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(Hypertension. 1996;27:735-739.)
© 1996 American Heart Association, Inc.
Articles |
Poor Glycemic Control Induces Hypertension in Diabetes Mellitus
From the Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson.
Correspondence to Michael W. Brands, PhD, Department of Physiology and Biophysics, University of Mississippi Medical Center, 2500 North State St, Jackson, MS 39216.
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Abstract |
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Abstract We conducted this study to test the hypothesis that hypertension is a primary consequence of poor glycemic control per se very early in insulin-dependent diabetes mellitus. Sprague-Dawley rats (n=15) were instrumented with artery and vein catheters, placed in metabolic cages, and sodium intake was clamped throughout the study. Mean arterial pressure was measured 24 h/d. After a precontrol period, streptozotocin (70 mg/kg IV) was administered, and 15 hours later a continuous intravenous insulin infusion was begun at 4 U/rat per day. The insulin infusion was titrated on an individual rat basis to maintain good glycemic control, and after this 7-day control period, blood glucose, urinary sodium excretion, and mean arterial pressure were not different from precontrol values, averaging 8.8±0.6 mmol/L, 2.8±0.2 mmol/d, and 103±2 mm Hg, respectively, for control days 5 through 7. Subsequently, a 4-day period of poor glycemic control was initiated by reducing the insulin infusion rate. Blood glucose, urinary sodium excretion, and mean arterial pressure began to increase on day 1; for diabetes days 3 and 4, they averaged 23.4±1.0 mmol/L, 3.6±0.1 mmol/d, and 110±2 mm Hg, respectively. All were significantly elevated. When insulin treatment was restored, all variables returned to control levels during the next 4 days. A second 4-day diabetic period yielded similar results. These results indicate that elevated blood pressure is a primary consequence of poor glycemic control in insulin-dependent diabetes, occurring before renal injury has had time to develop, and therefore, may be a factor contributing to the initiation of end-organ injury.
Key Words: blood pressure • diabetes mellitus, insulin-dependent • sodium
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Introduction |
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TopAbstractIntroductionMethods Results Discussion References |
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Associated with the progression of insulin-dependent diabetes mellitus (IDDM) to diabetic nephropathy is the development of hypertension.1 2 3 Because impaired renal function is known to raise systemic blood pressure,4 5 and because hypertension rarely is diagnosed in the patient with IDDM before the onset of nephropathy, hypertension in IDDM traditionally has been considered a secondary complication of diabetes.1 2 3 However, since it also is clear that hypertension exacerbates the renal damage,1 2 3 6 7 8 9 it has long been considered possible that increased blood pressure might be a direct consequence of poor glycemic control very early in IDDM, and therefore, that increased blood pressure might contribute to the onset of the renal damage.3
Evidence for this potential role of early increases in blood pressure, despite the low frequency of overt hypertension in prenephropathic patients, comes from the results of multiple studies that suggest that there is a mild but progressive rise in blood pressure in IDDM patients that parallels the rise in urinary albumin excretion.10 11 This suggests that the deleterious relationship between blood pressure and renal damage in IDDM does not begin with nephropathy but rather is a continuous relationship beginning at the earliest stages of diabetes. However, even when the earliest detectable increases in blood pressure and albumin excretion have been taken into consideration, it has been difficult to determine clinically which abnormality comes first.
The finding of increased glomerular basement membrane thickness 2 to 3 years after diagnosis of IDDM12 13 in patients with normoalbuminuria and normal blood pressure suggests that glomerular damage precedes the rise in blood pressure. Most hypotheses focus on a role of hyperglycemia in causing the renal damage, either directly14 15 16 17 18 or mediated through effects of hyperglycemia on intrarenal hemodynamics.6 19 20 However, it is important to note that much of the rationale for considering increased blood pressure in IDDM solely as a phenomenon secondary to hyperglycemia-induced renal damage may stem from an inability to measure early elevations in blood pressure. But is that because blood pressure really is not elevated or because of an inability to accurately assess the effect of poor metabolic control per se on arterial pressure early in IDDM?
The answer to this question is essential to determine whether elevated blood pressure in IDDM is solely a secondary complication of renal damage or is a primary consequence of poor glycemic control, which then could contribute significantly to the initiation of end-organ damage in diabetes. Therefore, the goal of this study was to test the hypothesis that mean arterial pressure will increase significantly immediately after the onset of poor glycemic control in IDDM.
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Methods |
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Experiments were conducted in 15 male Sprague-Dawley rats (approximately 350 g, Harlan Sprague-Dawley, Madison, Wis), and the protocols were approved by the Institutional Animal Care and Use Committee at the University of Mississippi Medical Center. Under sodium pentobarbital anesthesia (50 mg/kg IP) and aseptic conditions, a laparotomy was performed and a nonocclusive polyvinyl catheter was inserted into the abdominal aorta, caudal to the kidneys, via a puncture made with an 18-gauge needle tip. The insertion point was sealed with cyanoacrylate adhesive, and the catheter was exteriorized through the lateral abdominal wall. A femoral vein catheter was implanted through a separate incision, and the tip was maneuvered into the vena cava. Incisions were infiltrated with penicillin G procaine (300 000 U/mL) and bupivacaine (0.25%) at closure and the catheters were routed subcutaneously to the scapular region and exteriorized through a Dacron-covered stainless steel button sutured subcutaneously over the scapulae.
The rats were allowed to recover from surgery and then were placed in individual metabolic cages in a quiet, air-conditioned room with a 12-hour light/dark cycle. The catheters were passed through a stainless steel spring that was attached to the button, and the opposite end of the spring was connected to a dual-channel hydraulic swivel (Instech) mounted above the cage. The venous catheter was immediately connected, via the hydraulic swivel, to a syringe pump (Harvard Apparatus) that ran continuously throughout the study. All solutions contained antibiotic (25 000 U penicillin G/rat per day and 0.03 g mezlocillin/rat per day) and were infused through a Millipore filter (0.22-mm, Cathivex, Millipore Corp). The arterial catheter was filled with heparin solution (1000 United States Pharmacopeia U/mL) and connected, also via the swivel, to a pressure transducer (Cobe) mounted on the exterior of the cage at the level of the rat. The analog signals from the transducer were amplified and sampled for 4 seconds each minute, 24 h/d, by computer with customized software.
Total sodium intake throughout the experiment was maintained constant at approximately 3.1 mmol/d by continuous intravenous infusion of 20 mL/d sterile 0.9% saline combined with sodium-deficient rat chow (0.006 mmol sodium/g; Teklad). A sodium-deficient diet ensured that the daily sodium intake could be controlled precisely by the infusion. This infusion was begun immediately after placement of the rat in the metabolic cage, and 5 to 7 days were allowed for acclimation before control measurements were recorded.
Experimental Protocol
After sodium balance, stable arterial
pressure, and
blood glucose level were determined, streptozotocin (STZ) was
administered (70 mg/kg IV) at 4:00 PM. At 7:00
AM the next day, after determining the rats were
hyperglycemic, a continuous intravenous infusion of regular
insulin (porcine, Norvo Nordisk) was begun at 4 U/d. The insulin dose
was titrated over the next 6 days, on an individual rat basis, to
maintain glycemic control.
After establishing normal blood glucose concentrations, the insulin dose was reduced to induce diabetes. This period of poor glycemic control lasted 4 days and the insulin dose was adjusted to yield blood glucose levels of approximately 22 mmol/L (400 mg/dL) in each rat. After the 4-day period of poor control, the insulin dose was increased to restore glycemic control and to determine whether the effects of diabetes were reversible (recovery period). To determine whether the effects could be repeated after 4 days of good glycemic control, diabetes was induced a second time by lowering the insulin dose for 4 days.
Analytical Methods
Blood glucose level was determined daily
with the use of
approximately 50 uL of blood from the arterial catheter and
an Accucheck II glucose analyzer.
Urinary sodium and potassium concentrations were determined with the use of ion-sensitive electrodes (Nova). Results are presented as mean±SE. Experimental data were compared with control data using ANOVA for repeated measures and Dunnett's test, with the precontrol period serving as the control value for the Dunnett's comparisons.21 Data from the second diabetic period were analyzed using a separate ANOVA in which the last 2 days of the recovery period served as the control. Statistical significance was considered to be P<.05.
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Results |
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TopAbstractIntroductionMethods Results Discussion References |
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STZ Plus Insulin Therapy
The daily blood glucose values are presented in Fig 1
. Blood glucose averaged 6.2±0.1
mmol/L during the
precontrol period and rose to 22.8±1.6 mmol/L 15 hours after STZ
administration. Initiation of insulin therapy (control period) promptly
restored blood glucose to levels not significantly different from
precontrol values, averaging 8.8±0.6 mmol/L for control days 5 through
7 and 7.7±0.9 mmol/L on day 7. The insulin dose required to maintain
glycemic control averaged 4.1±0.5 U/day for control days 5 through 7
(Fig 2). Fig 3 shows that no significant
change in mean arterial pressure from the precontrol value
of 105±2 mm Hg occurred during the control period, with mean
arterial pressure averaging 103±2 mm Hg for control
days 5 through 7. An approximate 70% increase in urinary sodium
excretion, from 2.3±0.2 to 3.9±0.4 mmol/d, occurred with STZ
administration, but by control day 3 sodium excretion had returned to
levels that were not significantly different from precontrol levels
(Fig 4). Thus, the continuous intravenous
insulin-replacement therapy that followed STZ administration was
effective in maintaining glycemic control, arterial
pressure, and renal sodium excretory function at levels not different
from pre-STZ conditions.
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Induction of Diabetes: First Period of Poor Glycemic
Control
Diabetes was induced by reducing the insulin infusion rate
after 7
days of STZ plus insulin. Blood glucose levels increased significantly,
to 17.8±2.1 mmol/L on diabetes day 1 and averaged 23.4±1.0
mmol/L for
diabetes days 3 and 4 (Fig 1
). This resulted in a significant
increase
in mean arterial pressure, to 110±2 mm Hg by diabetes day
4, compared with the precontrol blood pressure (Fig 3). (If the
average
arterial pressure on control days 5 through 7 is used as
the control value for the diabetic period, then the increase in blood
pressure is statistically significant for all 4 days.) This increase in
mean arterial pressure occurred despite significant sodium
loss during the diabetic period; urinary sodium excretion averaged
3.6±0.1 mmol/d during diabetes days 3 and 4, and 2.8 mmol of sodium
(approximately 1 day's total sodium intake) was lost during the 4-day
diabetic period.
Recovery From Diabetes
After 4 days of poor glycemic control,
insulin therapy was resumed
(Fig 2) and blood glucose returned to levels that were not
different
from control values, averaging 7.5±1.7 mmol/L by day 4 of recovery
(Fig 1). The restoration of good glycemic control was marked by
a
decrease in mean arterial pressure (Fig 3) and urinary
sodium excretion (Fig 4) to control levels. For recovery days 3
and 4,
arterial pressure averaged 102±2 mm Hg and sodium
excretion averaged 2.7±0.2 mmol/d; thus, the hypertensive and
natriuretic effects of poor glycemic control were
reversible with restoration of insulin therapy and normalization of
blood glucose.
Induction of Diabetes: Second Period of Poor Glycemic
Control
Because the rise in blood pressure with poor glycemic control
was
relatively modest despite statistical significance, a second period of
poor glycemic control was induced in eight rats to confirm the link
between glycemic control and blood pressure and to better evaluate
physiological significance.
Reducing the insulin infusion dose a second
time (Fig 2) in eight rats
again caused significant increases in blood glucose (Fig 1) and
mean
arterial pressure (Fig 3), and the rise in
arterial pressure again occurred despite significant
urinary sodium loss (Fig 4). Blood glucose averaged
23.8±0.7 mmol/L
during diabetes days 3 and 4, and mean arterial pressure
rose to 110±3 mm Hg by diabetes day 4. With the increase in urinary
sodium excretion during the second period of poor glycemic control, to
3.6±0.2 mmol/d by diabetes day 4, an average of 4.0 mmol sodium was
lost.
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Discussion |
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TopAbstractIntroductionMethods Results Discussion References |
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Progressive renal injury is a complication of IDDM, but the mechanisms contributing to its induction remain poorly understood. Previous studies have reported that blood pressure was higher in young diabetic patients without overt signs of diabetic renal complications when glycemic control was poor and that improved control with insulin therapy lowered blood pressure.22 23 If this relationship between glycemic control and blood pressure is operative from the very earliest stages of the disease, this would indicate that elevated blood pressure in IDDM patients is not solely a secondary complication of renal damage and therefore would suggest that early derangements in blood pressure control could contribute significantly to the initiation of end-organ damage in diabetes.
In the present study, the onset of poor glycemic control in IDDM patients caused a significant and sustained increase in mean arterial pressure. An important feature of the experimental model was that the immediate effects of poor glycemic control were compared with the conditions under good glycemic control in the same subject. This within-subject design combined with 24-h/d measurement of blood pressure and renal function provided a powerful means for evaluating the effects of poor glycemic control. In addition, elimination of uncertainty about when diabetes actually began revealed that the effects of poor glycemic control occurred before renal pathological changes had time to develop. These results therefore indicate that poor glycemic control in IDDM can independently raise mean arterial pressure.
Other studies have attempted to investigate the chronic blood pressure effect of IDDM with the use of the STZ-infused rat experimental model of IDDM,6 8 20 24 25 26 but the results have been conflicting. More importantly, however, previous techniques for studying blood pressure in this model have had limitations that may have confounded accurate assessment. First, all studies have measured blood pressure acutely, and in most circumstances, with the tail-cuff method. The handling stress associated with any acute measurement of blood pressure in rats (due to moving the rat from its home cage to the laboratory, to disturbing the normal sleep pattern with daytime handling, and to restraining methods if employed) may prevent accurate assessment of the average arterial pressure over a 24-hour period.27 In the present study this potentially confounding influence was eliminated by measuring mean arterial pressure continuously, 24 h/d.
Another limitation of previous studies is that most began measurements 2 to 4 weeks after STZ administration, and evidence that increases in urinary albumin excretion begin to occur during that time period26 indicates that the potential contribution of early glomerular damage cannot be eliminated. Moreover, even when blood pressure was measured immediately after STZ administration, the independent effect of diabetes cannot be separated from the simultaneous and potentially confounding side effects of STZ. This problem was avoided in the present study by quickly restoring glycemic control after STZ administration and demonstrating that glycemic control, mean arterial pressure, and renal sodium excretory function in the insulin-infused STZ rats were not different from pre-STZ conditions; diabetes then was induced by reducing the insulin infusion rate.
Additional difficulties have arisen in previous studies because rats generally have been provided chow ad libitum, which proves problematic because STZ rats tend to be hyperphagic, therefore consuming more sodium than their nondiabetic control group,28 29 30 and there is evidence that blood pressure in IDDM may be salt sensitive.28 31 32 In the present study, the rats were fed a sodium-deficient diet so that sodium intake could be clamped throughout the study, independent of food intake, with a fixed intravenous infusion of isotonic saline. Therefore, the increases in blood pressure and sodium excretion during poor glycemic control were independent of a change in sodium intake. Moreover, because of the significant sodium loss during each 4-day diabetic period, averaging approximately 1 day's total sodium intake for each period, the rise in arterial pressure was even more striking, which prompts speculation about whether blood pressure would have risen further if sodium intake had increased during the diabetic period.
The increases in sodium excretion that occurred during the periods of poor glycemic control in the present study closely resemble the changes observed in human IDDM patients on removal of insulin therapy. This strengthens the relevance of this experimental model to IDDM in humans but also raises questions regarding the mechanism for the rise in blood pressure that is associated with poor glycemic control. One possibility is that the blood pressure increase is due to changes in intravascular volume. Blood volume has been proposed to increase with removal of insulin therapy, despite the increase in sodium excretion, because of hyperglycemia-induced osmotic fluid shifts.31 33 However, an increase in blood pressure due to this mechanism, with no shift in the renal pressure-natriuresis relationship, would only be transient because pressure natriuresis would quickly return blood pressure to control levels.4 5 Thus, although an osmotic diuresis undoubtedly contributed to the natriuresis during the diabetic period, this could have been exacerbated by pressure natriuresis.
Consequently, if the period of poor glycemic control had been extended, blood pressure might have returned to control levels. However, because arterial pressure appeared to plateau during each 4-day diabetic period, with little evidence of a decrease, the pressor and natriuretic responses may have been parallel effects of poor glycemic control that were not mechanistically linked. This again, however, raises the question of whether blood pressure would have increased further with a high sodium intake.
The natriuresis associated with removal of insulin therapy in IDDM patients and antinatriuresis after the restarting of treatment has been attributed, at least in part, to a sodium-retaining action of insulin.33 34 35 36 In fact, insulin has been reported to increase renal tubular sodium chloride transport directly,35 36 and this has been postulated to underlie a hypertensive action of insulin in hyperinsulinemic conditions such as obesity and non–insulin dependent diabetes mellitus.35 In support of this possibility, we have reported that hyperinsulinemia raises blood pressure in normal rats.37 38 However, although the relationship between insulin treatment and sodium excretion in the diabetic rats in the present study closely resembles the response observed in IDDM patients, the changes in blood pressure are opposite to what would be predicted based on the sodium-retaining actions of insulin (ie, when insulin was removed, sodium excretion increased and blood pressure rose).
It is uncertain how these results, in which blood pressure increased with low levels of insulin, compare with our previous studies reporting hypertension with high insulin levels.37 38 It is important to note, however, that in the present study, a low level of insulin was accompanied by poor glycemic control and hyperglycemia, whereas in the insulin-hypertension studies, high insulin levels were present in a normoglycemic state.37 38 Thus, one possible explanation is that insulin has a biphasic effect, or perhaps the different glucose levels contribute to the blood pressure actions of insulin. Another, possibly related, explanation is that the loss of insulin's vasodilator action when insulin was lowered from normal levels contributed to the rise in blood pressure. We have reported that chronic hyperinsulinemia causes marked and sustained vasodilation in normal, insulin-sensitive dogs,39 40 and acute insulin infusions also induce vasodilation in normal humans.41 42 Attenuation of this hemodynamic action of insulin in insulin-resistant states, such as obesity and non–insulin dependent diabetes mellitus, has been proposed to contribute to the elevated blood pressure associated with those conditions.41 42 43 Whether low insulin per se is quantitatively important in contributing to the blood pressure rise induced by the onset of poor glycemic control in IDDM, however, will require additional study.
Also relegated to future studies must be the investigation of other factors potentially involved in this response, such as the renin-angiotensin system, the sympathetic nervous system, and possibly, endothelial factors. However, although the mechanism for the rise in blood pressure in this study is not known, the demonstration that blood pressure increased immediately, before renal damage had time to develop, that it was sustained for at least 4 days, and that it was reversible indicates that elevated blood pressure is a primary consequence of poor glycemic control in IDDM. In addition, the rise in blood pressure occurred despite significant and sustained natriuresis during the poorly controlled period, prompting speculation that increased sodium intake may have yielded a greater increase in blood pressure. Moreover, since autoregulation is impaired in diabetes,44 45 46 it is likely that end-organ transmission of the elevated pressure would be exaggerated. Thus, these results provide new evidence which suggests that increases in blood pressure very early in IDDM may be a factor contributing to the initiation of end-organ damage in diabetes.
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Acknowledgments |
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This research was supported by grant HL-51971 from the National Institutes of Health and by a Grant-in-Aid from the American Heart Association, with funds contributed in part by the AHA, Mississippi Affiliate. The authors thank John R. Acord, Jr, for technical assistance.
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