(Hypertension. 1995;25:214-218.)
© 1995 American Heart Association, Inc.
Articles |
Insulin and Forearm Vasodilation in Hypertension-Prone Men
From the Departments of Endocrinology (U.L.H.) and of Medicine (T.E., I.M., G.B.), Lund University, Malmö University Hospital (Sweden).
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Abstract |
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Abstract Insulin-stimulated peripheral glucose uptake and insulin-mediated forearm vasodilation were investigated in 38 normotensive men with a family history of hypertension (relatives) compared with 27 age- and body mass index–matched normotensive men with no family history of hypertension (control subjects). The euglycemic hyperinsulinemic clamp technique was used to measure peripheral glucose uptake (insulin sensitivity index) and the metabolic clearance rate of insulin. Intra-arterial blood pressure and forearm blood flow were determined simultaneously, and forearm vascular resistance was calculated. The insulin sensitivity index was lower in relatives than in control subjects. The metabolic clearance rate of insulin was reduced and did not correlate to glucose disposal in the relatives as opposed to the control subjects. Forearm blood flow increased and forearm vascular resistance decreased to a similar extent in the two groups during the clamp. The vasodilator response was positively correlated to glucose disposal only in the relatives. In conclusion, impaired insulin-stimulated peripheral glucose uptake in normotensive sons from hypertensive families was accompanied by retained insulin-mediated forearm vasodilation. Thus, skeletal muscle blood flow supply does not seem to be the major determinant for glucose disposal. On the other hand, the positive correlation between glucose disposal and decrease in forearm vascular resistance in the relatives suggests that insulin-mediated vasodilation may be a limiting factor for peripheral glucose uptake in insulin-resistant individuals.
Key Words: glucose clamp technique • hypertension, family history of • forearm • insulin resistance • insulin
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Introduction |
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Essential hypertension is associated with insulin resistance and hyperinsulinemia,1 2 and recent studies have shown that normotensive offspring of patients with essential hypertension also have decreased insulin-stimulated glucose uptake.3 4 5 6 7 This insulin resistance is located in peripheral tissues, primarily involving glucose uptake in skeletal muscle,1 8 and insulin-resistant subjects with obesity or diabetes mellitus have an impaired insulin-mediated increase in skeletal muscle blood flow.9 10 11 This may in part explain the decrease in peripheral glucose uptake. It recently has been hypothesized that insulin resistance and essential hypertension are associated through a decrease in skeletal muscle blood supply.12 13 The aim of the present study was to investigate insulin-mediated forearm vasodilation as related to insulin-stimulated peripheral glucose uptake in normotensive men with and without a family history of hypertension.
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Methods |
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Subjects
Two groups of healthy men were investigated. The selection procedure was described in detail earlier.7 Briefly, one group included sons of families with a documented family history of essential hypertension in (1) both parents, (2) one parent and one grandparent on the same side of the family, or (3) one parent and one sibling (relatives). The other group included sons of families with no family history of hypertension (control subjects). All subjects included were aged 25 to 46 years and had a supine diastolic blood pressure (BP) consistently below 90 mm Hg and a normal oral glucose tolerance test.14 Subjects with a serum
-glutamyl
transpeptidase greater than 0.80 µkat/L were excluded. None of the
subjects had any disease that was judged to influence the results of
the experimental study, and none of them had been on any regular
medication for at least 12 months before the investigation. Of 68 men investigated with a euglycemic hyperinsulinemic clamp (39 relatives and 29 control subjects), simultaneous measurements of intra-arterial BP and forearm blood flow were successfully performed in 65 men (38 relatives and 27 control subjects).
Study Design
Before the investigation, all subjects were instructed to adhere
to their normal lifestyle and to avoid changes in food intake, alcohol
consumption, and exercise. The subjects were nonsmoking and fasted
overnight.
The investigation was performed in a quiet room with a constant temperature of 20° to 22°C. The subjects were recumbent for the entire investigation. Between 7:30 and 8 AM, polyethylene catheters (Viggo) were inserted into one cubital vein and one vein on the dorsoradial side of the wrist, both on the right side of the subject. With the subject under local anesthesia (mepivacaine chloride 20 mg/mL, Astra) a polyethylene catheter was inserted into the brachial or radial artery of the left arm. The catheters were kept patent by a slow infusion of heparin-containing 0.9% saline. Intra-arterial BP was measured by using Baxter's uniflow pressure set model DTS 150 (Bentley Laboratories Europe). BP and electrocardiogram (ECG) were monitored on a Nihon Kohden Life Scope 6 model OEC-6105K. Left forearm blood flow was measured by venous occlusion mercury–in–silicone elastomer (Silastic) strain-gauge plethysmography (Hokansson EC-4) with the arm elevated above the level of the heart.15 The analysis of the slope of the plethysmographic curves was done by a specially trained research assistant, who did not know to which group the subjects belonged. The mean value of at least six measurements was used for each determination. Mean BP was calculated as diastolic BP plus 1/3(systolic minus diastolic BP) and forearm vascular resistance as mean BP divided by forearm blood flow.
From 8:30 AM, BP, ECG, and forearm blood flow were registered on a Siemens-Elema polygraph every 15 minutes for 4 hours. The intraindividual coefficients of variation for mean BP and forearm blood flow measured from 9:30 to 10:30 AM were 3% and 15%, respectively.
From 10:30 AM to 12:30 PM, a hyperinsulinemic euglycemic clamp was performed,16 with measurement of arterial glucose concentration by a glucose oxidase–peroxidase method every 5 minutes and a target level of 5.0 mmol/L. Arterial blood samples for measurement of insulin were collected hourly. The glucose disposal rate was calculated as the amount of glucose infused during the second hour and was expressed as milligrams per kilogram body weight per minute. The metabolic clearance rate of insulin was calculated as the infusion rate of insulin (47 mIU/m2 body surface area per minute) divided by the increase in serum insulin concentration greater than the basal level during the clamp.16
The insulin sensitivity index was calculated as the amount of glucose metabolized per unit of serum insulin (mean serum insulin concentrations during the clamp multiplied by 100).16 Arterial blood samples for determination of plasma norepinephrine and epinephrine were collected hourly.
The study protocol was approved by the Ethics Committee, Medical Faculty of Lund University, and informed consent was obtained from each individual.
Analytical Procedures
Plasma norepinephrine and epinephrine were determined by
radioenzymatic assay.17 The intra-assay coefficient of
variation was 11% for norepinephrine (range, 0.7 to 8.5 nmol/L) and
15% for epinephrine (range, 0.1 to 8.5 nmol/L). Serum insulin was
measured with a radioimmunoassay technique18 and is
expressed in international units.
Statistical Analyses
Nonparametric methods were used for statistical evaluation. The
Wilcoxon signed rank test was used for paired data, the Mann-Whitney
U test for unpaired data, and Spearman's rank correlation
test to calculate correlation coefficients (
). Values are
presented as medians and quartiles (25th:75th percentile), and the
level of significance was taken at a value of P<.05.
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Results |
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The two groups were well matched for age, body mass index, and waist-to-hip ratio (Table 1). The circumference of the left forearm was similar in the two groups. The basal serum insulin level was not significantly different in relatives versus control subjects.
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Systolic BP, forearm blood flow, forearm vascular resistance, and plasma levels of norepinephrine and epinephrine did not differ between the groups, whereas heart rate and diastolic BP tended to be higher in the relatives (Table 2).
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During the hyperinsulinemic euglycemic clamp, glucose disposal rate did not significantly differ between groups (Table 1). Mean serum insulin level during the clamp was higher and the metabolic clearance rate of insulin was lower in relatives than control subjects. The insulin sensitivity index was decreased in relatives compared with control subjects (Fig 1). There was a positive correlation between the glucose disposal rate and the metabolic clearance rate of insulin in control subjects but not in relatives (Fig 2).
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, top) and 38 normotensive sons of families with a documented
history of hypertension (
, bottom).
During the second hour of the hyperinsulinemic euglycemic clamp,
the increase in plasma norepinephrine was greater in the control
subjects than in the relatives, and plasma epinephrine increased only
in the control group (Table 3). Systolic BP was
significantly reduced in the relatives, whereas diastolic BP decreased
and heart rate increased to the same extent in both groups. The
increase in forearm blood flow and the decrease in forearm vascular
resistance were not significantly different between the two groups, and
this also applied when expressed as percent change from baseline (Table 3). The decrease in forearm vascular resistance was also similar in
relatives and control subjects when adjusted for the mean serum insulin
level during the clamp (Fig 1). The absolute and percent increases in
blood flow were positively correlated to glucose disposal in the
relatives (=.36, P=.031 and =.39, P=.018,
respectively) but not in the control subjects (=.27,
P=.18 and =.21, P=.28, respectively). The
absolute and percent decreases in forearm vascular resistance (Fig 3) were also positively correlated to glucose disposal
in the relatives (=-.35, P=.035 and =-.38,
P=.023, respectively) but not in the control subjects
(=-.09, P=.65 and =-.07, P=.74,
respectively). The forearm vasodilator response was not correlated to
basal BP, heart rate, body mass index, or the change in plasma
catecholamines in any of the groups.
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Discussion |
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The finding of reduced insulin sensitivity index in first-degree relatives of patients with essential hypertension is in accordance with earlier studies.3 4 5 6 This is most likely due to reduced insulin-stimulated peripheral glucose uptake as endogenous glucose release from the liver is completely blocked in normotensive and hypertensive individuals at an insulin level of 100 mIU/L.1 19 Relatives had a higher steady-state insulin concentration during the euglycemic hyperinsulinemic clamp compared with control subjects, which is probably a result of the lower metabolic clearance rate for insulin in the relatives. This may reflect a reduced hepatic insulin extraction, as reported in women with a high waist-to-hip ratio,20 or a decreased insulin clearance in skeletal muscle and kidney, as shown in spontaneously hypertensive rats.21 22 The positive correlation between glucose disposal and the metabolic clearance rate of insulin in the control subjects suggests a coupling between insulin receptor binding action and insulin degradation in the skeletal muscle. Studies in streptozotocin-diabetic rats have indicated such a relation between insulin binding and degradation by skeletal muscle.23 However, there was no significant correlation between glucose disposal and the metabolic clearance rate of insulin in the relatives (Fig 2).
Because of the difference in serum insulin concentration between the groups, the glucose disposal rate corrected for steady-state insulin concentration during the clamp was used as the most appropriate measure of insulin sensitivity. A linear relation between insulin concentration and peripheral glucose disposal has been shown for the insulin levels achieved in the present study.10 11 24
Insulin has been shown to induce activation of the sympathetic nervous system in healthy subjects with an increase in plasma norepinephrine concentration.25 26 27 In these studies, heart rate increased but BP was unchanged or decreased as a result of a vasodilator action of insulin, the mechanism of which is still unknown.26 28 A minor increase in arterial epinephrine concentration cannot explain the forearm vasodilation seen during the clamp as higher levels of epinephrine are required to induce vasodilation in the skeletal muscles and reduction of diastolic BP.29 30 It is more likely that increased muscle sympathetic activity during the hyperinsulinemic euglycemic clamp,26 27 reflected in elevated arterial norepinephrine concentration, induces a vasoconstriction that is overridden by a vasodilator action of insulin. In the present study, plasma catecholamine levels increased less in relatives than in control subjects, but the increase in heart rate and the decrease in diastolic BP were similar in the two groups during the clamp.
Anderson et al,26 31 who gave volumes of the same magnitude as we did during the hyperinsulinemic euglycemic clamp, have done vehicle-control experiments in normotensive and borderline hypertensive subjects. They found no appreciable effect of volume infusion on forearm blood flow or forearm vascular resistance. Kelley et al32 observed no change in forearm blood flow after an oral glucose load to healthy volunteers, but the increase in serum insulin concentration to 30 to 40 mIU/L may have been insufficient to induce forearm vasodilation. In the study of Natali et al,33 infusion of insulin into the brachial artery in a dose giving a concentration of 125 mIU/L had no detectable effect on forearm blood flow or vascular resistance. This suggests that the forearm vasodilator response to insulin is not mediated by a local action.
In the present study, the insulin-induced vasodilator response in the forearm, expressed as absolute or relative increase in forearm blood flow or decrease in forearm vascular resistance, did not differ between relatives and control subjects. This is in accordance with the finding by Anderson et al26 31 of a similar increase in forearm blood flow to insulin in normotensive and borderline hypertensive subjects and indicates that the decreased glucose uptake in the relatives is not mainly due to hemodynamic factors.
On the other hand, Laakso et al9 10 11 reported an attenuated
insulin-mediated increase in leg blood flow in patients with obesity
and diabetes mellitus. The reason for this difference may be that the
subjects investigated by Laakso et al were more insulin resistant than
those studied by us and by Anderson et al.31 Baron et
al,34 however, recently reported a positive correlation
between peripheral glucose uptake and the increase in leg blood flow in
normotensive subjects during euglycemic clamp with a maximal dose of
insulin that gave a plasma insulin concentration approximately 25 times
higher than in the present study. We found a positive correlation
between insulin-stimulated glucose disposal and the decrease in forearm
vascular resistance only in the relatives. This correlation was partly
dependent on one insulin-resistant individual showing a marked
vasoconstrictor response to insulin (Fig 3), but the percent increase
in forearm blood flow and the percent decrease in forearm vascular
resistance remained significantly related to glucose disposal in the
relatives after he was excluded (=.35, P=.034 and
=-.34, P=.044, respectively). A positive correlation
between forearm blood flow and forearm glucose uptake has been found in
insulin-resistant hypertensive patients at an insulin concentration
comparable to that in the present study.35 These
findings suggest that at a physiological serum insulin level,
insulin-mediated vasodilation is a limiting factor for peripheral
glucose disposal only in insulin-resistant individuals. The discrepancy
between these studies and that of Baron et al may be due to
methodological differences and the much higher dose of insulin used in
the latter study.
Baron et al34 also found a negative correlation between basal BP and insulin-stimulated glucose uptake as well as insulin-mediated vasodilation. An impairment of insulin-mediated venodilation with increasing BP and body mass index has recently been reported in normotensive and mildly hypertensive subjects.36 In the present study, insulin-induced forearm vasodilation was related to neither basal BP nor body mass index.
In conclusion, first-degree normotensive relatives of patients with essential hypertension had decreased insulin-stimulated glucose uptake but retained insulin-mediated forearm vasodilation compared with control subjects. Thus, skeletal muscle blood flow supply does not seem to be the major determinant of glucose disposal. On the other hand, the positive correlation between glucose disposal and the decrease in forearm vascular resistance found in the relatives suggests that insulin-induced vasodilation may be a limiting factor for peripheral glucose uptake in insulin-resistant individuals.
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Acknowledgments |
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This study was supported by grants from the Swedish Heart and Lung Foundation, the Nordic Insulin Fund, the Ernhold Lundströms Research Foundation, the Swedish Hoechst Diabetes Fund, the Albert Påhlsson Research Foundation, the Malmö Diabetes Association, the Research Funds of Malmö General Hospital, and the Medical Faculty of Lund University.
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Footnotes |
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Reprint requests to Dr U. Lennart Hulthén, Department of Endocrinology, Malmö General Hospital, S-214 01 Malmö, Sweden.
Received March 16, 1994; first decision April 26, 1994; accepted September 14, 1994.
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