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Decreased Prorenin Processing Develops before Autonomic Dysfunction in Type 1 Diabetes¹

Departments of Medicine (R.D.H., K.D.B., P.K.), Mathematics (I.C., G.G.), and Community Medicine and Statistics (G.R.H.), West Virginia University, Morgantown, West Virginia 26506-9159

Address correspondence and requests for reprints to: Robert D. Hoeldtke, M.D., Ph.D., Department of Medicine, Section of Endocrinology/Metabolism, Robert C. Byrd Health Sciences Center, P.O. Box 9159, Morgantown, West Virginia 26506-9159.

	Abstract

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It is well documented that diabetic patients with chronic complications have decreased renin secretion and elevations in the renin precursor prorenin. It is uncertain, however, whether the abnormal processing of prorenin is reflective of microvascular disease, hypertension, or autonomic neuropathy. Dechaux et al. (Transplant Proc. 18:1598–1599, 1986) observed abnormalities in prorenin processing in uncomplicated diabetes and suggested that it was the result of subclinical autonomic neuropathy. To test this hypothesis, we measured renin, prorenin, and autonomic function in early type 1 diabetes at a time when there is little or no microvascular disease or hypervolemia. Thirty-seven patients (10 males, 27 females) enrolled 2–22 months after diagnosis in a longitudinal study in which renin, prorenin, and autonomic function were measured annually for 3 years. Forty-one age-matched control subjects were also studied.

PRA in the diabetic patients at the time of the second and third evaluations was 1.71 ± 0.24 ng angiotensin I/mL·h and 1.67 ± 0.24 ng angiotensin I/mL·h, respectively, significantly lower (P < 0.05) than that of the control subjects in whom PRA was 2.96 ± 0.38 ng angiotensin I/mL·h. Prorenin was not different in the diabetic patients in comparison with controls. The renin to prorenin ratio in the diabetic patients at the time of the first, second, and third evaluations was 0.260 ± 0.03, 0.235 ± 0.05, and 0.227 ± 0.05, respectively, significantly lower (P < 0.01) than in control subjects in whom the renin to prorenin ratio was 0.475 ± 0.08. Despite this, at the time of the first and second evaluations, there was no evidence of autonomic dysfunction and no correlation between any test of autonomic function and the renin to prorenin ratio. At the time of the third evaluation, however, the intermediate frequency (0.04–0.15 Hz) power spectra while patients were supine (an index of sympathetic modulation of heart rate variability) showed a highly significant (P < .001) correlation with the renin to prorenin ratio. High frequency (0.15–0.40 Hz) spectra from supine patients at the third evaluation also correlated with the renin to prorenin ratio (P < 0.01).

We conclude abnormal processing of prorenin develops in diabetic patients prior to microvascular disease, even before the first evidence of autonomic dysfunction. Although the latter may play a contributory role, additional as yet unidentified mechanisms seem to interrupt the processing of prorenin in early diabetes.

	Introduction

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DIABETIC patients with microvascular complications and autonomic neuropathy have decreased synthesis and secretion of renin (1). This has been linked to deficient processing of the renin precursor prorenin, an abnormality that is reflected in the plasma renin to prorenin ratio (2). Because sympathetic neurons that innervate the juxtaglomerular apparatus promote the conversion of prorenin to renin, it has been postulated that autonomic neuropathy is the cause of the defective prorenin processing in patients with diabetes (1, 3), and multiple clinical studies have supported this theory (1, 3, 4, 5). Franken et al. (6), however, observed in their patient population that decreased renin to prorenin ratios in chronic diabetes correlated better with the presence of microvascular disease and argued that the latter suppressed renin secretion and led to the release of its precursor, prorenin. This theory assumed potential clinical importance following the report of Luetscher et al. (7) that patients with uncomplicated type 1 diabetes and elevated prorenin were at increased risk for microvascular complications in the future. Dechaux et al. (5) similarly reported low renin to prorenin ratios in uncomplicated diabetes and interpreted this to mean that subclinical autonomic neuropathy caused decreased prorenin processing.

The purpose of the present study was to test the hypothesis that subclinical autonomic dysfunction is the cause of the decreased prorenin processing in early diabetes. We studied type 1 diabetic patients early in their disease when we anticipated there would be little or no microvascular disease, hypertension, or hypervolemia. Patients were studied longitudinally for 3 years and had annual measurements of plasma renin, prorenin, and a comprehensive assessment of autonomic nerve function.

	Materials and Methods

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Patients

Thirty-seven patients (10 males, 27 females) with type 1 diabetes were enrolled 2–22 months after diagnosis in a longitudinal study of autonomic nerve function. The mean age of the patients was 20.3 yr (range, 10–40), and the mean duration of diabetes was 10.4 months (range, 2–22). No patients had other systemic illnesses, hypertension, symptoms of neuropathy, or evidence of microvascular disease. All patients were taught home glucose monitoring and were instructed to adjust their insulin dose as necessary to maintain optimal glycemic control. Glycosylated hemoglobin was measured one to four times each year. Thirty-six patients underwent three annual evaluations; one patient withdrew after the second year. Autonomic function tests were also performed, and biochemical parameters were measured in 41 age- and sex-matched controls (14 males, 27 females) to provide a basis of comparison with the diabetic patients. The mean age of the control subjects was 21 yr (range, 10–42).

The research protocol was approved by the Institutional Review Board of West Virginia University Hospital, and informed consent obtained from the participants.

Annual evaluations. The diabetic patients were admitted to a bed designated for research at West Virginia University Hospital to control their dietary intake, activity, and glucose before and during the autonomic function tests. Patients were administered a weight-maintaining diet containing 130 meq sodium daily, and 24-h urine samples were collected for the measurement of sodium and creatinine clearance. Caffeine, aspirin, and cigarette smoking were not allowed on the morning of the tests because of possible effects on autonomic function. The control subjects were also admitted to the hospital, administered the same diet, and subjected to the same restrictions.

Cardiovascular autonomic function: beat-to-beat variation with deep breathing. Patients were studied in the supine posture after relaxing comfortably for at least 10 min. Heart rate was monitored electrocardiographically while they breathed slowly (5-sec inspiration/5-sec expiration) as deeply as possible for 5 min. The difference between the maximum and minimum instantaneous heart rates (max-min) reflects the intregrity of the parasympathetic innervation of the heart (8). In addition, vector analysis of the instantaneous heart rate was performed and the mean circular resultant determined. This alternative index of heart rate variability minimizes error introduced by variation in intrinsic heart rate or ectopic cardiac beats (9).

Heart rate response to the Valsalva maneuver. The heart rate was monitored electrocardiographically while the patients were supine and instructed to expire into a sphygmomanometer until a pressure of 40 mm Hg was maintained for 20 sec. The Valsalva ratio was calculated by dividing the maximal instantaneous heart rate during the maneuver by the minimal heart rate observed after release (8). The test was performed twice, and the average result was calculated.

Heart rate response to standing. Patients were asked to stand for 1 min while the heart rate was measured electrocardiographically (10). The ratio of the longest R-R interval (at approximately 30 sec of standing) to the shortest R-R interval (approximately 15 sec of standing) was calculated and expressed as the 30:15 ratio.

Power spectral analysis. Instantaneous heart rate was measured with a Hokanson electrocardiograph monitor, which allows each R-R interval to be recorded into a computer program (DE Hokanson Incorporated, Bellevue, WA). The R-R interval data file was then interpolated and averaged, and power spectral analysis was performed using the Fast Fourier Transform (ESA, Inc., Bedford, MA) (11). Respiration was monitored simultaneously with a thermistor so that spurious low-frequency spectra resulting from sighing or deep breathing could be eliminated. High frequency spectra (0.15–0.40 Hz) indicate parasympathetic cardiac innervation, whereas intermediate frequency spectra (0.04–0.15 Hz) were interpreted to signify predominately sympathetic modulation.

Biochemical measurements

Active renin was measured as the rate of conversion of renin substrate to angiotensin I by plasma collected in ethylenediaminetetraacetate (12). Total renin (active plus inactive) was prepared in a separate 1-mL aliquot of plasma by preincubating the latter for 1 h with 10 ug trypsin from porcine pancreas (Sigma Chemical Co., St. Louis, MO). The reaction was stopped by the addition of 20 ug soybean trypsin inhibitor (Sigma Chemical Co.). Total and active renin were then assayed by determining angiotensin I by RIA using ¹²⁵I-labeled angiotensin I (INCSTAR Corp., Stillwater, MN). The conversion of angiotensin I to angiotensin II was inhibited by phenylmethylsulfonylfluoride. Prorenin was calculated as the difference between total and active renin (13). To avoid the confounding effect of ovarian prorenin, blood sampling was rescheduled for females who were menstruating at the time of their annual evaluation (14).

Urinary vanillylmandelic acid was measured by high-performance liquid chromatography and coulometric detection using isoVMA as an internal standard (15).

Statistical Analysis

Differences between the diabetic patients and control subjects and between year differences in the diabetic patients were assessed using ANOVA techniques (16). Association between biochemical parameters and autonomic nerve function was tested with the Pearson correlation coefficient (17).

	Results

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None of the diabetic patients showed evidence of retinopathy, developed microalbuminuria, or had signs or symptoms of neuropathy. One patient developed mild hypertension. Fifty-eight percent of patients maintained the glycosylated hemoglobin concentration within American Diabetes Association guidelines (<1% above the upper limits of normal for patients without diabetes).

PRA in the diabetic patients at the time of the second and third evaluations was 1.71 ± 0.24 ng angiotensin I/mL·h and 1.67 ± 0.24 ng angiotensin I/mL·h, respectively, significantly lower (P < 0.05) than that of the control subjects in whom PRA was 2.96 ± 0.38 ng angiotensin I/mL·h (Table 1). Prorenin was slightly higher but not significantly different in the diabetic patients than in the control subjects. The renin to prorenin ratio was dramatically decreased in the diabetic patients throughout the study. The renin to prorenin ratio in the diabetic patients at the time of the second and third evaluations was 0.235 ± 0.05 and 0.227 ± 0.05 respectively, significantly lower than in control subjects in whom the renin to prorenin ratio was 0.475 ± 0.08. The changes in the renin were not evident at the time of the first evaluation of the diabetic, whereas the renin to prorenin ratio was decreased at the time of all evaluations. The changes in renin to prorenin ratio were more dramatic and those in renin itself and highly significant (P < 0.01) during the second and third evaluations (Table 1).

Heart rate variability with deep breathing was slightly greater in the diabetic patients at the first evaluation compared with controls (P < 0.05) (Table 2). The mean circular resultant was greater in the diabetic patients at both the first and second evaluations. The heart rate response to the Valsalva maneuver during the third evaluation was lower in the diabetic patients than in the control subjects. Power spectra were no different in the diabetic patients vs. the controls.

View larger version (12K): [in this window] [in a new window]   Figure 1. Intermediate frequency power spectra and the renin to prorenin ratio. Intermediate frequency cardiac autonomic power spectra were determined in diabetic patients at the time of their third evaluation while they were supine. Spectra are expressed as (beats/min2)/Hz.

View larger version (11K): [in this window] [in a new window]   Figure 2. High frequency power spectra and the renin to prorenin ratio. High-frequency cardiac autonomic power spectra were determined in diabetic patients at the time of their third evaluation while they were supine. Spectra are expressed as (beats/min2)/Hz.

View larger version (12K): [in this window] [in a new window]   Figure 3. Mean cardiovascular autonomic Z scores and the renin to prorenin ratio. The mean cardiovascular autonomic age-adjusted Z scores integrates the mean circular resultant, the post-valsalva R-R interval, and the high-frequency power spectra in supine patients. These were the three autonomic function tests that showed the greatest agreement with each other. Data shown were gathered in diabetic patients at the time of their third evaluation.

The creatinine clearance was higher in the diabetic patients at the time of the third evaluation (127 ± 6.5 mL/min) than in the control subjects (103 ± 5.6, P < .01). There was no correlation between renin to prorenin ratio or the autonomic function tests and creatinine clearance.

There was no correlation between renin, prorenin, or the renin to prorenin ratio and performance on most autonomic function tests for the control subjects. Many tests of autonomic function correlated negatively with age for both the diabetic patients and control subjects. PRA decreased with age in the control subjects (P < 0.05), prorenin increased (P < 0.01), and the renin to prorenin ratio decreased (P < 0.01).

Glycosylated hemoglobin did not correlate with any of the autonomic function tests or biochemical parameters.

	Discussion

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The results of this study confirm that abnormal processing of prorenin takes place early in type 1 diabetes before the development of overt neuropathy, microvascular disease, or hypertension. Although there was no correlation between renin or the renin to prorenin ratio with performance on the individual conventional autonomic function tests, at the time of the third patient evaluation, we observed a correlation between the mean age-adjusted cardiovascular autonomic Z score and the renin to prorenin ratio (P < 0.05). We observed stronger correlations between the renin to prorenin ratio and the resting cardiac autonomic power spectra, a more sensitive index of early autonomic dysfunction in patients with diabetes (11). The renin to prorenin ratio correlated with total power (P < 0.005), intermediate frequency power (0.04–0.15 Hz) (P < 0.001) and high-frequency power (0.15–0.40) (P < 0.01); it is noteworthy that the strongest correlation with the renin to prorenin ratio (r = 0.55 P < 0.001) was observed with the intermediate frequency spectra an index of sympathetic modulation of heart rate variability. There is strong evidence that the sympathetic nervous system stimulates renin secretion. Physiological stimuli, such as standing, as well as administration of the adrenergic agonist isoproteronol, increase renin secretion, whereas adrenergic antagonists are inhibitory (1, 18). Moreover, patients with pure autonomic failure have profound deficits in renin secretion (19). Thus, we interpret the intermediate frequency power spectra data (specifically its correlation with the renin to prorenin ratio) to indicate that after 3–4 yr of diabetes sympathetic dysfunction develops and contributes to the abnormality in prorenin processing. Accordingly, the excretion of vanillylmandelic acid, an alternative index of the integrity of the sympathetic nervous system, was slightly lower in the diabetic patients at the time of their final evaluation than in age-matched controls. Previous studies have documented that patients with overt autonomic neuropathy have decreased excretion of vanillylmandelic acid (20, 21).

The results of this study do not agree with previous studies of the natural history of autonomic dysfunction in patients with diabetes. We failed to confirm reports that patients with recently diagnosed diabetes, as a group, have poorer performance on autonomic function tests than age-matched control subjects (22, 23). Our results are consistent, however, with those of Ziegler et al. (24), as well as those of the Diabetes Control and Complications Trial (25), in which autonomic function in early diabetes was generally normal. Furthermore, our results call into question the conventional teaching that sympathetic neuropathy is a late complication of diabetes typically developing after parasympathetic dysfunction (8). This perspective may be fallacious because it is based on comparisons between sensitive tests of parasympathetic function, such as the heart rate variability with deep breathing, and insensitive tests of sympathetic function, such as the orthostatic change in blood pressure or plasma norepinephrine. Power spectral analysis provides a more sensitive measure of sympathetic function and may prove to refute the view that sympathetic involvement occurs only late in the natural history of diabetes (11, 23). The presently observed correlation between the intermediate power spectral analysis and the renin to prorenin ratio suggest that subtle degrees of sympathetic dysfunction, too minor to be reflected in the mean performance of the diabetic patients as a group, may nevertheless have a physiological impact on prorenin processing. Thus, the intermediate frequency power spectra data (26) coupled with the changes in vanillylmandelic acid excretion indicate that sympathetic dysfunction may develop earlier in type 1 diabetes than has been previously recognized. We acknowledge that more direct measures of sympathetic function are needed to confirm this.

A number of previous studies have concluded that diabetes-related abnormalities in renin and prorenin reflect the presence of microvascular disease. Prorenin, for example, is present in increased concentrations in the vitreous humor of diabetic patients with retinopathy, suggesting that it is released directly by the diseased vessels (27). Moreover, prorenin is increased in rheumatoid vasculitis, an entity not generally recognized to be complicated by autonomic neuropathy (28). These observations suggest that prorenin release may be a nonspecific response to vascular injury and may explain the elevation of prorenin seen in patients with retinopathy or nephropathy, but it does not explain the presently observed abnormalities in prorenin processing that were documented in patients without these complications. Thus, our data refute the view that decreased renin to prorenin ratios in diabetic patients merely reflects concurrent microvascular disease (6, 29). Our study was only short term, however, and does not disprove the theory that elevated prorenin predicts the development of microvascular disease during long-term follow-up (7).

In the present study, we observed that the renin to prorenin ratio was decreased at the time of the first patient evaluation when there was no evidence of autonomic dysfunction and no correlation between any test of autonomic function and the renin to prorenin ratio. This indicates that neither autonomic neuropathy nor microvascular disease are critical determinants of the decreased prorenin processing associated with diabetes. Lush et al. (30) have argued that multiple potential intrarenal mechanisms, such as dysfunction of the macula densa, have been shown to differentially affect renin and prorenin and there is no need to invoke neurological dysfunction or other extrarenal mechanisms to explain diabetes-related abnormalities. Unfortunately, most of the intrarenal abnormalities postulated by Lush et al. (30) are difficult to test in the whole patient.

In summary, we have documented that the renin to prorenin ratio is decreased early in type 1 diabetes when patients are normotensive and have little or no microvascular disease or hypervolemia. Thus, it seems unlikely that any of these factors directly mediate the abnormal prorenin processing. We observed a correlation between global cardiovascular autonomic function and cardiac autonomic power spectra and the renin to prorenin ratio at the time of the third patient evaluation. Although this supports previous studies implicating autonomic dysfunction, decreased renin to prorenin ratios were documented at the first and second patient evaluations when autonomic function was still apparently normal. Thus, additional as yet unidentified factors must also disrupt prorenin processing in early diabetes.

	Footnotes

 
¹ This study was supported by the National Institutes of Health Grant DK-32239 (to R.D.H.) and the Compton Nutrition Foundation.

Received September 10, 1999.

Revised October 18, 1999.

Accepted October 27, 1999.

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