Diabetic Control and the Renin-Angiotensin
System, Catecholamines, and Blood Pressure
J. B A R R Y F E R R I S S , JAMES A.
M A R G A R E T M.
O ' H A R E , CECILY C. M.
KELLEHER, PATRICK A.
C O L E , H A Z E L F. R O S S , AND DENIS J.
SULLIVAN,
O'SULLIVAN
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SUMMARY Diabetic ketoacldosis is usually associated with marked secondary hyperaldosteronism. Plasma levels of renin, angiotensin II, and aldosterone are markedly raised before treatment in
most patients, with values falling rapidly toward normal as metabolic control is restored. In a few
patients, mostly those with long-term complications of diabetes, plasma levels of renin, angiotensin II,
and aldosterone before treatment remain within the normal range. In moderately hyperglycemic
patients who have glycosuria but not ketonuria, plasma levels of all three substances are significantly
higher than when control is improved. Occasionally, moderately hyperglycemic patients have mild
secondary hyperaldosteronism. Improved metabolic control in such patients causes a rise in plasma
volume and a rise in total exchangeable sodium, the latter to levels significantly above normal. Plasma
catecholamine levels are markedly elevated in diabetic ketoacidosis, probably as a consequence of the
ketoacidotic state. In nonketotic patients with moderate hyperglycemia, basal plasma norepinephrine
levels are normal; catecholamine responses to exercise may be exaggerated, however. Epidemiological
and animal studies suggest a relationship between blood pressure and blood glucose levels. There are
few clinical studies of the effects of altering metabolic control of diabetes on blood pressure, and this is
an important area for further study. (Hypertension 7 [Suppl II]: II-58-11-63, 1985)
KEY WORDS • angiotensin II • aldosterone • plasma renin activity • plasma volume
exchangeable sodium * norepinephrine * diabetes mellitus • hypertension
T
HE abnormalities that occur in diabetic ketoacidosis have been investigated in detail. Less
attention has been given to disturbances associated with poorly controlled nonketotic diabetes, although this metabolic state is all too common among
our diabetic patients. In particular, the long-term effect
of poor metabolic control on blood pressure is poorly
understood.
In this review we briefly discuss abnormalities of the
renin-angiotensin system and catecholamines in ketoacidosis. Disturbances that occur in nonketotic, poorly
controlled diabetes mellitus are also examined; these
include changes in the renin-angiotensin system, body
sodium, and plasma volume with altering metabolic
control. The findings emphasize the importance of assessing metabolic control when examining these variables in diabetic patients. Finally, the possible effect of
poor metabolic control of diabetes on blood pressure is
discussed.
The Renin-Angiotensin System in Ketoacidosis
Ten years ago Christlieb et al. 1 described marked
secondary hyperaldosteronism in diabetic ketoacidosis. Plasma renin activity (PRA) was grossly elevated
in 13 patients in ketoacidosis, levels falling rapidly
toward normal as metabolic control was restored. Plasma aldosterone concentrations, measured in four patients, were also raised.
Several groups confirmed these observations. Scott
et al. 2 reported raised levels of PRA and aldosterone in
seven of eight patients in ketoacidosis. Waldhausl et
al.3 also described marked elevations of renin and aldosterone in a small group of severely hyperglycemic
and mostly ketoacidotic patients. We found high levels
of plasma angiotensin II4 and aldosterone 5 in most patients in ketoacidosis (Figure 1). Plasma angiotensin II
concentrations were within the normal range in 5 of 14
patients, however, all of whom had long-term complications of diabetes such as retinopathy, neuropathy,
and nephropathy. Even in these patients there was
some decrease in plasma angiotensin II with improved
metabolic control.
High renin levels in ketoacidosis have been attributed to fluid volume depletion,' although other factors
From the Department of Medicine and Department of Statistics
(M.M. Cole), Regional Hospital and University College, Cork,
Ireland.
Address for reprints: Prof. J. Barry Ferriss, Department of Medicine, Regional Hospital, Cork, Ireland.
11-58
CHANGING DIABETIC CONTROL/Ferriss et al.
11-59
KETOACIDOSIS
PLASMA ANGtOTENSlNI
PtASMA. AIDOSTERONE
PO/ml
nfl/lOOmi
2SO
P«0 0O2
200-
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Before
When
Treatment
f
P<0001
led
JI_LJ- J J
Free of long Term Complication*
With Lang Term Complication!
Wort
Whan
Treatment
Controlled
•
•
FIGURE 1. Individual plasma concentrations of angiotensin II and aldostewne in 14 patients with ketoacidosis
before treatment and when metabolic control was restored (mean interval 9 days). Mean blood glucose (± SEM)
before treatment was 33.3 ± 4.2 mmollL, and when control was restored, meanfasting blood glucose was 11.5 ±
1.7 mmollL fp < 0.001). The stippled areas represent the respective normal ranges in supine subjects.
may also be important. Among our patients, pretreatment plasma angiotensin II concentrations were not
related to indirect indexes of dehydration but were
inversely related to pH (r = - 0 . 6 5 , p < 0.01). It is
probable that hydrogen ions do not directly stimulate
renin secretion,6 but pH may reflect the metabolic disturbance that stimulates renin more accurately than
indexes of dehydration.4 Activation of the renin-angiotensin system in ketoacidosis may be clinically important. Circulating angiotensin II may be important in
maintaining blood pressure in sodium-depleted subjects, 7 while secondary hyperaldosteronism, which increases renal potassium wasting, may also protect patients from even more marked hyperkalemia than
actually occurs.' In some circumstances, high angiotensin II concentrations may cause multifocal myocardial necrosis and cardiac arrest8; it is not known if the
grossly raised concentrations sometimes seen in ketoacidosis can cause myocardial damage.
Plasma Catecholamines in Ketoacidosis
Circulating catecholamine levels are also elevated in
established ketoacidosis. Christensen9 described consistently raised plasma norepinephrine values in untreated patients, levels being positively related to the
severity of the metabolic disturbance. Plasma epineph-
rine concentrations were elevated in only some patients. Once metabolic control was restored, both norepinephrine and epinephrine values were similar to
those of healthy controls. Waldhausl et al. 3 reported a
10-fold increase in mean plasma norepinephrine and a
20-fold increase in mean plasma epinephrine levels in
poorly controlled diabetic patients, mostly in ketoacidosis. Plasma concentrations again fell rapidly toward
normal as metabolic control was restored.
The lipolytic and ketogenic action of catecholamines may further aggravate established ketoacidosis. A rise in plasma norepinephrine and epinephrine
does not precede the development of ketoacidosis
when insulin is withdrawn, however.10 This suggests
that elevated levels are sequelae of ketoacidosis rather
than an initiating cause.
The Renin-Angiotensin System in Poorly
Controlled Nonketotic Diabetes
Abnormalities of the renin-angiotensin system in
poorly controlled nonketotic diabetes are less marked
than in ketoacidosis. Christlieb et al. 1 were unable to
demonstrate a significant change in PRA with improved metabolic control in nonketotic patients, while
in the alloxan-diabetic rat, PRA was suppressed in
proportion to the severity of diabetes."
H-60
DIABETES AND HYPERTENSION
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As illustrated in Figure 2, we found a significant fall
in PRA, plasma angiotensin n, and plasma aldosterone
with improved metabolic control of diabetes.3'l2> 13 All
patients were free of ketonuria, but most had glycosuria when metabolic control was poor. The changes
were observed in types I and II diabetes and in patients
with and without complications of diabetes. On the
other hand, patients studied on two occasions without
alteration of metabolic control failed to show a change
in any of these variables (see Figure 2). During poor
metabolic control, plasma concentrations of angiotensin II were more than two standard deviations above
the mean of healthy controls in 7 (22%) of 32 patients,
while plasma aldosterone concentrations were similarly elevated in 6 (20%) of 30 patients. This indicates
that some patients with poorly controlled diabetes have
mild secondary hyperaldosteronism, even in the absence of ketosis.5
These findings illustrate the need to define the degree of metabolic control when studying the reninangiotensin system in diabetic patients. Plasma levels
of angiotensin II close to or within the normal range
may exert a pressor effect14 and the higher plasma
angiotensin II concentrations during poor metabolic
control may contribute to higher blood pressure levels.
SUPPL
II HYPERTENSION, VOL 7, No 6, NOV-DEC 1985
Plasma Catecholamines in Poorly Controlled
Nonketotic Diabetes
Altered metabolic control of diabetes does not cause
marked changes in basal circulating catecholamine
concentrations in the absence of ketosis. Improvement
of metabolic control by continuous subcutaneous insulin infusion did not alter basal concentrations of
epinephrine or norepinephrine.131 l6 Catecholamine responses to exercise were exaggerated during conventional control, however, returning to normal during
insulin infusion.15
We measured plasma norepinephrine in 11 nonketotic diabetic patients free of long-term complications,
both when metabolic control of diabetes was poor and
again when control improved. Plasma norepinephrine
was determined using the solvent extraction system of
Smedes et al.17 and analysis by high-performance liquid chromatography (Waters Associates, Milford,
MA, USA), with electrochemical detection (Bio-Analytical Systems, West Layfayette, IN, USA) (detection
limit < 75 pg/ml; intraassay and interassay coefficients of variation < 10%). Samples were taken when
patients were supine after overnight rest and again
when upright for 10 minutes.
Supine and upright plasma norepinephrine concen-
Control Improved
Control Unchanged
PR A
(ng/ml/h)
0.6-
0.3-
FIGURE 2. Mean values ( ± SEM) of plasma renin activity (PRA), plasma angiotensin II, and aldosterone in diabetic patients
free of ketonuria studied when fasting and
supine overnight. Values during poor metabolic control (open circles) and when control improved (closed circles) are shown on
the left; the mean of five to six blood glucose
measurements over 24 hours were 15.9 ±
0.5 and 7.9 ± 0.4 mmollL respectively (p
< 0.001); mean urinary volumes were 1589
± 118 and 1436 ± 112 ml respectively (NS)
on the two study occasions. The mean interval between studies was 6 weeks. Values
when metabolic control was unchanged on
two occasions (closed triangles) are shown
on the right. Means of five to six blood
glucose measurements over 24 hours were
12.9 ± 1.4andl2.6 ± 1.7mmoULrespectively (n = 10, NS). The mean interval between studies was 6 weeks.
n= 1 5
P < 0.0 1
n=6
NS
n = 32
P < 0.02
n=10
NS
n=6
NS
PLASMA
ANGIOTENSIN H
(pg/ml)
30-
1O J
PLASMA
ALDOSTERONE
(ng/ 100ml)
20
n = 30
P < 0.0 1
CHANGING DIABETIC CONTROL!Ferriss et al.
trations were similar and the postural response was
unchanged when metabolic control improved (Figure
3). Values were similar in patients receiving and not
receiving insulin on each occasion. The findings were
in keeping with observations that basal plasma catecholamines are unchanged by poorly controlled nonketotic diabetes.
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Plasma Volume and Exchangeable Sodium in
Poorly Controlled Nonketotic Diabetes
It has been suggested that osmotic volume expansion associated with hyperglycemia may contribute to
the increased prevalence of hypertension in younger
diabetic patients.18 Blood volume was increased in
both alloxan-diabetic" and streptozotocin-diabetic19
rats. In humans, plasma volume was higher in normotensive diabetic patients than in matched controls in
one study,20 but others found a similar plasma volume
in normotensive diabetics and controls.21-22 Christlieb
et al.1 did not note a change in blood volume when
metabolic control improved in nonketotic patients.
We studied 12 patients with nonketotic diabetes
when metabolic control was poor and again when control improved.12 On each occasion, blood pressure was
measured under standardized conditions after overnight rest, using a London School of Hygiene Sphygmomanometer (Cinetronics Ltd., Mildenhall, England), and the average of five readings taken over 20
minutes was calculated. Plasma volume was measured
in 11 of these patients and exchangeable sodium in 9.
The mean interval between studies was 3 weeks. With
improved metabolic control of diabetes, there was a
significant fall in both systolic and diastolic blood
pressures, while plasma volume and exchangeable sodium each rose significantly (Figure 4). Exchangeable
sodium was similar to that of healthy control subjects
when metabolic control was poor, but rose to levels
significantly above normal when metabolic control improved.12 In this small series there was an inverse relationship between the change in exchangeable sodium
and the change in both systolic (r = — 0.78, p < 0.01)
and diastolic (r = — 0.66, p < 0.05) blood pressures.
An elevated exchangeable sodium has been described in metabolically controlled diabetic patients,21"24 and the increased values when metabolic
control was improved are in keeping with these observations. The rise in exchangeable sodium with improved control is in keeping with short-term balance
studies that showed sodium retention." It may reflect
the reversal of sodium loss associated with even a mild
osmotic diuresis during poor control and the direct
sodium-retaining effect of insulin on the kidneys.26 In
view of the negative association between changes in
blood pressure and in exchangeable sodium, sodium
retention could also result from an antinatriuresis associated with a fall in blood pressure. The rise in plasma
volume with improved control in humans contrasts
with findings in diabetic rats. Our findings do not
support the hypothesis that plasma volume is osmotically expanded in humans when metabolic control of
diabetes is poor.
The Effect on Blood Pressure of Altering
Metabolic Control
Epidemiological studies indicate an independent association between blood pressure and blood glucose. A
positive relationship has been shown between both
systolic and diastolic pressures and blood glucose after
a glucose load in middle-aged populations. This persisted when controlled for age, body weight, and heart
rate.27-M An independent relationship between blood
PLASMA
NOREPINEPHRINE
( pg/ml)
600
11-61
P < 0.001
P < 0.001
400Poor Control
Improved Control
FIGURE 3. Plasma norepinephrine (mean values ± SEM) in 11 diabetic patients when supine (open circles) and
after 10 minutes standing (closed circles), when metabolic control was poor (left-hand pair) and when control
improved (right-hand pair). The mean of five to six blood glucose measurements over 24 hours was 15.9 ± 0.8
mmol/L when control was poor and 8.1 ± 0.4 mmol/L when control improved (p < 0.001); mean 24-hour urinary
volumes were 1984 ± 128 and 1765 ± 233 ml respectively (NS). The mean interval between studies was 3 weeks.
All patients were free of clinical evidence of long-term complications of diabetes and none had ketonuria. There
were no significant differences in supine or upright values when metabolic control was altered.
11-62
DIABETES AND HYPERTENSION
SUPPL
II
HYPERTENSION, VOL
7, No 6,
NOV-DEC
1985
DIASTOLIC BP
(mmHg)
SYSTOLIC BP
(rnmHg)
80
130-
P < 0.0S
120-
70
3300-
PLASMA VOLUME
(ml)
3400
NaE
(mmol)
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3000-
3100-
Improved Control
Improved Control
Poor Control
Poor Control
FIGURE 4. Mean values (± SEM) of systolic and diastolic blood pressure (n = 12), exchangeable sodiun (n =
9), and plasma volume (n = 11), when metabolic control was poor (open circles) and when control improved
(closed circles). The mean of five to six blood glucose measurements over 24 hours was 16.5 ±0.9 mmoltL when
control was poor and 8.0 ± 0.5 mmollL when control improved (n = 12, p < 0.001); mean 24-hour urinary
volumes were 1803 ± 153 and 1507 ± 232 ml respectively (NS). The mean interval between studies was 3 weeks.
All patients were free of ketonuria.
pressure and postprandial glucose was also noted in
schoolchildren.29 The association in these populations
raises the possibility of a similar relationship in diabetic subjects.
The metabolic control of diabetes may influence
blood pressure levels in the rat. In streptozotocin-diabetic rats there was a dose-related blood pressure rise
in normotensive animals at least,30-31 and hypertension
may be reduced by insulin injections.32
There are few clinical studies of the effects of altering metabolic control of diabetes on blood pressure. As
mentioned, we found a small but significant fall in
systolic and diastolic pressures with improved metabolic control (see Figure 4). Blood pressure often falls
on repeated measurement, however, 33 and despite efforts to standardize measurements, familiarization
may have contributed to the reductions observed. We
would have liked to study patients in reverse, when
control was good and subsequently when control deteriorated, but had ethical reservations about allowing
deliberate worsening of metabolic control for a prolonged period.
Gunderson34 studied acute changes in young patients
with insulin-dependent diabetes with altering metabolic control. Some were newly diagnosed as having dia-
betes, but in most, insulin was withdrawn under supervision. Mean arterial pressure was significantly higher
when metabolic control was poor, compared with values when control was optimal. Blood pressure changes
with altering control were not related to changes in
blood glucose but were significantly related to changes
in standard bicarbonate and free fatty acids. Some patients developed mild ketoacidosis, however.
The influence of metabolic control of diabetes on
blood pressure is an important area for further investigation. Because of blood pressure variation even under
standardized conditions, it is difficult to demonstrate
small changes. This may explain why alteration of
metabolic control in small groups may not be associated with significant alterations in blood pressure, even
if the degree of metabolic control does influence blood
pressure levels. Because of blood pressure variability,
we calculate that to detect an independent, unidirectional 4-mm change in systolic pressure between two
study occasions, it would be necessary to investigate
approximately 45 patients for a change at the 5% significance level and approximately 100 patients for a
change at the 1% level.
Hypertension is an important prognostic indicator
for the diabetic patient.18 Even small changes in blood
CHANGING DIABETIC CONTROL/Ferriss
pressure may have long-term importance, and the effect of long-term poor metabolic control of diabetes on
blood pressure needs fuller evaluation. If poor metabolic control causes even a small increase in blood
pressure, this may be an additional explanation for the
association between hypertension and diabetes. Hypertension is a quantitative disorder and any definition
is arbitrary. 35 In a diabetic population, poor metabolic
control may move some patients from just below to
just above an arbitrary upper limit of normal blood
pressure for the particular age and sex. This change
would cause an increased prevalence of hypertension
in a diabetic population at any given time unless all are
in good metabolic control, an unlikely event in current
diabetic practice.
Acknowledgment
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We are grateful for the financial support of the Medical Research
Council of Ireland.
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Diabetic control and the renin-angiotensin system, catecholamines, and blood pressure.
J B Ferriss, J A O'Hare, C C Kelleher, P A Sullivan, M M Cole, H F Ross and D J O'Sullivan
Hypertension. 1985;7:II58
doi: 10.1161/01.HYP.7.6_Pt_2.II58
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