(Hypertension. 1996;27:854-858.)
© 1996 American Heart Association, Inc.
Articles |
Angiotensin Mediates Forearm Glucose Uptake by Hemodynamic Rather Than Direct Effects
From the Division of Hypertension, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor.
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Abstract |
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Abstract Insulin sensitivity may be improved with the angiotensin-converting enzyme inhibitor captopril, suggesting that inhibition of angiotensin II (Ang II) improves insulin resistance. However, the administration of systemic Ang II has also been associated with an improvement in rather than worsening of glucose utilization. Since both stimulating and antagonizing the renin-angiotensin system improve glucose uptake and both angiotensin-converting enzyme inhibitors and intravenous Ang II elicit skeletal muscle vasodilation, it is conceivable that hemodynamic factors rather than a direct effect of either Ang II or angiotensin-converting enzyme inhibitors on skeletal muscle metabolism modulate the increase in glucose utilization. The direct effects of Ang II on glucose extraction in intact human skeletal muscle have not been previously described. We investigated the effects of local infusion of Ang II on glucose uptake in the forearm of 20 healthy subjects. With the use of the isolated insulin-perfused forearm model, local plasma insulin values were raised to 100 mU/mL over fasting values and maintained there for a 90-minute infusion period. After the first 60 minutes of insulin alone, Ang II was infused into the brachial artery for the last 30 minutes. Intra-arterial Ang II infusion caused a 38% decrease in forearm blood flow (P<.05) and 59% increase in the arteriovenous glucose gradients (P<.05) to maintain a steady glucose utilization (a decrease of 4%, P=NS). Thus, local Ang II infusion does not impair insulin-stimulated glucose utilization. Furthermore, glucose extraction increases to compensate for the decrease in forearm blood flow (as the Fick principle would predict for freely diffusible substances). We conclude that the described increase in glucose utilization from systemic infusion of Ang II and during angiotensin-converting enzyme inhibitor treatment is mediated by hemodynamic factors rather than a direct effect of Ang II on skeletal muscle metabolism.
Key Words: angiotensin II • angiotensin-converting enzyme • glucose • insulin
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Introduction |
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Recent explorations into the influence of the renin-angiotensin system on insulin resistance have yielded conflicting results. In clinical trials, when subjects with hypertension are treated with converting enzyme inhibitors1 to lower blood pressure, they show an increase in insulin sensitivity. However, experiments of three independent investigators2 3 4 appear to have the common finding that systemic (intravenous) infusion of angiotensin II (Ang II) causes an increase in insulin sensitivity. Given the main pharmacological action of Ang II and angiotensin-converting enzyme inhibitors, these findings are contradictory: both antagonizing and stimulating the Ang II receptors lead to an improvement in glucose utilization. This discrepancy could have several explanations. Ang II itself may in fact enhance glucose metabolism, whereas treatment with angiotensin-converting enzyme inhibitors, resulting in the simultaneous buildup of bradykinin, could facilitate glucose utilization and thereby obscure the effect of antagonizing Ang II.5 Alternatively, the observed enhancement of glucose utilization may reflect one of many indirect actions of systemic infusion of Ang II and insulin during glucose clamping experiments.
Systemic infusion of insulin is associated with both activation of the sympathetic nervous system and a direct effect of insulin on hepatic and pancreatic functions.6 Systemic effects of insulin include an increase in plasma angiotensin-converting enzyme,7 the promotion of aldosterone secretion,8 and augmentation of the effects of Ang II on vascular smooth muscle.8 Systemic Ang II may stimulate hepatic glycogenesis, thereby increasing endogenous insulin production9 and stimulating insulin-mediated glucose uptake.10 Furthermore, it has been proposed that a pressor response to the acute systemic infusion of Ang II causes a withdrawal of sympathetic tone through arterial baroreceptors, which may lead to vasodilatation in some vascular beds.11 Therefore, the increase in glucose utilization from the systemic infusion of Ang II and insulin reported in previous work represents an integrated whole-body response in glucose metabolism.
In contrast to previous investigations into the effects of Ang II on glucose metabolism, in this study we use local instead of systemic infusion of both Ang II and insulin. Thus, the systemic effects of Ang II and insulin are virtually eliminated by our study design, and we are able to significantly enhance the understanding of the direct hemodynamic and metabolic effects of Ang II on intact human skeletal muscle.
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Methods |
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Subjects and Protocol
Subjects were recruited by advertisement in local newspapers. The protocol was reviewed and approved by the Committee to Review Grants for Clinical Research and Investigation Involving Human Subjects at the University of Michigan Medical Center. Young, healthy men and women were admitted to the General Clinical Research Center after a 12-hour fast. Subjects taking prescription medications were excluded from the study. Women on oral contraceptive pills were studied at the end of the 5 days of their cycle when they were on estrogen withdrawal. After informed consent and a medical history were obtained, anthropometric data were collected. Subjects were made recumbent before placement of a brachial arterial line and retrograde cannulation of a deep forearm vein in the antecubital fossa. The placement of catheters to isolate the forearm and the measurement of forearm blood flow (FBF) by plethysmography have been previously described.12
The electrocardiogram and intra-arterial blood pressure were monitored continuously for the duration of the procedure.
After placement of the catheters, subjects rested for 15 minutes and then had a 30-minute baseline period during which FBF was measured at 10-minute intervals and arterial and venous samples for plasma glucose and blood gases were obtained every 10 minutes.
After this baseline period, an intra-arterial infusion of insulin was begun with a Harvard pump and stock concentration of insulin (Humulin) of 0.01 mU/mL in 1% albumin at a rate calculated to raise plasma insulin concentrations in the forearm to 100 µU/mL over baseline fasting plasma insulin values. During the 60-minute insulin infusion period, FBF was measured at 10-minute intervals; plasma insulin and arterial and venous samples for glucose and blood gases were obtained at 40, 50, and 60 minutes of insulin infusion.
After 60 minutes of insulin infusion, vasoconstriction was induced by Ang II infusion into the brachial artery. Ang II was reconstituted from a 2.5-mg stock vial with 1 mL of sterile water. One milliliter was diluted into a 60-mL syringe of normal saline, and then 1 mL was taken from the 60-mL syringe and added to 40.6 mL of normal saline to arrive at a concentration of 1.0 µg/mL. Ang II was infused for 3 minutes, and FBF was measured during minute 4 for determination of whether FBF had been reduced by at least 20%. This degree of vasoconstriction was chosen because of recently published results that physiological vasoconstriction by inflation of bilateral thigh cuffs causes a 20% decrease in FBF and elicits a decrease in glucose utilization in the forearm.12 Vasoconstriction was maintained for 30 minutes by constant Ang II infusion. Blood flow, arterial and venous glucose concentrations, and plasma insulin concentration were measured at 10-minute intervals during this infusion period.
Plasma glucose and insulin samples were immediately centrifuged at 3000 rpm and analyzed at the Michigan Diabetes Research and Training Center. Glucose was analyzed by hexokinase reaction and insulin by radioimmunoassay. Complete blood gas analyses were done with an Instrumentation Laboratory System 1302 and 282 COxymeter.
Glucose Extraction
Forearm glucose extraction was expressed in two ways: as
arteriovenous gradient of glucose (AV gradient) and as glucose
utilization, the product of the AV gradient and
simultaneous ipsilateral measurement of FBF
(strain-gauge plethysmography, Hokanson).13
Analysis
The statistical software package StatView II was used for all
data analyses. The values were averaged for each condition
(baseline, insulin infusion, and insulin infusion plus
vasoconstriction) and expressed as mean±SE. Student's t
test for paired values was used to compare results between conditions.
Comparisons of hemodynamic and metabolic
data within a single study condition were analyzed by ANOVA and
simple regression. A value of P<.05 was considered
significant.
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Results |
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Table 1
shows baseline characteristics of the study
group and demonstrates that subjects were young, white, and
predominantly male; had normal blood pressure and plasma insulin; and
were within 20% of their ideal body weight.
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Hemodynamic and Metabolic Effects of
Insulin Infusion
With the use of the insulin-perfused forearm model, fasting
venous plasma insulin values were increased from a baseline
of 10.4±0.9 to 119±16.1 µU/mL (P=.0001 in the study arm)
(Table 2). The observed local
hyperinsulinemia was within the range of
physiological postprandial values. The
physiological increase in plasma insulin values was
associated with a significant increase in FBF (Table 3).
This vasodilating effect of insulin has been consistently
found in our studies with the forearm model. The insulin-induced
local vasodilation was detectable within the first 10 minutes of the
study, whereas no effect of insulin was observed on systemic blood
pressure or heart rate during the 90-minute study period.
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The AV glucose gradient and glucose utilization began to increase over
the first 40 minutes of insulin infusion and then reached a plateau.
Previous investigators using the perfused forearm model have shown
glucose utilization to remain constant up to 180 minutes without
systemic effects if there is no other intervention.14 The
local arterial plasma glucose levels in the study arm
remained constant over the course of the infusion. Glucose utilization
increased significantly as local hyperinsulinemia
increased the utilization from a baseline value of 14.8 to 102 mg/dL
per minute (average of last 30 minutes of insulin infusion)
(P=.0001, Table 2
). The change in AV glucose gradients in
response to insulin paralleled the trends in glucose
utilization. In response to a 38% decrease in FBF from the infusion of
insulin plus Ang II, AV glucose gradients widened from 19.0±2.8 to
30.3±2.3 mg/dL (Table 3). Oxygen utilization increased
slightly but significantly with insulin infusion, and serum free fatty
acid levels decreased, demonstrating the well-described effects of
insulin on impeding lipolysis (Table 2).
Hemodynamic and Metabolic Effects
of Ang II Infusion
Tables 2 and 3 demonstrate the hemodynamic and
metabolic effects of local Ang II infusion.
Intra-arterial Ang II in addition to reduced FBF by an
average of 38% from the values after 60 minutes of insulin infusion
alone for the group (P<.05). Ang II infusion had the
desired local hemodynamic effects without any evidence
of systemic spillover, as heart rate and blood pressure did not
change over the course of the study (Table 3) and FBF did not decrease
in the contralateral (control) arm. The local
hemodynamic effects of Ang II were discernible within
the first 3 minutes of the infusion, whereas no systemic effect
of Ang II was seen over the course of the 30-minute infusion. Over the
relatively short period of vasoconstriction in this study, there was no
discernible change in substrate for metabolism as local
serum free fatty acid concentration remained unchanged from the
infusion of insulin alone to the infusion of insulin plus Ang II.
Fig 1 demonstrates the trends in AV glucose gradients,
glucose utilization, and FBF over the course of the study. AV glucose
extraction increased in the face of the decrease in FBF, such that the
net effect of Ang II on forearm glucose metabolism resulted
in no change in glucose utilization. There was a significant increase
in plasma insulin values as a result of vasoconstriction and a relative
decrease in the local volume of distribution in the forearm.
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Discussion |
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The present study demonstrates clearly that local infusion of Ang II is not associated with a net increase in skeletal muscle glucose utilization in healthy volunteers. Over a broad range of achieved reductions in FBF (1% to 62% reduction from insulin infusion alone to insulin plus Ang II), the extraction of glucose increased to match the decrease in FBF, resulting in no net change in glucose utilization (Fig 2
). With the present study, we examined Ang
II–induced vasoconstriction in the physiological
range as well as twofold and threefold greater than the expected
physiological response
(physiological vasoconstriction; a 25% decrease in
FBF was determined in previous studies by inflating bilateral thigh
cuffs, causing a reflex-induced decrease in FBF).12
Under the local influence of Ang II and insulin, we found that glucose
behaves as a substance that is freely taken up by skeletal muscle in
the human forearm and follows the Fick principle for substances in
equilibrium. We cannot reliably determine whether a steady state was
achieved during the course of our study; however, the total infusion
time of Ang II was 30 minutes, and the mean transit time for glucose in
a limb is 7 to 8 minutes.15 Thus, it is reasonable to
assume that the observed changes from Ang II infusion are
representative of the equilibrium state. Plasma insulin
values increased significantly in the study arm as a result of Ang II
infusion. In this study as well as in our previous work with
vasoconstriction in the forearm, we found
hyperinsulinemia that is partly due to a contracted
plasma volume. The increase in local insulin values in response to Ang
II infusion should have optimized our ability to detect an increase in
glucose utilization if enhanced glucose uptake were an effect of local
Ang II infusion.
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The potential contribution of the renin-angiotensin system in mediating tissue insulin sensitivity has been explored by three other groups.2 3 4 Flisner et al2 infused Ang II into healthy volunteers and assessed their insulin-mediated glucose uptake before and after the insulin infusion during the 4th hour of a euglycemic hyperinsulinemic clamp study. They found no effect of Ang II on glucose utilization during the first 3 hours of the study; however, during the 4th hour glucose uptake increased 20%. Interestingly, the 4th hour of the study was the only time interval during which Ang II had a significant effect on peripheral blood flow, an increase of 12% as measured by plethysmography.
Other recent reports on the effects of systemic infusion of Ang II on glucose metabolism also support the notion that Ang II can mediate an increase in glucose utilization. Peripheral blood flow was measured in the studies by Buchanan et al3 and Townsend et al,16 and Ang II, a potent vasoconstrictor, was found to be associated with increased peripheral muscle flow and enhanced glucose utilization. The work of these investigators seems to imply that the increase in limb blood flow induced by systemic infusion of Ang II is associated with an increase in glucose utilization. It could have been conceivable that systemic Ang II infusion has direct local metabolic effects. Our results demonstrating that local infusion of Ang II causes vasoconstriction but does not cause an increase in glucose utilization provide strong evidence that the increase in glucose utilization seen in previous work with systemic infusion of Ang II was likely due to an Ang II–induced increase in limb blood flow.
Vasoconstriction found with local infusion of Ang II in our study contrasts with the vasodilatation associated with systemic infusions found in previous studies. In the previous studies, investigators measured plasma levels of Ang II or monitored a systemic response to Ang II infusion as a primary objective. Flisner et al2 examined the effect of a physiological dose of systemic Ang II on glucose metabolism, whereas Buchanan et al3 infused systemic Ang II to achieve either a pressor or subpressor response in systemic blood pressure. Buchanan et al examined the regional blood flow in various vascular beds and demonstrated that the blood flow response to systemic Ang II infusion is not uniform. There was marked vasoconstriction in the renovascular beds, whereas the blood flow to skeletal muscle was significantly increased. The vasoconstriction achieved with local infusion versus the vasodilation with the previous studies is an important finding that explains why our results diverge from previous reports. We did not measure local plasma concentration of Ang II because our goal was to assess the effects of Ang II–induced vasoconstriction (a predetermined amount of vasoconstriction that we found to be physiological in previous investigations) on forearm glucose metabolism and not the response to any particular plasma concentration of Ang II.
The notion that increased blood flow is associated with increased glucose utilization has considerable bearing on the proposed hemodynamic theory of insulin resistance. Recent reviews provide evidence to suggest that hemodynamic factors influence insulin sensitivity in subjects with essential hypertension.17 18 Maneuvers such as aerobic exercise training,19 vasodilator therapy,20 21 and anatomic evidence of increased capillary surface area in skeletal muscles22 23 24 25 are associated with enhanced insulin sensitivity, whereas conditions associated with a decrease in capillary surface area (diabetes, hypertension, obesity) all worsen insulin sensitivity. Consequently, we would expect that vasodilatation or an increase in blood flow to skeletal muscles would cause an increase in glucose utilization, as was the case with systemic infusion of Ang II in studies by previous investigators. This hypothesis is further supported by our present work, which demonstrates that Ang II has no direct metabolic effect on skeletal muscle glucose metabolism, thereby implicating hemodynamic factors as causative of the changes in glucose utilization observed after systemic infusion of Ang II.
Whereas our findings support the hemodynamic explanation for improvement in glucose utilization with intravenous Ang II infusion and thereby uphold the hemodynamic hypothesis of insulin sensitivity/resistance, they also raise some new conceptual problems. The hemodynamic hypothesis calls not only for vasodilation to improve insulin sensitivity but also for vasoconstriction to decrease insulin sensitivity. In this study, reduction of FBF with Ang II did not decrease glucose utilization in the forearm. This contrasts with our recent findings with norepinephrine infusion which showed that a similar reduction in FBF resulted in a decrease of glucose utilization.26 It is not clear why vasoconstriction elicited by two different receptor agonists does not have an equal effect on glucose utilization in the forearm. We propose to investigate in our future research the hypothesis that vasoactive substances may elicit different patterns of capillary blood flow in the skeletal muscle and differentially direct blood flow to (or away from) nutritional beds.
In summary, previous work has suggested that Ang II infusion is associated with an increase in glucose utilization. Furthermore, treatment of subjects with angiotensin-converting enzyme inhibitors has been associated with improved insulin sensitivity.27 28 These observations implicate the renin-angiotensin system in the modulation of insulin sensitivity. However, in previous studies both insulin and Ang II were infused systemically. In the present study, we infused Ang II and insulin locally and found that Ang II has no direct effect on insulin-stimulated glucose uptake in the forearm skeletal muscle. We conclude that the hemodynamic effects of Ang II are responsible for the increase in glucose metabolism seen in previous work. Furthermore, the present results support our hypothesis that hemodynamic factors are in part responsible for the frequent association of essential hypertension and insulin resistance.
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Acknowledgments |
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This study was supported in part by grants from the American Diabetes Association and a MERIT Award from the National Heart, Lung, and Blood Institute, National Institutes of Health (NIH) (R37 HL-37464). Dr Jamerson is the recipient of a General Clinical Research Center MCAP Award from NIH (5-MO1-RR-00042). Dr Nesbitt is the recipient of a Minority Investigator Research Supplement Award from NIH (R37 37464-S). The studies were conducted in the General Clinical Research Center (supported by NIH 5-MO1-RR-00042). The biochemical analyses were performed by the Michigan Diabetes and Research Training Center (NIH NIDDK [National Institute of Diabetes and Digestive and Kidney Diseases] DK-20572).
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Footnotes |
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Reprint requests to Dr Kenneth A. Jamerson, Division of Hypertension, University of Michigan Medical Center, 3918 Taubman Center, 1500 E Medical Center Dr, Ann Arbor, MI 48109-0356. E-mail kjamerson@uv1.im.med.umich.edu.
Received October 10, 1995; first decision November 9, 1995; accepted December 7, 1995.
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