Journal of Human Hypertension (1997) 11, 307–312
 1997 Stockton Press. All rights reserved 0950-9240/97 $12.00
Losartan mediated improvement in insulin
action is mainly due to an increase in
non-oxidative glucose metabolism and
blood flow in insulin-resistant
hypertensive patients
G Paolisso, MR Tagliamonte, A Gambardella, D Manzella, P Gualdiero, G Varricchio,
M Verza and M Varricchio
Department of Geriatric Medicine and Metabolic Diseases, II University of Naples, Naples, Italy
We investigated the possible role of losartan on insulinmediated glucose uptake, substrate oxidation and blood
flow in insulin-resistant hypertensive patients. Sixteen
newly diagnosed patients with mild-to-moderate hypertension were studied. The study design was a singleblind, randomised, placebo-controlled trial. After a 1
week run-in period, each patient was randomly assigned
to placebo (n = 7) and losartan (n = 9). Both treatment
periods lasted 4 weeks. At baseline, and at the end of
the placebo and losartan treatment periods, euglycaemic hyperinsulinaemic glucose clamp and indirect
calorimetry were performed. Before and along each glucose clamp, blood flow was also determined in the femoral artery by image-directed duplex ultrasonography
combining B-mode imaging and pulse Doppler beams.
Losartan vs placebo lowered systolic blood pressure by
163 6 3.5 and 147 6 4.1 mm Hg (P , 0.001), and diastolic
blood pressure by 95 6 3.2 and 85 6 3.2 mm Hg
(P , 0.001). Losartan enhanced glucose metabolic clearance rate by 5.1 6 0.3 and 6.3 6 0.4 mg/kg 3 min
(P , 0.05), and whole body glucose disposal (WBGD) by
29.2 6 0.5 and 38.1 6 0.4 mmol/kg free fatty mass (FFM)
3 min (P , 0.01) but did not affect heart rate. Insulinmediated change in blood flow was greater after losartan than placebo administration (111 6 4 vs 84 6 3%,
P , 0.01). Per cent change in insulin-mediated stimulation of blood flow and WBGD were also correlated
(r 5 0.76, P , 0.01). Analysis of substrate oxidation
revealed that losartan adminstration improved insulin
action and non-oxidative glucose metabolism (NOGM)
(30.8 6 2.2 vs 22.8 6 2.8 mmol/kg FFM 3 min, P , 0.05).
In conclusion losartan improves insulin-mediated glucose uptake through an increase in NOGM and blood
flow in hypertensive patients.
Keywords: losartan; insulin action; non-oxidative glucose metabolism
Introduction
Insulin resistance in patients with arterial hypertension may be due to sympathetic nervous system
overdrive1 with a reduction in non-oxidative glucose metabolism (NOGM) and in blood flow.1–3 By
contrast, vasodilatation with an increase in blood
flow lowers arterial blood pressure (BP) and
improves insulin-mediated glucose uptake.2 Several
drugs have been tested to examine those combining
the antihypertensive effect with metabolic benefits.
Angiotensin-converting enzyme (ACE) inhibitors1,4,5
and a1-adrenergic antagonists1,6 seem to meet such
criteria. Recently, the first non-peptide angiotensin
II antagonist (losartan) has been developed and
made available for clinical use. Briefly, the antihypertensive effect of losartan is due to the high
specificity inhibition of angiotensin II receptor (AT 1
subtype). Thus, vasodilation and BP reduction occur
Correspondence: Giuseppe Paolisso, Department of Geriatric
Medicine and Metabolic Diseases, Servizio di Astanteria Medica,
Piazza Miraglia 2, I-80138 Napoli, Italy
Received 22 October 1996; revised 2 February 1997; accepted 12
February 1997
following losartan administration. ACE-inhibitor
administration is also associated with a rise in
plasma bradykinin concentration7 which contributes to the hypotensive effect8 and to the improvement in insulin action.9 Angiotensin II antagonists
lack the bradykinin potentiating action of ACE
inhibitors10 thus allowing one to differentiate the
effect due to angiotensin II blockade from that of bradykinin. Recently, angiotensin II antagonism has
been shown to improve insulin action.11 Nevertheless, in such studies no data on substrate oxidation
and blood flow were provided. Thus, we tested the
hypothesis that AT1 antagonism improves insulin
action through a rise in blood flow and a change in
substrate oxidation in insulin-treated hypertensive
patients. To assess this hypothesis, hypertensive
patients were treated with losartan while changes in
insulin-mediated glucose uptake, substrate oxidation and blood flow were determined by euglycaemic hyperinsulinaemic glucose clamp, indirect
calorimetry and echodoppler techniques respectively.
Angiotensin II receptor antagonism and insulin action in hypertensives
G Paolisso et al
308
Materials and methods
Subjects
Sixteen newly diagnosed patients with mild-tomoderate hypertension volunteered for the study.
Patients were considered to be hypertensive according to their clinic BP levels (diastolic BP [DBP] .90
mm Hg taken as a mean of three different measurements in at least three different visits at 1-week
intervals). All patients had a normal glucose tolerance (75 g glucose) according to WHO criteria.12
Exclusion criteria from the study were a family history of diabetes and obesity, coronary artery disease,
congestive heart failure, valvular heart disease,
impaired glucose tolerance and diabetes mellitus.
All patients were free from cardiac medication and
drugs known to interfere with glucose metabolism
and had a similar sedentary lifestyle. All patients
were receiving a similar weight-maintenance diet of
35 kcal/kg/die, made up of 50% carbohydrate, 20%
fat and 30% protein, did not change their lifestyle
and gave their informed consent to participate in the
study which was approved by the Ethics Committee
of our Institution. Detailed characteristics of patients
are shown in Table 1.
Study design
The study was designed as a single-blind, randomised placebo-controlled trial. After a 1 week run-in
period, each patient was randomly assigned to placebo (n = 7) or losartan (n = 9) (50 mg/die; Lortaan;
Merck Sharp Dohme-Rome, Italy). Each treatment
period lasted 4 weeks. At baseline, and at the end of
placebo and losartan treatment periods, euglycaemic
hyperinsulinaemic glucose clamps were performed.
During the treatment periods, placebo and losartan
were given once daily before breakfast. The day of
the clamp, placebo and losartan were given 60 min
before starting insulin infusion. Arterial BP was
measured before performing the glucose clamp.
Cardiovascular determinations
Arterial BP was measured according to the criteria
of the Joint National Committee on Detection, Evaluation and Treatment of High Blood Pressure.13
Briefly, three BP measurements at 2 min intervals
were taken using a standard mercury sphygmomanTable 1 Clinical characteristics of patients (n = 16)
Mean ± s.d.
Age (yrs)
Gender (M/F)
BMI (kg/m2 )
SBP (mm Hg)
DBP (mm Hg)
FPG (mmol/L)
FPI (pmol/L)
2 h pG (mmol/L)
46.2 ± 0.4
9/7
25.6 ± 0.4
165 ± 4.8
97 ± 2.3
5.0 ± 0.5
79 ± 6
6.2 ± 0.3
BMI = body mass index; SBP = systolic blood pressure; DBP =
diastolic blood pressure; FPG = fasting plasma glucose; FPI = fasting plasma insulin: 2 h pG = 2 h plasma glucose.
ometer when patients had been sitting for approximately 1 h. The disappearance of sound (phase V)
was used for diastolic reading. Mean value of the
last two recorded measurements was considered
for analysis.
Before and along glucose clamp, blood flow was
determined in a segment of a common femoral artery
with a circular cross-section. Measurements were
made by image-directed duplex ultrasonography
combining B-mode imaging and pulse Doppler
beams (Apogee CX 200, Interstice ATL, Ambler, PA,
USA). Blood flow volumes were automatically calculated as the product of the vessel cross-sectional
area, and the time averaged blood velocity from
seven repeated measurements. Blood flow did not
differ between each leg and pooled data are
presented accordingly. The investigator performing
the duplex measurements was blinded to the treatment.
Metabolic determinations
Euglycaemic glucose clamp were performed according to De Fronzo et al.14 Using a fixed insulin
infusion rate (7.1 pmol/kg × min; Humulin R, Eli
Lilly, Florence, Italy) the pump delivered a variable
amount of glucose as 20% solution. Indirect calorimetry was employed in the basal state (from −60 to
0 min), and during the last 60 min of the clamp procedure to estimate substrate oxidation. A computerised open-circuit system was used to measure
gas exchange through a 25 L polyvinyl-chloride
plastic canopy (Deltatrac, Datex, Milan, Italy). The
monitor has a precision of 2.6% for oxygen consumption and 1.0% for carbon dioxide production.
All metabolic tests were carried out by investigators unaware of active or placebo treatment groups
and of arterial BP determination.
Sampling and analytical methods
Blood samples were drawn at −20 and 0 min and
then at 20 min intervals until the end of the glucose
clamp. Plasma sodium, potassium and calcium levels were determined at the end of the run-in period
and also after placebo and losartan periods by routine methods. Except for plasma glucose concentrations which were immediately determined by
using the glucose oxidase method (Beckman, AutoAnalyzer, Fullerton, USA) blood samples for insulin
were collected in ethylene-diaminetetraacetic acid
(EDTA) and stored in ice until centrifugation.
Plasma was drawn off and frozen for assay at a later
date. Plasma insulin was measured by the radioimmunoassay method (Sorin, Biomedica, Milan,
Italy; c.v. = 2.9 ± 0.3%).
Calculation and statistical analyses
Compliance with drug treatment was assessed by
capsule counting at each visit and was expressed as
a percentage of capsule consumed multiplied by the
total days of therapy. Fat free mass (FFM) and percentage body fat (%BF) were estimated by bioelectri-
Angiotensin II receptor antagonism and insulin action in hypertensives
G Paolisso et al
cal impedance analysis (BIA 101/s, Akern, Florence, Italy).15
Whole body glucose disposal (WBGD) was calculated according to Bonadonna et al.16 NOGM was
calculated as the difference between WBGD and oxidative glucose metabolism as determined by indirect
calorimetry.17 To avoid any interference of body
weight change on insulin sensitivity, WBGD and
substrate oxidation were related to FFM.
Per cent changes in insulin-mediated stimulation
of blood flow and in WBGD were calculated as per
cent increase above baseline values.
All data are expressed as mean ± s.d. Analysis of
variance (ANOVA) was used to compare multiple
group means. When ANOVA indicated a difference
at the 5% level or less, Scheffe’s test was employed
for individual group comparisons. Statistical analyses were made by SOLO software package system
(BMDP, Cork, Ireland) on an IBM PC computer.
glucose dispersal (28.3 ± 2.5 vs 29.6 ± 3.8 mmol/kg
FFM × min, P = NS), oxidative (11.3 ± 2.5 vs 12.2 ±
3.8 mmol/kg FFM × min, P = NS), and non-oxidative
(16.8 ± 3.4 vs 17.1 ± 4.1 mmol/kg FFM × min, P = NS)
glucose metabolism achieved similar values before
placebo and losartan administration, respectively.
Similarly, basal blood flow (0.223 ± 0.31 vs 0.219 ±
0.031 L/min, P = NS) and per cent insulin mediated
increase in blood flow (82 ± 9 vs 84 ± 7%, P = NS)
were also not different before placebo and losartan
administration, respectively.
Results
AT1 antagonism effects on metabolic parameters
Run-in period
Fasting plasma glucose (5.1 ± 0.4 vs 4.8 ± 0.3
mmol/l, P = NS) and insulin (81 ± 7 vs 75 ± 6 pmol/l,
P = NS) were not different after placebo and losartan
administration, respectively. Basal blood flow (0.224
± 0.030 vs 0.233 ± 0.031 L/min, P , 0.05) was significantly greater after losartan administration. During glucose clamp, plasma glucose concentration
was kept within a narrow range (c.v. = 3.2 ± 0.4 vs
3.1 ± 0.2%, P = NS), and close to basal values (5.1 ±
0.3 vs 5.0 ± 0.5 mmol/L, P = NS) after placebo and
losartan administration, respectively. Along with
insulin infusion, plasma insulin levels (478 ± 22 vs
493 ± 19 pmol/l, P = NS) were also not different
between placebo and losartan adminstration. In
metabolic conditions, losartan administration
against placebo was associated with a significant
increase in both WBGD and blood flow (Figure 1). In
the losartan group, the per cent increase in insulinmediated stimulation of blood flow and in WBGD
(r = 0.76, P , 0.01) were significantly correlated.
Evaluation of non-protein nitrogen concentration
in the urine (placebo: 4.2 ± 0.3 mg/ml; losartan: 4.3
± 0.1 mg/ml, P = NS), and urinary flow (placebo: 2.4
± 0.4 ml/min; losartan: 2.5 ± 0.4 ml/min, P = NS)
yielded similar estimates of total protein oxidation
in both experimental conditions. From these data,
substrate oxidation could be analysed. In the basal
state, placebo and losartan had similar effects
(Figure 2). Insulin infusion stimulated oxidative and
NOGM and inhibited lipid oxidation (Figure 2). Losartan was associated with a greater stimulation of
insulin-stimulated NOGM (Figure 2). No significant
correlation between plasma insulin concentration at
the steady-state of the glucose clamp and NOGM
(r = 0.07, P = NS) was found.
Systolic BP (SBP) and DBP, heart rate, body mass
index (BMI) and FFM were stable and unchanged
throughout the run-in period (data not shown). No
patient had intercurrent illness or took drugs that
were known to interfere with glucose metabolism.
As shown in Table 2, subjects in the placebo and
losartan groups were of similar age, gender distribution, BMI, FFM and cardiovascular parameters.
Baseline parameters
At baseline body weight (73.5 ± 2.6 vs 75.5 ± 3.1 kg,
P = NS), BMI (26.2 ± 0.4 vs 25.8 ± 0.3 kg/m2, P = NS),
%BF (25 ± 3 vs 26 ± 4%, P = NS), waist/hip ratio
(0.87 ± 0.03 vs 0.88 ± 0.04, P = NS), SBP (165 ± 4.8
vs 163 ± 5.3 mm Hg, P = NS), DBP (97 ± 2.3 vs 99 ±
3.3 mm Hg, P = NS) and heart rate (74 ± 2.9 vs 75
± 3.0 beats/min, P = NS) were not different between
losartan and placebo groups, respectively. Fasting
and steady state plasma glucose and insulin concentration and basal substrate oxidation were also not
different between the study groups (data not
shown). Along with insulin infusion, whole body
Table 2 Clinical characteristics of the patients after administration of placebo and losartan
Gender (M/F)
Body weight (kg)
Body weight change (kg)
BMI (kg/m 2)
FFM (kg)
Waist/hip ratio
SBP (mm Hg)
DBP (mm Hg)
Heart rate (beats/min)
Placebo
Losartan
4/3
75.5 ± 2.6
−0.8 ± 0.2
25.6 ± 0.4
51.4 ± 1.8
0.85 ± 0.04
163 ± 3.5
95 ± 3.2
73 ± 3.5
5/4
74.7 ± 3.1
0.3 ± 0.1
25.1 ± 0.3
51.8 ± 1.5
0.84 ± 0.03
147 ± 4.1*
85 ± 3.2*
76 ± 3.7
All results are mean ± s.d. BMI = body mass index; FFM = fat
free mass; SBP = systolic blood pressure; DBP = diastolic blood
pressure.
Statistically significant differences between placebo and losartan
were: *P , 0.001.
AT1 antagonism effects on cardiovascular
parameters
As seen in Table 2, SBP and DBP were significantly
reduced by losartan administration, while placebo
did not significantly affect arterial BP. Heart rate was
similar in both experimental conditions.
Changes in plasma electrolytes levels
Baseline plasma sodium (138 ± 4 vs 140 ± 5 mmol/L,
P = NS), potassium (4.2 ± 0.2 vs 4.1 ± 0.3 mmol/L,
P = NS), and calcium (3.4 ± 0.2 vs 3.5 ± 0.3 mmol/L,
P = NS) concentrations were not significantly different after placebo and losartan administration,
309
Angiotensin II receptor antagonism and insulin action in hypertensives
G Paolisso et al
310
Figure 2 Substrate oxidation at fasting and along with insulin
infusion after placebo and losartan administration. Statistically
significant difference against the same parameter after placebo
administration was: *P , 0.01.
Figure 1 WBGD and changes in blood flow when insulin infusion
was combined with placebo (j) and losartan (h) administration.
Statistically significant differences were: *P , 0.01.
respectively. Insulin infusion was associated with a
significant decline (P , 0.001 in both experimental
conditions) in plasma potassium concentration.
Adverse effects
Throughout the study no adverse effects were
reported, and no patients dropped out of the study
because of excessive or blunted antihypertensive
effects. Compliance with drug treatment was 91 ±
0.8%.
Discussion
Our study shows that AT1 antagonism improves
insulin action through an improvement in nonoxidative NOGM and blood flow.
The cardiovascular effects of AT1 receptor antagonism are well investigated.18 In particular, it has
been demonstrated that losartan, a potent non-peptide AT1 receptor antagonist, inhibits specifically
the binding of angiotensin II to its own receptor19
and shares an antihypertensive effect with a long
duration of action in both inpatients and outpatients.20 A minimal dose of 50 mg is necessary to
sustain the BP lowering effect, while 100 mg provides only minor additional antihypertensive efficacy. The key advantage of AT1 antagonism against
ACE inhibitors is the minimisation or untoward
effects as cough, urticaria and angioedema are very
rarely encountered. 21 Furthermore, angiotensin II
antagonism lacks the bradykinin potentiating action
of ACE inhibitors,10 thus allowing differentiation of
the effect due to angiotensin II blockade from that
of bradykinin.
Despite a growing body of evidence showing losartan to have several cardiovascular effects, very
little data regarding the effect of AT1 inhibition on
glucose handling have been reported. In particular,
it has been demonstrated that losartan administration is associated with an increase of insulin
action.11 Nevertheless, Moan et al11 did not measure
substrate oxidation and blood flow which might significantly affect WBGD. As far as blood flow is concerned, previous studies have demonstrated that
vasodilatation and constriction may have opposite
effects on insulin-mediated glucose uptake.22 Steinberg et al 23 demonstrated that insulin infusion
(120 mU × m2 × min) and consequent hyperinsulinaemia increased blood flow in the leg approximately
two-fold as well as insulin-mediated glucose uptake.
The role of leg blood flow on insulin-mediated glucose uptake is also highlighted by studies in insulinresistant states. Obese insulin-resistant patients
exhibit impaired metacoline-induced vasodilatation
under basal and insulin-stimulated conditions,2 a
haemodynamic phenomena paralleling the impair-
Angiotensin II receptor antagonism and insulin action in hypertensives
G Paolisso et al
ment in insulin action.2 Further, it has also been
demonstrated that the dose response curve between
insulin action and increased leg blood flow is
shifted to the right in insulin-resistant obese
patients with and without non-insulin dependent
diabetes mellitus.24 Such results have strengthened
the hypothesis that muscle perfusion contributes to
modulate in vivo glucose uptake. Therefore, a defect
in haemodynamic action could result in insulin
resistance. Thus, one can hypothesise, that after AT1
antagonism, vasodilatarion decreases the distance
between feeding capillaries (capillary recruitment)
with a secondary improvement in the insulin concentration gradient between the capillary and surrounding muscle. Such an event might give greater
stimulation to glucose uptake with a secondary
increase in NOGM.
With regard to the interaction between AT1 antagonism and insulin activity at plasma membrane
level, recent data have also provided evidence that
inhibition of AT1 receptor favours the translocation
of GLUT4 protein from an intracellular membrane
compartment to a plasma membrane fraction.25 It
has been hypothesised that such an effect is
mediated through the modulation of the sympathetic nervous system (SNS).25 In fact, several studies
have shown that angiotensin II increases the sympathoadrenal activity by enhancing noradrenaline
release,1,26 which in turn can lead to insulin resistance and inhibition of glucose uptake.27 Increased
mobilisation of sympathetic neurotransmitters by
angiotensin II is responsible for the inhibition of glucose uptake and reduction of the GLUT4 protein.25
In contrast, AT1 antagonism is able to reduce SNS
overdrive and to prevent the depletion of cathecolamine stores thus favouring the translocation of
GLUT4 at plasma membrane.11,28 Whether losartan
administration is associated with a significant
stimulation of NOGM, rather than with the improvement of both oxidative and NOGM is still unclear.
One can hypothesise that, NOGM being the main
gluco-metabolic defect in hypertensive patients, losartan administration might act mainly on this one
defect.
In conclusion, our study demonstrates that AT1
antagonism improves insulin-mediated glucose
uptake in hypertensive patients. Whether losartan
acts on insulin action through the improvement in
blood flow, or also through an effect on GLUT4 will
deserve further investigation.
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