(Hypertension. 1997;30:1156-1161.)
© 1997 American Heart Association, Inc.
Articles |
Angiotensin II Affects Basal, Pulsatile, and Glucose-Stimulated Insulin Secretion in Humans
From the Departments of Internal Medicine (D.F., D.S., E.R.) and Pediatrics (F.S.), Ruperto-Carola University, Heidelberg, Germany, and Department of Internal Medicine, Division of Endocrinology and Metabolism, University of Virginia Health Science Center and NSF Center for Biological Timing, Charlottesville, Va.
Correspondence to Danilo Fliser, MD, Department of Internal Medicine, Ruperto-Carola University, Bergheimerstr. 56a, 69115 Heidelberg, Germany.
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Abstract Angiotensin II (Ang II) modulates the tissue response to insulin (insulin sensitivity), but the effect of Ang II on the secretion of insulin has not been investigated thus far. Nineteen healthy volunteers (17 male; mean age, 26±1 years) were studied. In a double-blind, randomized, placebo-controlled study, seven volunteers were allocated on three occasions in random order after an overnight fast to three interventions: (1) solvent (placebo) infusion; (2) infusion of 1.0 ng Ang II · kg-1 · min-1 (subpressor dose); and (3) infusion of 5.0 ng Ang II · kg-1 · min-1 (pressor dose). Frequent blood samples (each minute) were obtained for estimation of plasma insulin concentrations over a period of 120 minutes to assess basal and pulsatile insulin secretion. In an ancillary study, plasma glucose and insulin levels were measured after an oral glucose tolerance test while solvent (placebo) or Ang II was infused in 12 fasting healthy volunteers. Plasma insulin concentrations were measured immunoenzymatically (enzyme-linked immunosorbent assay). Insulin secretion pulses were analyzed with the deconvolution technique, and the regularity of insulin secretion was analyzed with the approximate entropy technique. Plasma insulin half-life was assessed using the hyperinsulinemic euglycemic clamp method. The pressor dose of Ang II reduced total, basal, and pulsatile insulin secretion, and this effect was highly significant (P<.01). The subpressor dose tended to suppress insulin secretion. The burst frequency (number of peaks) and the regularity of insulin secretion were not affected by administration of Ang II. After the oral glucose load, the insulinemic response was significantly lower and plasma glucose concentrations were significantly higher with infusion of Ang II compared with placebo. Ang II affects both the basal (nonpulsatile) and the pulsatile component of spontaneous insulin secretion and the glucose-stimulated insulin secretion in humans. This observation is of potential interest with respect to the interaction of Ang II and insulin, eg, in the genesis of hyperinsulinemia and hypertension.
Key Words: angiotensin II • glucose tolerance • hyperinsulinemia • insulin secretion
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Introduction |
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It has been documented recently that angiotensin II (Ang II) enhances insulin sensitivity in healthy volunteers under euglycemic conditions1 2 3 ; this effect was attenuated in patients with type 2 diabetes mellitus (non–insulin-dependent; NIDDM).4 In some of these studies, a small increase of plasma insulin levels was observed during infusion of Ang II compared with placebo.1 2 4 It has been argued that the increase of plasma insulin concentrations may result from an Ang II–induced reduction in renal clearance of insulin. Nevertheless, an interaction of Ang II with insulin secretion has not been ruled out. An effect of Ang II on insulin secretion, ie, basal and pulsatile modes, has not been investigated thus far.
The pancreatic secretion of insulin is under control of complex mechanisms. Two types of cyclic oscillations of insulin secretion were described for the ß-cell, ie, fast pulsations with small amplitudes showing peaks every 10 to 13 minutes5 6 and slower waves with higher amplitudes and intervals of approximately 120 minutes.7 The former are thought to be triggered by an intrinsic pancreatic pacemaker. The latter apparently depend on the nonlinear glucose-insulin feedback.8 9 10 It has been shown that in patients with NIDDM and even in relatives of patients with NIDDM, the periodicity of the small insulin oscillations is lost, ie, endogenous insulin secretion is irregular.11 12
Clarification of a potential effect of Ang II on insulin secretion in humans could be of more general interest with respect to the metabolic and hemodynamic disturbances present in patients with the metabolic syndrome. The renin-angiotensin system is thought to play a role in the genesis of hypertension in these patients. To explore the effect of Ang II on insulin secretion, we administered Ang II in a double-blind, randomized, placebo-controlled study to healthy volunteers. Frequent blood samples were obtained for measurements of plasma insulin concentrations. In addition, in an ancillary study plasma glucose and insulin levels were measured after an oral glucose tolerance test while placebo or Ang II was infused.
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Methods |
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Subjects
Nineteen healthy normotensive nonsmokers were studied who were within 10% of ideal body weight and took no medication. Their family histories were negative for hypertension or metabolic diseases, especially diabetes mellitus. At entry into the study, a physical examination, routine chemistry, and urinalysis were performed in all participants. Normal glucose tolerance according to the WHO criteria was confirmed by a 100-g oral glucose tolerance test with simultaneous determinations of insulin levels.
Protocols
The protocols were approved by the Ethics Committee of the
University of Heidelberg. Written informed consent was given by all
participants. A double-blind, randomized, placebo-controlled study
design was adopted for the first part of the study. Seven male subjects
(mean age, 27±1 years; mean body mass index [BMI], 22.7±1.4
kg/m2) were allocated in random order (using random
numbers) to three interventions: (1) solvent (placebo) infusion (0.9%
NaCl; Kochsalz 0.9, Braun Melsungen AG); (2) infusion of 1.0 ng Ang
II · kg-1 · min-1 (Hypertensin
Ciba; Ciba Geigy); and (3) infusion of 5.0 ng Ang II ·
kg-1 · min-1, dissolved in 0.9% NaCl
solution. Two doses of Ang II were administered (subpressor and pressor
doses, respectively) to assess a potential dose-response relationship.
The infusion rate and consequently the volumes infused were the same
for all three infusion modalities. The interval between the
interventions was at least 14 days. All participants were admitted to
the clinic at 7 AM on the morning of the experiments after
an overnight fast. Thirty minutes after starting the infusion of either
Ang II or saline, blood samples for measurement of plasma insulin
concentration were withdrawn every minute for 120 minutes (from 8
AM to 10 AM). In parallel, mean
arterial blood pressure (MAP) and heart rate were monitored
oscillometrically with Dinamap (Critikon Co) at regular intervals. In
addition to the above protocol, insulin secretion was assessed in one
of the volunteers while he received first a placebo infusion for 45
minutes, subsequently thereafter an infusion of 5.0 ng Ang II ·
kg-1 · min-1 for another 45 minutes,
and immediately after that another placebo infusion for 45 minutes.
This examination was designed to show the time-profile of the Ang II
effect on infusion secretion.
For the second part of the study, a double-blind, randomized, placebo-controlled study design was adopted. An oral glucose tolerance test with simultaneous determinations of glucose and insulin levels was performed in 12 fasting healthy volunteers (10 males; mean age, 26±1 years; mean BMI, 22.5±1.3 kg/m2), whereas solvent (placebo) or Ang II (5.0 ng · kg-1 · min-1) was infused in random order on two separate occasions. Blood samples for measurements of plasma glucose and insulin concentrations were collected at -30, 0, 30, 60, 90, and 120 minutes. In parallel, MAP and heart rate were monitored with Dinamap. The infusions were started after the first blood sample had been obtained (at -30 minutes).
For 3 days before each investigation, all participants adhered to an isocaloric diet standardized with respect to carbohydrate and NaCl content. Compliance was controlled by measurement of the 24-hour urinary sodium excretion. The subjects had constant weight (±0.5%) for at least 4 weeks before and during the study. Alcohol consumption was not allowed. Physical activity was maintained at its usual level throughout the investigation.
Measurements
Plasma glucose levels were measured with the
Glucoanalyzer II (Beckmann Instruments GmbH). Plasma insulin
concentrations were measured immunoenzymatically (ES 22,
Boehringer Mannheim) using an enzyme-linked immunosorbent assay
with monoclonal insulin antibodies (normal range, 28 to 112
pmol/L). The cross-reactivity with proinsulin was less than 10%
(compared with a double-sandwich radioimmunoassay) and less than 1%
for C-peptide. The intraassay and interassay coefficient of variation
in healthy subjects was 5.2% and 7.5%, respectively, as assessed by
20 measurements of pooled random samples of healthy volunteers (n=10).
The intraindividual coefficient of variation of repeated pulsatile
insulin measurements was between 4.7% and 6.9%, as assessed by
duplicate measurements every 10 minutes during each study day in the
seven volunteers participating in the study on pulsatile insulin
secretion.
Analysis of Basal and Pulsatile Insulin Secretion
The profiles of plasma insulin concentrations during sham
infusion, infusion of 1.0 ng Ang II · kg-1 ·
min-1, and infusion of 5.0 ng Ang II ·
kg-1 · min-1 in each volunteer were
first analyzed using PULSE2, ie, a pulse detection program. The
number and approximate location of putative secretion episodes were
assessed. Thereafter, the plasma insulin concentration profiles were
analyzed with the multiparameter deconvolution
technique using the estimates obtained with PULSE2. The primary
assumption of the multiparameter deconvolution technique is
that the plasma insulin concentration profile at any given time is the
result of five interacting parameters
(multiparameter deconvolution): (1) a finite number of
discrete insulin secretory bursts occurring at specific time points,
and having (2) individual amplitudes (ie, maximal rates of secretion
attained within a single burst), with a (3) common half-duration (ie,
duration of an algebraically gaussian secretory pulse at half-maximal
amplitude), and (4) a subject-specific (individual)
monoexponential plasma insulin half-life; the discrete
pulses are superimposed on (5) a basal (tonic) time-invariant insulin
secretory rate. For all potential secretory events (pulses),
joint-parameter nonlinear asymmetrical confidence intervals
of 95% given experimental uncertainties in the data are computed to
confirm the inclusion of any peak in the final analysis (final
fit) of the data. The fitting pathway applied was validated previously
using computer-synthesized hormone profiles and true-positive insulin
pulses after hormone injection.13 14 15 Assuming a constant
plasma insulin disappearance rate in each individual, the following
parameters were estimated in each plasma insulin
concentration profile: number, locations, amplitudes and half-duration
of insulin secretory events (bursts), the mass of hormone secreted per
burst, and a nonnegative basal (tonic) insulin secretion rate. The
pulsatile secretion rate is the product of the number of bursts and
the mass of hormone secreted per burst. The basal hormone secretion
reflects the baseline amount of circulating hormone at the lower 5% of
the insulin data. The total hormone secretion rate is the sum of tonic
and pulsatile secretion rate. The mathematical concepts and description
of the deconvolution methodology are given in detail
elsewhere.13 14 15 In addition to the deconvolution
analysis, the regularity versus irregularity of the plasma
insulin concentration time-series with the three infusion protocols
(placebo, 1.0 and 5.0 ng Ang II · kg-1 ·
min-1) was analyzed with a model-independent
statistic, ie, approximate entropy (ApEn), as described in detail
elsewhere.16 17
For the analysis of hormone concentration profiles, knowledge of the individual plasma disappearance half-life is of importance. The plasma disappearance half-life of insulin was therefore assessed in each volunteer under fasting conditions using the euglycemic hyperinsulinemic clamp. Insulin sensitivity (M-value) was also calculated in each volunteer as described elsewhere.18 In brief, first a priming bolus infusion of 100 mU insulin/m2 per minute (H-Insulin, Hoechst AG) was given, and the rate of infusion was gradually decreased thereafter to a constant rate of 40 mU/m2 per minute. Plasma insulin levels were raised to about 560 pmol/L. Four minutes after the start of the insulin infusion, a 20% glucose infusion (Glucosteril 20%, Fresenius AG) was started. The infusion rate was adapted to keep the blood glucose concentration within 10% of the baseline level to maintain euglycemia. For this purpose, blood samples for measurements of plasma glucose levels were obtained throughout the clamp at 5-minute intervals. After 2 hours, the insulin infusion was stopped, and blood samples for measurement of insulin levels were withdrawn for another 60 minutes while the glucose infusion rate was reduced slowly to maintain euglycemia throughout. Blood samples for measurement of insulin concentrations were obtained every minute during the first 20 minutes after discontinuation of the insulin infusion, thereafter every 2 minutes for another 20 minutes, and every 5 minutes for another 20 minutes. The disappearance half-life of insulin was calculated from the plasma insulin concentration decay profile individually in each volunteer. The plasma insulin concentration time series was fitted to a decay model that takes into consideration the admixture of a persistent simultaneous low level of endogenous insulin secretion, given by the equation C(t)=C0*e-k/t+b, where k=ln2/half-life and b equals the postdecay baseline insulin concentration. Insulin disappearance was linear over the concentration range studied as documented by plotting the natural logarithm of the plasma insulin concentrations against time for all insulin decay curves of our volunteers.
To exclude a significant effect of Ang II on insulin half-life, additional euglycemic clamp studies were carried out in which four healthy subjects received in random order placebo and 5.0 ng Ang II · kg-1 · min-1 by intravenous infusion. The half-life of insulin was calculated as described above. Administration of Ang II did not alter insulin disappearance half-life; it was 3.48±0.78 minutes with placebo infusion and 3.47±0.52 minutes with infusion of Ang II. The individual placebo/angiotensin II data pairs were 3.80/3.37, 2.49/2.86, 4.32/4.13, and 3.30/3.53 minutes.
Statistics
Normality of data distribution was proven with the Shapiro-Wilk
test. The results of the deconvolution analysis and the ApEn
analysis were compared with a two-way ANOVA to assess
differences between the three infusion protocols. A Newman-Keuls test
was applied to compare means between groups if the ANOVA gave
significant differences. The results of the oral glucose tolerance
test, ie, plasma glucose and insulin concentrations at different time
points during placebo and Ang II infusion, were compared using ANOVA
and Student's t test. Bonferroni correction was performed
to account for multiple data comparison. All data are presented
as mean±SD. The differences were taken as statistically significant at
a level of P<.05.
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Results |
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Basal and Pulsatile Insulin Secretion
The calculated mean plasma disappearance half-life of insulin in the seven healthy subjects participating in the deconvolution study was 2.9±0.5 [2.1-3.8] minutes. The mean M-value (ie, insulin sensitivity) as assessed with the euglycemic clamp technique was 7.5±1.4 mg · kg-1 · min-1. It was comparable to the mean M-values of healthy subjects in previous studies performed in our and other laboratories, documenting normal insulin sensitivity.
Table 1
shows data on basal and pulsatile
insulin secretion as predicted with deconvolution during placebo
infusion, infusion of 1.0 ng Ang II · kg-1 ·
min-1, and infusion of 5.0 ng Ang II ·
kg-1 · min-1. The pressor dose of Ang
II reduced total, basal, and pulsatile insulin secretion, and this
effect was highly significant. The calculated insulin secretory burst
amplitude and the hormone mass secreted per burst were significantly
reduced by administration of Ang II, whereas the number of bursts and
the burst interval were not altered. The subpressor dose tended to
suppress insulin secretion. In addition, the regularity of insulin
secretion was not affected by Ang II, as documented by approximate
entropy analysis (Table 1).
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The time course of the effect of Ang II on insulin secretion was
documented in the volunteer receiving placebo infusion (45 minutes)
first, subsequent infusion of 5.0 ng Ang II ·
kg-1 · min-1 (45 minutes), and
immediately thereafter, another placebo infusion (45 minutes) (Fig 1). There was an immediate effect on
insulin secretion within minutes after the start of the Ang II infusion
as documented by a progressive decline of plasma insulin concentration
secondary to a prolonged interburst interval. During that period, the
plasma insulin concentrations were close to the detection limit of the
enzyme-linked immunosorbent assay. Regular insulin secretion was
subsequently reestablished, but the basal and pulsatile secretions
remained considerably reduced throughout the Ang II infusion period.
The reverse effect was seen after the Ang II infusion was replaced by
placebo infusion (at 90 minutes). The changes in insulin secretion
occurred in parallel with the changes in MAP (data not shown), ie, the
decrease in insulin secretion was accompanied by an increase in blood
pressure and vice versa.
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Table 1
further shows MAP and mean heart rate during placebo infusion
and infusion of Ang II in variable doses compared with the run-in
period. MAP was unchanged with solvent (placebo) infusion and with the
subpressor dose of Ang II (1.0 ng · kg-1 ·
min-1), whereas it increased significantly with the
pressor dose (5.0 ng · kg-1 ·
min-1). In contrast, mean heart rates did not change
significantly with any of the infusion modalities. The mean 24-hour
urinary sodium excretion in our volunteers was comparable on the days
before the three study periods, ie, 179±4 mmol (placebo),
172±4 mmol (1.0 ng Ang II · kg-1 ·
min-1), and 181±4 mmol (5.0 ng Ang II ·
kg-1 · min-1).
Glucose-Stimulated Insulin Secretion
Mean plasma glucose and insulin concentrations after the oral
glucose tolerance test in 12 healthy volunteers are shown in Table 2. Mean plasma insulin levels were
significantly lower during Ang II infusion and mean plasma glucose
levels were significantly higher compared with solvent (placebo)
infusion, ie, Ang II induced a hyperglycemic response in healthy
subjects. MAP levels remained unchanged with solvent (placebo) infusion
and increased with infusion of Ang II (Table 2).
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Discussion |
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The present study clearly demonstrates that Ang II modulates spontaneous insulin secretion. An inhibitory tendency is apparent at subpressor doses, and the suppressive effect is marked and highly significant at pressor doses. Apart from its action on spontaneous insulin secretion, Ang II also significantly suppresses glucose-stimulated insulin secretion and in parallel induces glucose intolerance, ie, hyperglycemia. Ang II increases insulin-mediated glucose uptake in target tissue, eg, skeletal muscle,1 2 3 4 but at the same time, insulin secretion is significantly decreased. As a net result, postload glycemia is significantly increased. Higher plasma glucose concentrations after a glucose load may well have biological significance.
The present study does not permit us to distinguish whether the action of Ang II on insulin secretion is the result of hemodynamic mechanisms, ie, reduced blood flow to the islets of Langerhans, or whether it is receptor mediated via Ang II receptors on ß-cells. To our knowledge, there are no experimental studies that have documented the presence of Ang II receptors on the surface of ß-cells nor has an effect of Ang II on isolated ß-cells been described. Consequently, it remains unresolved whether the above effect of Ang II on ß-cells is direct, ie, mediated by receptors on ß-cells, or indirect, ie, mediated by intestine vasoconstriction or counterregulatory responses to blood pressure elevation. The issue can probably be clarified only in experimental (animal) studies.
It has been known for years that Ang II has a variety of nonhemodynamic actions. It is involved in the mechanism of thirst and stimulates trophic processes in different tissues (eg, heart and kidney).19 Potential metabolic actions of Ang II were first investigated 30 years ago when synthetic Ang II became available for infusion.20 The results of these studies were inconsistent, however. It has been demonstrated only recently that Ang II increases insulin sensitivity under euglycemic conditions in healthy volunteers.1 2 3 This effect of Ang II was dose dependent, and the effect was thought to be mediated, at least in part, by an increase in skeletal muscle perfusion.1 2 Recent experimental studies suggested that the pressor action of Ang II (ie, vasoconstriction) is mediated through Ang II-1 receptors, whereas it has been proposed that Ang II-2 receptors may mediate an opposing effect.21 22 These observations would be consistent with a dual action of Ang II on the level of the microcirculation. Indeed, several experimental studies and studies in humans documented that the hemodynamic action of Ang II is variable and depends on the vascular bed that is studied. Ang II causes a decrease in blood flow to the less insulin-sensitive splanchnic (and renal) vascular beds and an increase of blood flow to the more insulin-sensitive vascular beds of skeletal (and possibly cardiac) muscle.1 4 23 24
The increase in blood flow to skeletal muscle, and in parallel the increase in its insulin sensitivity after administration of Ang II, is diminished in patients with NIDDM of recent onset.4 In this context, some observations are of interest. In patients with the metabolic syndrome, the pressor effect of Ang II is directly proportional to the degree of insulin resistance.25 In these patients, total body sodium content is known to be elevated, and the activity of the renin-angiotensin system is inadequately high.26 Angiotensin-converting enzyme (ACE) inhibitors (and recently also Ang II receptor antagonists) were shown to improve insulin sensitivity in patients with the metabolic syndrome.27 28 A beneficial effect of ACE inhibitors on insulin sensitivity was not demonstrable in all studies, however. Studies examining the effect of ACE inhibition in healthy subjects found no increase or even a decrease of insulin sensitivity.29 30 These contradictory results may be explained in part by differences between the subjects under study and it is therefore plausible to assume that a change in the responsiveness to Ang II is involved in some of the metabolic derangements encountered in patients with the metabolic syndrome.
Insulin secretion consists of a tonic (basal) and a pulsatile component.5 Recently, it has been shown that the basal (nonpulsatile) component of total insulin secretion accounts for less than 40% and the pulsatile component for more than 60% of total insulin secretion in the fasting state.31 These experimental data were obtained by direct catheterization of the portal vein in dogs. In our healthy subjects, deconvolution analysis of plasma insulin profiles sampled from a peripheral vein yielded an estimated 40% pulsatile and 60% nonpulsatile component of insulin secretion. The lower proportion of the pulsatile component obtained with an estimate based on posthepatic peripheral blood sampling is presumably the result of pulse "mixing" in the periphery causing a damped but still clearly pulsatile pattern of insulin secretion. As a result, the number of detectable bursts is less and the interburst interval is increased in comparison with analysis of concentration profiles obtained from portal venous blood.31 32 33 The number of bursts per unit time and the interburst interval (ie, approximately 12 minutes) in our healthy subjects are in agreement with previous reports applying the same sampling procedure and similar hormone pulse detection methodology.5 6 9 34 35
Experimental studies documented that the fast low- amplitude insulin
pulsations are triggered by an intrinsic pancreatic pacemaker within
the ß-cells.8 34 35 This pacemaker seems to be
remarkably stable because its periodicity is not influenced by
administration of glucagon, arginine, salicylate, or tolbutamide or by
endorphine, 
-adrenergic, ß-adrenergic, or parasympathetic
blockade.9 11 33 36 Instead, changes in the ATP/ADP ratio
and oxygen consumption, and very importantly, slow and fast
oscillations of cytoplasmatic calcium concentrations, are
thought to be involved in the generation of pulsatile insulin
secretion.35 37 Our observation that the amount of insulin
secreted per unit time is reduced by chronic (2-hour) Ang II infusion,
while the regularity (or approximate entropy) of insulin pulsatile
secretion remains unaffected, is in good agreement with these
experimental findings.
In summary, the results of our study show that Ang II affects basal (nonpulsatile) and pulsatile components of spontaneous insulin secretion and glucose-stimulated insulin secretion in humans. These observations may be of relevance with respect to the involvement of the renin-angiotensin-system in the genesis of hypertension and possibly also in the genesis of disturbances in glucose metabolism in human disease.
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Acknowledgments |
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We thank Lipha Pharma (Germany) for financial support of the study.
Received May 13, 1997; first decision May 21, 1997; accepted May 21, 1997.
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