595-601, 1985.
22 Berkman, J. and Rifkin, H., Unilateral nodular diabetic glomerulosclerosis (Kimmelsiel-Wilson): report of a case, Metabolism, 22: 717-721, 1973. 23 Slusher, M. M., Retinal sparing in diabetic retinopathy, South. Med. J., 68: 665-667, 1975. 24 Vondan, S., Mookherjee, S., Warner, R. and Smulyan, H., Systolic hypertension; direct and indirect BP requirements, Arch. hit. Med., 143: 935-938, 1983. 25 Perloff, D., Sokolow, M. and Cowan, R., The prognostic value of ambulatory blood pressure, J. Am. Med. Assoc., 249: 2792-2798, 1983. 26 Mancia, G., Grassi, G., Ponidossi, G. et al., Effects of blood pressure measurement by the doctor on patient's blood pressure and heart rate, Lancet ii: 695-697, 1983. 27 Drayer, J.I.M., Weber, M.A. and Hoeger, W.J., Whole-day BP monitoring in ambulatory normotensive men, Arch. Int. Med., 145: 271-274, 1985. 28 The 1984 Report of the Joint National Committee on Detection, Evaluation and Treatment of High Blood Pressure, Arch. hit. Med., 144: 1045-1057, 1984. 29 Parving, H.H., Microvascular permeability to plasma proteins in hypertension and diabetes mellitus in man: on pathogenesis of hypertensive and diabetic microangiopathy, Dan. Med. Bull.. 22: 217-233, 1975. 30 Kannel, W.B., Some lessons in cardiovascular epidemiology from Framingham, Am. J. Cardiol.. 37: 269-282, 1976. 31 Wieling, W., Bmst, C., Van Dangen Torman, M.A. et al., Relationship between impaired parasympathetic and sympathetic cardiovascular control in diabetes mellitus, Diahetologia, 24: 422-427, 1983. 32 Parving, H.H., Viberti, G.C., Keen, H., Christensen, J.S. and Lassen, N.A., Hemodynamic factors in the genesis of diabetic microangiopathy, Metabolism, 32: 943-949, 1983. 33 Rhie, P.H., Christlieb, A.R., Sender, T. et al., Retinal vascular reactivity to norepinephrinc and angiotensin il in normals and diabetics, Diabetes. 31: 1056-1060, 1982. 34 Christlieb, A.R., Janker, H.-U., Kraus, B. et al., Vascular reactivity to angiotensin II and to norepinephrine in diabetic subjects, Diabetes. 25: 268-274, 1976. 35 O'Brien, E., Fitzgerald, D. and O'Malley, K., Blood pressure measurement: current practice and future trends, Br. Med. J.. 290: 729-734, 1985.