(Hypertension. 1995;26:186-192.)
© 1995 American Heart Association, Inc.
Articles |
Glucose Metabolism in Abdominally Obese Hypertensive and Normotensive Subjects
From the Department of Medicine and the Clinical Research Center, Medical College of Wisconsin, Milwaukee, and the Division of Clinical Pharmacology, Departments of Pharmacology and Medicine, Medical University of South Carolina, Charleston.
Correspondence to Ahmed H. Kissebah, MD, PhD, Department of Medicine, Division of Endocrinology, Metabolism, and Clinical Nutrition, Froedtert Memorial Lutheran Hospital, 9200 W Wisconsin Ave, Milwaukee, WI 53226.
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Abstract |
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Abstract To determine whether the combination of obesity and hypertension results in additive defects in oxidative and nonoxidative glucose metabolism and the association of these changes with altered hemodynamic actions of insulin, we studied 11 abdominally obese hypertensive, 6 abdominally obese normotensive, and 7 lean normotensive nondiabetic subjects. Endogenous glucose production and glucose metabolized were calculated from a euglycemic clamp at 72 and 287 pmol insulin/m2 per minute. Glucose metabolized divided by insulin was lower at 72 pmol/m2 per minute in both obese groups than in lean normotensive subjects, at 148±14, 144±33, and 373±69 (µmol/m2 per minute)/(pmol/L), respectively (P<.01). Similar results were obtained during the higher insulin dose. Nonoxidative and oxidative glucose disposals by indirect calorimetry were lower in both abdominally obese groups (P<.05). Hepatic glucose production was completely suppressed in lean subjects at the lower insulin dose and in all three groups at the higher insulin dose. Hemodynamic responses during the clamp were not significantly different among the three groups. Abdominal obesity is associated with defects in insulin-regulated oxidative and nonoxidative glucose disposal as well as in insulin suppression of hepatic glucose production. Mild hypertension does not exacerbate these defects. Whereas the global impairment in glucose metabolism suggests the presence of an early defect or defects, including reduced tissue perfusion, systemic and regional hemodynamic responses to insulin were not altered. These findings do not support a direct role for insulin resistance in the pathogenesis of the hypertension associated with abdominal obesity.
Key Words: obesity • glucose clamp technique • glucose • hemodynamics • hypertension, obesity • insulin
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Introduction |
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Evidence for resistance to insulin-mediated glucose disposal has been observed in several studies comparing nonobese hypertensive patients with weight-matched normotensive control subjects.1 2 3 4 In contrast to the relatively consistent adverse effect of hypertension on glucose disposal in nonobese patients, the studies are more evenly divided between those that observed greater insulin resistance in obese hypertensive subjects than in obese normotensive subjects5 6 7 8 9 and those that did not.4 10 11 12 13
One of the major confounding variables in metabolic studies of obese patients is body fat distribution. Several reports have indicated that hypertensive patients have a more centralized and/or abdominal fat pattern than normotensive control subjects of similar weight.14 15 16 17 Our group has shown that abdominal obesity is associated with marked abnormalities of insulin-mediated glucose disposal compared with that in equally obese individuals with gluteofemoral obesity.18 19 Many of the studies on insulin resistance in obese hypertensive and normotensive subjects have not provided information on body fat distribution. Thus, the degree to which obese hypertensive and obese normotensive subjects were matched largely by chance for body fat distribution may explain why some studies observed differences of insulin-mediated glucose disposal while others did not.
Other reports indicate that hypertension is associated with resistance to the vasodilator actions of insulin, which purportedly contribute to the defect of insulin-mediated glucose disposal.20 21 However, hypertension in nonobese patients is associated with a defect in nonoxidative glucose disposal,2 whereas a reduced delivery of glucose and insulin would represent an early defect that would likely impair both oxidative and nonoxidative glucose utilization.22
Thus, the principal objectives of this study were to determine whether the combination of obesity and hypertension has additive and deleterious effects on glucose metabolism and to determine whether these defects are linked with resistance to the vasodilator actions of insulin. Insulin has several effects that could potentially raise blood pressure (BP), and others could lower BP.22 Impairment of the vasodilator actions of insulin may thus lead to predominance of the pressor effects, which could in turn contribute to elevated BP.20 The secondary objective of this study was to determine whether obese hypertensive subjects were resistant to the acute vasodilator actions of insulin and manifested a pressor response.
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Methods |
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Subjects
Volunteers were recruited from the Hypertension Clinic and by advertisement. Study participants, all white, signed a written consent approved by the Human Research Review Committee and the General Clinical Research Center Advisory Committee. Every individual had a medical history, physical, and laboratory examination before participation to exclude health problems except for obesity and hypertension. Eleven patients (45±2 years of age, 7 men and 4 women) were abdominally obese hypertensive subjects, defined as a body mass index greater than 27 kg/m2, waist-to-hip circumference ratio greater than 0.85 for women and greater than 0.90 for men, and mean of three BP measurements off medication greater than 140 mm Hg systolic and/or greater than 90 mm Hg diastolic. Six subjects, all men (43±3 years), were abdominally obese normotensive subjects based on the above body mass index and waist-to-hip circumference ratio and BP less than 140/90 mm Hg. Seven volunteers (6 men and 1 woman, 42±2 years) were lean normotensive subjects with body mass index less than 25.5 kg/m2 and BP less than 140/90 mm Hg.
Physiological Measurements
Insulin Sensitivity
Insulin sensitivity was assessed by the euglycemic
hyperinsulinemic clamp.23 In brief, a
primed continuous infusion of insulin was administered sequentially at
72 and 287 pmol/m2 per minute as previously
described.19 23 Oxidative and nonoxidative glucose
disposals were determined from continuous respiratory
measurements.2 Hepatic glucose production was
estimated from [3H]3-glucose (New England Nuclear)
kinetics with the use of Steele's equation.24
Blood Pressure
During the screening and enrollment process, BP was measured in
triplicate with a mercury sphygmomanometer and an appropriately sized
cuff after subjects rested for 5 minutes in the seated position. In the
laboratory, mean BP was measured with the Dinamap 1846SX (Critikon,
Inc). The agreement between three simultaneous,
opposite-arm, observer sphygmomanometer values minus Dinamap BP values
taken in the supine position was 1.7±0.8/4.6±0.6 mm Hg.
Systemic Hemodynamic Measurements
Stroke volume (milliliters) was measured by thoracic impedance
with the use of the Kubicek equation25 as
described.26 Cardiac output (liters per minute) was
calculated as stroke volume/1000xheart rate (beats per minute). Mean
BP was obtained during each measurement of cardiac output for
calculation of total systemic resistance as mean BP/cardiac output
(millimeters of mercury per liter per minute). Impedance cardiography
has been compared with both thermodilution and indocyanine green dye
dilution27 with good agreement between methods.
Regional Hemodynamic Measurements
Calf blood flow, basally and during euglycemic clamp
procedures, was obtained by mercury-in-Silastic strain-gauge, venous
occlusion plethysmography with the use of the EC-4 plethysmograph (DE
Hokanson, Inc) as described.28 We validated the
strain-gauge plethysmographic technique using a silicone elastomer
shell of a human forearm into which known amounts of water were
injected. The volumes calculated from the plethysmographic data were
within 2% of the injected volumes over a wide range of values. A cuff
on the thigh was inflated to 50 mm Hg for 15 seconds and deflated 5
seconds over four cycles. A separate cuff around the ankle was inflated
to 50 mm Hg and deflated simultaneously with the upper
cuff to prevent venous return from the foot during the limb flow
measurement. BP was obtained in duplicate during each regional flow
measurement for calculation of regional vascular resistance as mean BP
(millimeters of mercury)/limb flow (milliliters per deciliter per
minute).
Indirect Calorimetry
During the final 30 minutes of each phase of the
euglycemic hyperinsulinemic clamp
(baseline, 72 pmol/m2 per minute and 287
pmol/m2 per minute insulin infusion rates), a one-way
non-rebreathing valve was placed in the subject's mouth, and his or
her nose was closed with a nose clip. Expired air was analyzed
with an on-line open circuit metabolic measurement system
(Medical Graphics CPX). The air was continuously sampled and
analyzed for oxygen and carbon dioxide, with expired volume
being measured as well. These on-line measurements were summarized at
1-minute intervals. A pilot study indicated that data collected during
the first 10 minutes and last 5 minutes of each study phase were
subject to substantial variability (probably secondary to
acclimatization to the breathing apparatus and investigator
activity during the transition from one study phase to the next).
Therefore, only data collected during the middle 15 minutes of each
phase were analyzed. Additionally, data collected during other
disruptive situations (eg, restarting an intravenous
catheter) were not analyzed.
Biochemical Measurements
Serum insulin was measured in triplicate with a solid-phase
125I radioimmunoassay (Coat-a-Count Insulin,
Diagnostic Products Corp) with a sensitivity of 7.2
pmol/L and a coefficient of variation of 6.5% at insulin
concentrations of 7 to 140 pmol/L and 3.7% at 720 to 2200
pmol/L.19 Plasma glucose was measured in duplicate with a
glucose analyzer (Beckman Instruments, Inc).
[3H]3-Glucose was measured in duplicate. After
deproteinization with 0.4 mL perchloric acid (0.5 mol/L) and
centrifugation, aliquots of supernatant were
transferred to scintillation vials and allowed to air dry overnight
under a ventilation hood. The residues were dissolved in 1.0 mL
distilled water, and 10 mL Insta-Gel (Packard Instruments Co) was
subsequently added. Samples were counted in a refrigerated Packard
Autogamma Counter (model 5650) with corrections for quenching using
internal [3H]glucose standards.
Anthropometric Measurements
Anthropometric measurements and calculations were performed as
described.19 29 In brief, height and weight were obtained
from lightly clothed volunteers without shoes, and body surface area
was calculated.30 Triceps, biceps, subscapular, and iliac
skinfold thicknesses were measured with Lange calipers (Cambridge
Scientific Instruments). Percentage of body fat was determined by
bioelectrical impedance. Abdominal (waist) and gluteal (hip)
circumferences were measured with subjects in the standing position,
and the waist-to-hip ratio was calculated.
Dietary Control
Each volunteer was interviewed by the Clinical Research Center
(CRC) dietitian. An isocaloric diet was designed with the
NUTRITIONIST III diet-analysis software
(N-Squared Computing). The diet was controlled for sodium (2000 mg/d),
potassium (2500 mg/d), calcium (800 mg/d), and magnesium (300 mg/d).
The caloric composition of the diet followed guidelines for the
American Heart Association phase I diet of 55% carbohydrate, 30% fat
with a ratio of polyunsaturated to saturated fat of 1:1, and 15%
protein. Subjects followed this diet for 1 month before the inpatient
CRC study. They were seen weekly, and the caloric intake was adjusted
to maintain body weight within 1.5% of baseline. To enhance
compliance, volunteers received all food and beverages from the CRC
kitchen during the week before admission. A 24-hour urine sample was
collected just before admission to confirm compliance.
Protocol
Preadmission
After qualifying for the study, subjects met with the dietitian
and began the diet prescribed. Volunteers were seen weekly in the
outpatient CRC where weight and BP were measured. After 1 week on the
study diet, subjects had a 2-hour oral glucose tolerance test after an
overnight fast. Individuals with fasting blood sugar greater than 7.8
mmol/L or 2-hour glucose greater than 11.1 mmol/L were excluded.
Admission
After 4 weeks on the study diet, subjects began a 24-hour urine
collection at 7 AM and were admitted to the CRC at 6
PM and fasted after 9 PM. The urine
collection was closed at 7 AM the following morning.
The following morning, a 6-hour euglycemic hyperinsulinemic clamp was initiated at 8 AM as described.19 23 An 18-gauge plastic catheter was inserted retrogradely into a dorsal hand vein for arterializing venous blood. A second catheter was placed in an antecubital vein of the opposite arm for infusion of insulin and both labeled and unlabeled glucose. At the beginning of the euglycemic clamp procedure (0 minute), a 40 µCi IV bolus of [3H]3-glucose was given and followed by a continuous infusion of 0.4 µCi/min for 6 hours. During the first 2 hours (basal period), no exogenous unlabeled glucose or insulin was given. At 120 and 240 minutes, a priming dose of human insulin (Humulin, Eli Lilly & Co) was administered over 10 minutes and followed by a continuous insulin infusion at 72 pmol/m2 per minute (130 to 240 minutes) and 287 pmol/m2 per minute (250 to 360 minutes). Fasting euglycemia, defined by mean glucose values during the 2-hour basal period, were maintained during the subsequent 4 hours by measuring plasma glucose every 5 minutes and adjusting the intravenous infusion rate of the 20% glucose in water. Blood samples were obtained at 10-minute intervals during the last 40 minutes of each of the 2-hour periods for measurements of plasma insulin and [3H]3-glucose specific activity. Systemic and regional hemodynamic measurements were obtained at 10-minute intervals during this 6-hour study. Indirect calorimetry was performed during the last 30 minutes of each 2-hour period.
Data Analysis
All data are reported as mean±SEM. The amount of glucose
metabolized (micromoles per meter squared per minute) during the 72 and
287 pmol/m2 per minute insulin infusions were calculated
from the exogenous glucose infusion rate and the endogenous
glucose production rate estimated by Steele's
equation.24 Comparisons across the three groups for
descriptive and other single time point variables were made with
ANOVA. Within-group changes of metabolic and
hemodynamic variables from baseline values during
the glucose tolerance test and clamp procedure were assessed with ANOVA
and a post hoc Student-Newman-Keuls multiple comparisons test.
Between-group differences for metabolic and
hemodynamic responses to the clamp were performed with
multiple-factor ANOVA. The null hypothesis was rejected at a value of
P<.05.
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Results |
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Patient Demographics
As described above, the three study groups were well matched for age. Table 1 shows that the two obese groups did not differ in body surface area, waist-to-hip ratios, skinfold thicknesses, or percent body fat and that these parameters are all significantly greater than those of the lean control subjects. The obese hypertensive subjects had higher fasting blood glucose levels than the obese normotensive subjects (5.3±0.2 versus 4.6±0.2 mmol/L), but fasting blood insulin levels did not differ significantly. The lean normotensive subjects had significantly lower fasting blood insulin levels than either of the obese groups, as indicated by the data below.
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Euglycemic Insulin Clamp
Glucose Metabolism
Blood glucose levels did not differ significantly within or among
the three study groups throughout the 6-hour study, with glucose values
ranging between 5.1 and 5.6 mmol/L. Basal insulin concentrations in the
two obese groups (131±22 pmol/L in the hypertensive obese and 177±50
pmol/L in the normotensive obese) were significantly greater than the
values in the lean normotensive subjects (57.4±7.2 pmol/L), but at
both insulin infusion rates plasma insulin concentrations rose
similarly in all three groups. At the lower rate, insulin concentration
of the lean normotensive subjects was 223±43 pmol/L, whereas that of
the obese normotensive subjects was 322±57 pmol/L and of the obese
hypertensive subjects was 302±29 pmol/L. Similarly, plasma insulin
concentrations were increased at the higher insulin infusion rate
(804±115 pmol/L in the lean normotensive subjects, 725±108 pmol/L in
the obese normotensive subjects, and 898±79 pmol/L in the obese
hypertensive subjects).
Table 2 summarizes the data for hepatic glucose production and glucose metabolized during each clamp interval in the three study groups. Hepatic glucose production was significantly decreased relative to the lean control subjects (464±51 µmol/m2 per minute) in each of the obese groups (323±19 µmol/m2 per minute in the hypertensive obese, and 316±45 µmol/m2 per minute in the obese normotensive group), but there was no difference between the obese hypertensive and obese normotensive subjects at any insulin infusion level. All groups responded with a sharp decline in glucose production at an insulin infusion rate of 72 pmol/m2 per minute, and production was eliminated in all groups at 287 pmol/m2 per minute.
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Basal glucose metabolism was significantly decreased in parallel with the changes in hepatic glucose production, there being no difference in glucose metabolism between the two obese groups (313±18 µmol/m2 per minute in the obese hypertensive subjects and 316±45 µmol/m2 per minute in the obese normotensive subjects) and glucose metabolism being significantly decreased from that of the lean control subjects (474±60 µmol/m2 per minute). However, the increase in glucose metabolism seen in the lean control subjects (726±126 µmol/m2 per minute) was nearly eliminated in both the obese hypertensive subjects (430±39 µmol/m2 per minute) and obese normotensive subjects (371±27 µmol/m2 per minute) at an insulin infusion rate of 72 pmol/m2 per minute and was significantly blunted at 287 pmol/m2 per minute (2017±115, 1152±84, and 1117±169 µmol/m2 per minute, respectively). There were no statistical differences in glucose metabolism between the two obese groups at either infusion rate.
During the insulin infusion rate of 72 pmol/m2 per minute, the amount of glucose metabolized over the prevailing insulin concentration (M/I) in the abdominally obese hypertensive subjects, abdominally obese normotensive subjects, and lean normotensive subjects was 148±14, 144±33, and 373±69 (µmol/m2 per minute)/(pmol/L), respectively (Fig 1). The mean M/I was significantly lower in the two obese groups (and did not differ significantly from each other) than in the lean normotensive group. During the 287 pmol/m2 per minute infusion rate, the mean M/I for these same three groups was 136±12, 171±36, and 283±31 (µmol/m2 per minute)/(pmol/L). Again, M/I was significantly lower in the two obese groups compared with the lean normotensive group. The difference between the two obese groups was not statistically significant. Fig 2 depicts the relationship between glucose metabolism, in micromoles per meter squared per minute, and insulin concentration in the three study groups. At all prevailing insulin concentrations, including during the basal period, the regression lines for the two obese groups were nearly identical and shifted to the right compared with the lean normotensive group. The slopes of the regression lines for both upper-body obese groups were significantly different from that of the lean normotensive subjects.
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P<.005 vs LN,NT.
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Fig 3 shows rates of oxidative and nonoxidative glucose production for the three study groups at the higher insulin infusion rate. Oxidative glucose metabolism was significantly higher in the lean normotensive group (950±61 µmol/m2 per minute) than in obese normotensive subjects (528±50 µmol/m2 per minute, P<.001) and obese hypertensive subjects (711±50 µmol/m2 per minute, P<.02). Values for the two obese groups were not significantly different from each other. In a similar fashion, nonoxidative glucose metabolism (glucose storage and glycolysis) was suppressed in both hypertensive and normotensive obese groups compared with the lean normotensive group (444±67, 589±189, and 1067±139 µmol/m2 per minute, respectively, P<.05). Again, both obese groups were significantly decreased relative to the lean normotensive subjects, whereas there was no significant difference between the two obese groups.
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Systemic and Regional Hemodynamics
Hemodynamic changes during the last two levels of
euglycemic hyperinsulinemia were not
different between the three groups (Fig 4). There were
significant within-group increases in heart rate in both the lean
normotensive (increasing from 57±2 to 62±2 beats per minute) and
obese hypertensive (72±2 to 76±2 beats per minute) groups but no
change in the obese normotensive subjects. Similarly, cardiac output
was increased by 0.46±0.18 L/min in the lean normotensive subjects and
by 0.26±0.13 L/min in the obese hypertensive subjects, again with no
change in the obese normotensive subjects. A similar increase in
cardiac output was observed in obese normotensive subjects (0.39±0.27
L/min), but this was not statistically significant. Calf blood flow
also increased significantly in both normotensive groups, from 2.1±0.3
to 2.5±0.3 mL/dL per minute in the lean subjects and from 2.7±0.3 to
3.3±0.5 mL/dL per minute in the obese normotensive subjects, but there
was no change in the obese hypertensive subjects. Although mean
increases in calf blood flow tended to be greater in obese normotensive
subjects than in obese hypertensive subjects, there was no significant
difference between these groups. There were also no significant
differences in mean BP among these groups.
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indicates upper-body obese hypertensive subjects (UBO,HTN);
, upper-body obese normotensive subjects (UBO,NT); and 
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lean normotensive subjects (LN,NT). Significance is shown vs baseline
for 72 pmol/m2 per minute or for last 30 minutes of 287
pmol/m2 per minute; *P<.05 vs UBO,HTN;
P<.05 vs UBO,NT. |
Discussion |
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In this study, the presence of mild hypertension did not significantly exacerbate the marked defect of insulin-mediated glucose disposal present in abdominally obese subjects. In fact, multiple measurements were not significantly different in the two obese groups, including fasting insulin and, more importantly, glucose metabolized over the prevailing insulin concentration during both levels of euglycemic hyperinsulinemia.24 The abdominally obese hypertensive group included four female subjects who may have had less severe insulin resistance than the obese normotensive men. However, the results were unchanged when these four women were excluded from the analysis.
Glucose metabolism was diminished in both the obese hypertensive and normotensive groups. To further evaluate the mechanism of insulin resistance in the abdominally obese subjects, we performed indirect calorimetry to provide measures of both glycogenesis and glycolysis. Oxidative and nonoxidative glucose metabolisms were comparably lower in the two obese groups than in lean normotensive subjects, suggesting that the metabolic fate of glucose is not altered by the coexistence of mild elevation of BP in the abdominally obese subjects. Thus the defect or defects in insulin-mediated peripheral glucose metabolism were quantitatively and qualitatively similar in the normotensive and hypertensive subgroups, and consequently, resistance to insulin-mediated glucose disposal could not be the cause of the increase in BP seen in some abdominally obese subjects.
Defects in both oxidative and nonoxidative glucose disposals in the abdominally obese point to an early abnormality in glucose metabolism. An impaired vasodilator response to the glucose and/or insulin stimulus could account for a global defect in glucose utilization by impairing substrate delivery to the key target, ie, skeletal muscle.31 However, calf hemodynamic responses during euglycemic hyperinsulinemia did not differ significantly between the two abdominally obese groups and lean normotensive subjects. These observations do not exclude the possibility that microcirculatory abnormalities such as microvascular rarefaction32 might contribute to the defect in glucose metabolism by reducing the surface area available for glucose transport, lengthening diffusion distances for glucose and insulin to skeletal muscle fibers, or contributing to an increased proportion of nonoxidative to oxidative muscle fibers.
Although the finding in this study that the presence of mild hypertension does not significantly exacerbate the defect of insulin-mediated glucose disposal in obese subjects agrees with several previous reports,4 10 11 12 13 the results are discordant with studies that observed differences between the two groups.5 6 7 8 9 Istfan and coworkers,8 who used the minimal model,33 was the only group to identify greater insulin resistance in obese hypertensive subjects than obese normotensive subjects, with no differences in waist-to-hip ratio. In that report, 70% of the obese normotensive subjects were women (versus 50% of hypertensive subjects), and their mean waist-to-hip ratio was 0.82, which is below the minimum value of 0.85 used to define abdominal obesity among women in the present study. The demographic and anthropometric differences between volunteers in our study and those in the prior report may partially explain the contrasting findings. Moreover, in the present study, several components of the diet that may affect insulin dynamics and action, including multiple cations34 35 36 and dietary fat,37 38 were controlled for 1 month before study, whereas dietary control was less strict in the earlier report.8 All medications were discontinued a minimum of 1 month (6 months for diuretics) before laboratory evaluation in the present study but for as little as 5 days in the previous report. On the other hand, in our study obese normotensive subjects manifested a nonsignificant tendency toward greater values for insulin-mediated glucose disposal than obese hypertensive subjects at the 287 pmol/m2 per minute euglycemic insulin infusion. These differences may have been significant at higher insulin infusion rates or with a larger number of subjects.
Evidence suggests that resistance to the vasodilator actions of insulin may contribute to the elevated peripheral vascular resistance20 21 39 that is the pathophysiological hallmark of essential hypertension.40 In a previous study, however, we found that the forearm vasodilator response to a regional insulin infusion at 718 pmol/L was comparable in abdominally obese hypertensive subjects and lean normotensive subjects.26 In another study we found that the forearm vasodilator response during an oral glucose tolerance test was not impaired in obese hypertensive patients, even when corrected for the greater insulin response, compared with lean normotensive volunteers.41 During the second hour of the oral glucose tolerance test, obese hypertensive subjects manifested less systemic vasodilation and a tendency to a pressor response in contrast to lean control subjects. Along this line, systolic BP was significantly higher in obese hypertensive subjects during the last 30 minutes of the 287 pmol/m2 per minute insulin infusion than during the last 30 minutes of the lower infusion rate. Nevertheless, the response of systolic BP was not different among the three groups. Although this tendency to a late pressor response may reflect in part the effects of a long laboratory procedure, Minaker and colleagues42 reported that younger but not older men manifested a rise of systolic BP, heart rate, and plasma norepinephrine during a euglycemic clamp, with insulin levels higher than those that are generally observed under physiological conditions. In response to more physiological hyperinsulinemia, Anderson and coworkers43 44 observed an increase of muscle sympathetic nerve activity but a decrease of forearm vascular resistance and BP in both comparatively lean normotensive subjects43 and relatively overweight borderline hypertensive subjects.44 Using a different approach, Gudbjornsdottir et al45 found that somatostatin lowered mean BP by 3 mm Hg in obese hypertensive subjects, whereas the addition of insulin to somatostatin in these subjects raised BP 4 mm Hg compared with somatostatin alone. However, BP during the combined infusion of somatostatin and insulin was not different from control values. Thus, consistent evidence is lacking for a clinically relevant and significantly greater pressor response to physiological hyperinsulinemia in hypertensive subjects than in normotensive subjects.
In summary, mild hypertension does not significantly exacerbate the marked defect of insulin-mediated glucose disposal in abdominally obese subjects. The limited rate of both the oxidative and nonoxidative pathways implicates an early defect in glucose metabolism including circulatory factors. Although the hemodynamic responses to oral glucose and the euglycemic hyperinsulinemic clamp are not significantly altered in these abdominally obese individuals, the observations do not exclude the possibility that a functional or structural microvascular abnormality contributes to insulin resistance. With or without insulin resistance, however, the hemodynamic data do represent further evidence against a direct role for insulin in the pathogenesis of hypertension.
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Acknowledgments |
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This work was supported by General Clinical Research Center grant M01-RR00058 to the Medical College of Wisconsin from the National Institutes of Health (NIH) Division of Research Resources, National Heart, Lung, and Blood Institute R01-43164, HL-34989, and NIH postdoctoral fellowship training grant HL-07260 to Dr Nazzaro. Dr Stepniakowski is the recipient of a Clinical Research Fellowship grant from the Medical University of South Carolina. The authors greatly appreciate the skillful assistance of the General Clinical Research Center nurses, nutrition, data management, and core laboratory staff and of Dr Glenn Krakower for assistance and comments about the preparation of the manuscript.
Received July 1, 1994; first decision September 8, 1994; accepted April 5, 1995.
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