Content uploaded by Roy Harper
Author content
All content in this area was uploaded by Roy Harper on Aug 10, 2014
Content may be subject to copyright.
Insulin
resistance
in
offspring
of
hypertensive
parents
Olivia
L
Beatty,
Roy
Harper,
Brian
Sheridan,
A
Brew
Atkinson,
Patrick
M
Bell
Abstract
Objective-To
determine
if
insulin
resistance
is
present
in
normotensive
adults
at
increased
risk
of
developing
hypertension.
Design-Normotensive
subjects
with
at
least
one
hypertensive
parent
were
paired
with
offspring
of
normotensive
parents
(controls),
being
matched
for
age,
sex,
social
class,
and
physical
activity.
Setting-Outpatient
clinic.
Subjects-30
paired
subjects
(16
men
and
14
women)
with
and
without
a
family
history
of
hyper-
tension,
aged
18-32,
with
a
body
mass
index
<
25
kg/mi,
with
blood
pressure
<
130/85
mm
Hg,
and
not
taking
drugs.
Interventions-Euglycaemic
glucose
clamp
(two
hour
infusion
of
insulin
1
mU/kg/min)
and
intra-
venous
glucose
tolerance
test
(injection
of
100
ml
20%
glucose).
Main
outcome
measures-Insulin
mediated
glucose
disposal
and
insulin
secretion.
Results-The
offspring
of
hypertensive
parents
had
slightly
higher
blood
pressure
than
did
the
controls
(mean
117
(SD
6)
v
108
(5)
mm
Hg
systolic,
p=0013;
76
(7)
v
67
(6)
mm
Hg
diastolic,
p=0.017).
Their
insulin
mediated
glucose
disposal
was
lower
than
that
of
controls
(29.5
(6
5)
v
40-1
(8.6)
[imol/kg/min,
p=0.002),
but,
after
adjustment
for
blood
pressure,
the
difference
was
not
significant
(difference
6-9
(95%
confidence
interval
-1
5
to
15.3),
p=010).
Insulin
secretion
in
the
first
hour
after
injection
of
glucose
was
slightly
but
not
sig-
nificantly
higher
in
the
offspring
of
hypertensive
patients
(9320
(5484)
v
6723
(3751)
pmol.min/l).
The
two
groups
had
similar
concentrations
of
plasma
glucose
(5.2
(0
3)
v
5
1
(0.4)
mmolIl),
serum
choles-
terol
(4.4
(0
8)
v
4*6
(0
8)
mmol/l),
serum
triglyceride
(0.89
(0.52)
v
0*68
(0.27)
mmolI),
and
serum
low
density
lipoprotein
cholesterol
(2.81
(0
65)
v
2-79
(0.61)
mmol/1).
The
offspring
of
hypertensive
parents,
however,
had
lower
serum
concentrations
of
high
density
lipoprotein
cholesterol
(1.24
(0.31)
v
1-56
(0.35)
mmol/l,
p=0.002)
and
higher
serum
concentrations
of
non-esterified
fatty
acids
(0.7
(0.4)
v
0
4
(0.4)
mmol/l,
p=0039).
Conclusions-Young
normotensive
subjects
who
are
at
increased
risk
of
developing
hypertension
are
insulin
resistant.
Introduction
Evidence
from
epidemiological
and
clinical
studies
indicates
that
essential
hypertension
is
associated
with
insulin
resistance
and
that
this
is
independent
of
obesity,
glucose
tolerance,
and
age.'
One
explanation
for
the
association
is
that
some
feature
of
essential
hypertension
causes
insulin
resistance:
obvious
candidates
are
the
commonly
used
antihypertensive
drugs,
especially
thiazide
diuretics
and
i
adrenergic
blockers.46
The
presence
of
impaired
insulin
action
in
relatively
young,
untreated
patients,
however,
argues
against
antihypertensive
medication
being
the
sole
aetiological
factor
in
insulin
resistance.78
Altema-
tively,
insulin
resistance
(and
associated
hyperinsulin-
aemia)
may
cause
raised
blood
pressure:
suggested
mechanisms
include
insulin
inducing
increased
renal
tubular
reabsorption
of
sodium
and
release
of
pressor
hormones.91'
If
insulin
resistance
comes
first,
what
determines
a
person's
degree
of
insulin
sensitivity?
In
order
to
investigate
these
issues
we
made
use
of
the
observation
that
offspring
of
hypertensive
parents
are
more
likely
to
develop
hypertension
than
offspring
of
normotensive
parents.'2-4
By
examining
insulin
action
in
groups
of
such
offspring,
themselves
normo-
tensive,
we
hoped
to
establish
whether
insulin
resist-
ance
precedes
clinical
hypertension.
The
presence
of
impaired
insulin
action
in
a
group
with
a
familial
predisposition
to
essential
hypertension
would
raise
the
possibility
that
insulin
resistance
is
also
determined
as
a
familial
trait,
which
could
be
important
in
the
pathogenesis
of
subsequent
hypertension.
Subjects
and
methods
Potential
subjects
for
the
study
were
identified
from
records
of
three
suburban
general
practices
in
greater
Belfast.
Subjects
were
considered
eligible
if
they
were
aged
18-32,
their
body
mass
index
((weight
(kg)/
(height)
(M))2)
was
<25,
their
blood
pressure
was
<
130/85
mm
Hg
(to
be
below
the
mean+
one
SD
blood
pressure
of
the
population
of
greater
Belfast'5),
and
they
were
not
taking
any
drugs.
Subjects
with
un-
certainty
about
a
family
history
of
hypertension
and
those
with
a
family
history
of
diabetes
mellitus
in
any
first
degree
relative
were
excluded.
Information
on
the
blood
pressure
of
hypertensive
parents
was
obtained,
with
their
consent,
from
general
practice
records.
Hypertensive
parents
were
defined
as
those
who
had
a
blood
pressure
>
160/95
mm
Hg
on
two
occasions
before
receiving
antihypertensive
treat-
ment
and
for
whom
there
was no
evidence
to
suggest
secondary
forms
of
hypertension,
but
since
these
patients
had
been
managed
in
general
practice,
detailed
investigations
had
not
been
carried
out.
The
mean
(SD)
untreated
blood
pressure
of
the
hyperten-
sive
parents
(aged
45-65)
was
177
(19)/108
(8)
mm
Hg.
Normal
blood
pressure
in
the
normotensive
parents
was
defined
as
<
140/90
mm
Hg
on
two
occasions
in
both
parents.
This
information
was
obtained
from
general
practice
records
or,
when
this
was
unavailable,
blood
pressure
was
measured
by
one
of
the
investi-
gators.
In
the
normotensive
parents
mean
(SD)
current
blood
pressures
were
126
(13)/77
(8)
mm
Hg
in
the
mothers
and
125
(14)/68
(11)
mm
Hg
in
the
fathers.
Fifteen
pairs
of
subjects
(16
men
and
14
women)
were
identified
who
were
carefully
matched
for
age
and
sex
and
broadly
matched
for
physical
activity
(allowing
a
difference
of
one
band'6)
and
social
class
(allowing
a
difference
of
one
category).
Physical
activity
at
work
and
leisure
in
the
four
weeks
before
the
test
was
assessed
by
a
simple
self
reporting
questionnaire.
All
the
subjects
were
non-smokers.
Of
the
subjects
who
had
hypertensive
parents,
13
had
one
parent
with
hypertension
and
two
had
both
parents
with
hyper-
tension.
Written
consent
was
obtained
from
each
subject
for
participation
in
the
clinical
studies.
CLINICAL
STUDIES
Euglycaemic
hyperinsulinaemic
glucose
clamps
and
BMJ
VOLUME
307
1
0
JULY
1993
Sir
George
E
Clark
Metabolic
Unit,
Royal
Victoria
Hospital,
Belfast
BT12
6BA
Olivia
L
Beatty,
research
fellow
Roy
Harper,
research
fellow
A
Brew
Atkinson,
consultant
physician
Patrick
M
Bell,
consultant
physician
Regional
Endocrine
Laboratory,
Royal
Victoria
Hospital
Brian
Sheridan,
principal
biochemist
Correspondence
to:
Dr
Bell.
BM7
1993;307:92-6
92
intravenous
glucose
tolerance
tests
were
performed
for
each
subject
at
least
one
week
apart.
For
three
days
before
each
test
the
subjects'
diets
contained
at
least
150
g
carbohydrate
daily.
Women
were
studied
in
the
first
10
days
of
their
menstrual
cycle
to
avoid
variation
in
insulin
sensitivity
at
different
times
of
the
cycle.'7
Systolic
and
diastolic
blood
pressure
was
measured
in
triplicate
after
at
least
10
minutes
in
the
supine
position
with
a
Hawksley
random
zero
sphygmomanometer.
Insulin
sensitivity
was
determined
with
the
eugly-
caemic
glucose
clamp
technique.8
Briefly,
the
subjects
were
admitted
to
our
unit
at
8
00
am
after
an
overnight
fast
of
10
hours.
A
plastic
18
French
gauge
cannula
(Venflon,
Viggo,
Helsinborg,
Sweden)
was
inserted
into
a
left
antecubital
vein
for
infusions,
and
this
was
quickly
followed
by
a
21
French
gauge
cannula
(Venflon,
Viggo)
inserted
retrogradely
into
a
dorsal
vein
of
the
right
hand.
This
was
maintained
at
55°C
in
a
thermostatically
controlled
Perspex
enclosure
(Automaton
Division,
Ashby
Institute,
Queen's
Uni-
versity
of
Belfast).
Basal
(fasting)
blood
samples
were
then
collected
for
determination
of
plasma
glucose,
serum
insulin,
serum
lipids,
free
fatty
acids,
glycerol,
and
,3-hydroxybutyrate.
After
25
minutes'
rest
to
re-establish
basal
conditions,
insulin
(Humulin
S,
Eli
Lilly,
Basingstoke)
was
administered
at
1.0
mU/kg/min
for
two
hours.
Arterialised
blood
samples
were
obtained
at
five
minute
intervals
for
estimation
of
plasma
glucose.
The
samples
were
centrifuged
immediately
at
the
bedside
and
analysed
with
a
glucose
oxidase
method
(Beckman
Glucose
Analyser
II,
Beckman
RIIC,
High
Wycombe).
Plasma
glucose
concentration
was
maintained
at
the
fasting
level
by
a
variable
exogenous
infusion
of
20%
glucose
solution.
During
the
last
30
minutes
of
the
clamp
the
rates
of
glucose
infusion
were
corrected
for
slight
variations
from
target
plasma
glucose
to
give
an
estimate
of
overall
insulin
mediated
glucose
disposal.'8
Blood
samples
for
determination
of
insulin,
free
fatty
acids,
glycerol,
and
3-hydroxybutyrate
were
collected
in
plain
glass
tubes.
Samples
were
separated
as
soon
as
clotting
was
complete
and
were
stored
at
-20°C
until
analysis.
Intravenous
glucose
tolerance
tests
were
performed
with
13
pairs
of
subjects
(two
subjects
were
unable
to
reattend),
who
were
admitted
at
8
00
am
after
an
overnight
fast
of
10
hours.
An
intravenous
cannula
was
placed
in
an
antecubital
vein
for
blood
sampling.
An
injection
of
20
g
glucose
(100
ml
of
20%
solution)
was
given
rapidly,
and
blood
samples
were
taken
at
2,
4,
6,
8,
10,
20,
40,
and
60
minutes
after
injection
for
estimation
of
plasma
glucose
and
insulin.
Plasma
glucose
was
analysed
at
the
bedside
as
described
above.
Serum
insulin
was
determined
by
a
radioimmuno-
assay
with
insulin
antibody
precipitate.'9
Commercial
kits
were
used
to
estimate
serum
non-esterified
free
fatty
acid
(interassay
coefficient
of
variation
4.2%)
(Wako
Chemicals,
Neuss,
Germany),
f-hydroxybuty-
Characteristics
of
offspring
of
hypertensive
and
normotensive
parents.
Figures
are
means
(standard
deviations)
unless
stated
othenvise
Children
of
Children
of
hypertensive
normotensive
parents
parents
Mean
difference
(n=
15)
(n=
15)
(95%
confidence
interval)
Age
:years)
25-8
(3-9)
25
7
(3
9)
Body
mass
index
(kgtml)
22-8
(2
3)
22-4
(1
5)
0
4
(-0
9
to
1
7)
Blood
pressure
(mm
Hg):
Systolic
117(6)
108
(5)*
8(3
to
14)
Diastolic
76
(7)
67
(6)*
9
(3
to
15)
Serum
concentration
(mmol/l):
Cholesterol
4-4
(0-8)
4-6
(0
8)
-0-2
(-0-88
to
0-42)
Triglyceride
0-89
(0
52)
0-68
(0
27)
0
20
(-0
04
to
0
45)
Low
density
lipoprotein
cholesterol
2
81
(0
65)
2-79
(0
61)
0.02
(-0-47
to
049)
High
density
lipoprotein
cholesterol
1
24
(0
31)
1-56
(0
35)**
-0-32
(-0-51
to
-0-12)
*p
<
0-05;
**p
<
0
005.
0-_
Offspring
of
hypertensive
parents
(n=
15)
O-O
Offspring
of
normotensive
parents
(n+
5)
X1
c=
6
-
o
o
5_-
125.
~,
4
574
-
0
287-
'n
E
c
-
45-
o
._
u
E
'a
i-
30
-
.C
E
c
_
V)
T
T-n
-
T--T-
,gT-
T-
-30
0
30
60
90
20
Time
(minutes)
FIG
1
-Mean
(SE)
concentrations
of
plasma
glucose
and
serum
insulin
and
insulin
mediated
glucose
disposal
in
offspring
of
hypertensive
and
normotensive
parents
during
euglycaemic
glucose
clamp.
Insulin
infusion
started
at
time
Q
rate
(interassay
coefficient
of
variation
1-2%),
and
serum
glycerol
(interassay
coefficient
of
variation
5.2%)
(Randox
Laboratories,
Crumlin)
by
enzymatic
methods
and
spectrophotometry.
Serum
cholesterol
was
measured
by
a
cholesterol
oxidase
method
and
serum
triglycerides
were
measured
by
lipase-glycerol
kinase
end
point
(Technion
500
RA
reagents).
High
density
lipoprotein
cholesterol
was
measured
by
manganese-heparin
precipitation,
and
low
density
lipoprotein
cholesterol
was
derived
with
the
Friede-
wald
formula.20
STATISTICAL
METHODS
Results
are
described
as
means
(SD)
unless
stated
otherwise.
Areas
under
the
glucose
and
insulin
curves
were
calculated
for
the
glucose
tolerance
tests
and
analysed
by
paired,
two
tailed
Student's
t
tests.
Paired
t
tests
were
also
used
for
comparison
of
all
baseline
data
and
results
obtained
during
the
euglycaemic
glucose
clamp.
Analysis
of
covariance
was
used
to
adjust
for
the
potentially
confounding
influence
of
blood
pressure
on
insulin
mediated
glucose
disposal.
Results
The
table
shows
that
the
offspring
of
hypertensive
parents
had
slightly
higher
blood
pressures,
systolic
(p=0-013)
and
diastolic
(p=0-017),
than
those
of
the
control
group
(offspring
of
normotensive
parents).
The
serum
concentrations
of
cholesterol,
triglyceride,
and
low
density
lipoprotein
cholesterol
did
not
differ
significantly
between
the
groups,
but
that
of
high
density
lipoprotein
cholesterol
was
lower
in
the
offspring
of
hypertensive
parents
(p=0
002).
The
offspring
of
hypertensive
and
normotensive
parents
had
similar
fasting
concentrations
of
plasma
glucose
(5-2
(0 3)
v
5-1
(0
4)
mmol/l,
p=0
22),
serum
insulin
(41-6
(11
1)
v
32-3
(5
5)
pmol/l,
p=009),
serum
(B-
hydroxybutyrate
(0-12
(0
11)
v
0
07
(0
07)
mmol/l,
(p=022),
and
serum
glycerol
(70-6
(27-1)
v
57-2
(30
6)
mmol/l,
p=0
27),
but
offspring
of
hypertensive
parents
had
significantly
higher
fasting
serum
non-
BMJ
VOLUME
307
10JuLY
1993
93
60-
r-
bo
u
0
E
-a
45-
0~
0.
0)
E
-3
C
5a3-
0
0
*
6
0
0
0
0
8
0
Offspring
of
hypertensive
parents
(n=
I5)
Offspring
of
normotensive
parents
(n=
5)
FIG
2-Individual
rates
of
insulin
mediated
glucose
disposal
in
offspring
of
hypertensive
and
normotensive
parents
esterified
free
fatty
acid
concentrations
(0
7
(0-4)
v
0
4
(0
4)
mmol/l,
p=0-039).
Figure
1
shows
the
results
of
the
glucose
clamp
studies.
The
mean
(SD)
plasma
glucose
concentration
and
coefficient
of
variation
were
5-2
(0
3)
mmol/l
and
3-9
(1-7)
in
the
offspring
of
hypertensive
parents
and
5-1
(0
2)
mmol/l
and
4-3
(1
9)
in
the
control
group.
The
mean
serum
insulin
concentrations
were
similar
in
the
two
groups
(369-5
(119
1)
v
346-5
(944)
pmol/l,
p=0
29).
During
the
last
30
minutes
of
the
glucose
clamp
insulin
mediated
glucose
disposal
was
signifi-
cantly
lower
among
the
offspring
of
hypertensive
parents
(29-5
(6
6)
v
40-1
(8
5)
pmol/kg/min).
The
mean
difference
in
glucose
disposal
was
10-6
p.mol/kg/
min
(95%
confidence
interval
5-5
to
15-7,
p=0
002).
The
range
of
values
for
glucose
disposal
was
20
7-47-3
pmol/kglmin
for
the
offspring
of
hyper-
tensive
parents
and
28-3-57-9
,umol/kg/min
for
the
control
group
(fig
2).
When
the
influence
of
baseline
blood
pressure
was
taken
into
account
with
simple
regression
analysis
the
difference
in
glucose
disposal
between
the
groups
was
reduced
and
was
no
longer
significant-after
adjustment
for
systolic
blood
pres-
sure
the
mean
difference
was
6-9
(95%
confidence
interval
-
1-5
to
15-3)
(p
=0
10),
and
after
adjustment
for
diastolic
blood
pressure
it
was
7-1
(-2-2
to
-14-4)
(p=0O06).
Serum
concentrations
of
non-esterified
free
fatty
acids,
glyc
pressed
equ
Figure
4
s
tolerance
te
glucose
cor
The
offspriu
group
were
secretion
(a]
(3049
(181(
second
pha
(1914)
pmo
Discussion
Our
stud
present
in
y
80
E
4040
0]E
0)
-i
C
oE
I
0.3
-
0.2
-
0.1
0.
0.8
-
.t_
u
CU
0
0.4-
,
E
02
Fi(;
3-Mean
rate,
and
non-i
normotensive
started
at
time
20-
0
E
E
0
0
u
2
10-
0
-
574-
0
E
-
I-,287-
._c
C
0
-
0-O
Offspring
of
hypertensive
parents
(n=
13)
O-O
Offspring
of
normotensive
parents
(n=
13)
I
I
-30
0
30
Time
(minutes)
60
FIG
4-Mean
(SE)
concentrations
of
plasma
glucose
and
serumi
insulin
in
offspring
of
hypertensive
and
normotensive
parents
during
intra-
venzous
glucose
intolerance
test.
Glucose
givenat
time
0
erol,
and
3-hydroxybutyrate
were
sup-
developing
essential
hypertension
but
who
are
not
yet
Lally
in
both
groups
during
the
clamp
(fig
3).
hypertensive.
Our
subjects
were
carefully
chosen
to
shows
the
results
of
the
intravenous
glucose
eliminate
other
factors
which
influence
insulin
resist-
zst.
After
the
infusion
of
glucose,
plasma
ance,
especially
obesity,
drug
treatment,
other
illness,
icentrations
were
similar
in
both
groups.
and
a
family
history
of
diabetes
mellitus.28-23
As
well
as
ng
of
hypertensive
parents
and
the
control
reduced
insulin
sensitivity,
subjects
with
a
parental
also
similar
in
their
first
phase
insulin
history
of
hypertension
had
raised
fasting
concentra-
rea
under
curve
of
graph
in
first
10
minutes)
tions
of
non-esterified
fatty
acids
and
reduced
concen-
0)
v
2597
(1862)
pmol.min/l,
p=0
60)
and
trations
of
high
density
lipoprotein
cholesterol.
Insulin
vse
insulin
secretion
(5761
(3414)
v
4118
secretion
in
response
to
intravenous
glucose
was
1.min/I,
p=
0
32).
similar
in
the
two
groups.
We
have
previously
shown
that
hepatic
insulin
sensitivity
is
normal
in
hypertensive
subjects,
and
there
is
general
agreement
that insulin
resistance
is
ly
demonstrates
that
insulin
resistance
is
located
in
skeletal
muscle.78'4
Hepatic
insulin
action
oung
adults
who
have
an
increased
risk
of
was
not
assessed
in
the
present
study,
and
our
observations
in
the
offspring
of
hypertensive
parents
*
*
Offspring
of
hypertensive
can
give
only
an
overall
measure
of
insulin
action.
A
parents
(n=
I5)
possible
mechanism
of
reduced
peripheral
insulin
0-
Offspring
of
normotensive
sensitivity
is
impaired
stimulation
of
muscle
blood
parents
(n=
15)
flow,
which
is
an
important
determinant
of
tissue
glucose
uptake
after
administration
of
insulin.
2
92
No
studies,
however,
have
examined
skeletal
muscle
blood
flow
in
essential
hypertension.
One
other
group
has
examined
insulin
action
in
people
with
a
hypertensive
parent,
by
means
of
an
intravenous
glucose
tolerance
test:
this
group
also
concluded
that
such
people
had
impaired
insulin
sensitivity.27
Another
factor
possibly
contributing
to
insulin
resistance
in
our
study
was
increased
lipid
oxidation:
serum
non-esterified
free
fatty
acid
concentrations
were
significantly
higher
in
the
offspring
of
hyper-
tensive
parents.
Increased
free
fatty
acid
oxidation
due
to
increased
substrate
supply
leads
to
impaired
oxidation
of
glucose
and
the
formation
of
glycogen.2'
Our
results
suggest
that
insulin
resistance
precedes
clinical
hypertension.
In
a
study
of
non-obese
subjects
(mean
age
53)
with
untreated
essential
hypertension
we
found
that
the
mean
(SD)
infusion
rate
of
exogenous
glucose
required
to
maintain
euglycaemia
during
an
____________
__
infusion
of
insulin
(1
mU/kg/min)
was
27-5
(9
3)
1jmol/
-30
0
30
60
90
120
kg/l,
compared
with
38-1
(7
3)
,umol/kg/l
in
non-
hypertensive
controls
matched
for
age
(95%
confidence
Time
(minutes)
interval
for
mean
difference
7-8
to
13-4,
p<0
005).'
(SE)
serum
concentrations
of
glycerol,
3-hydroxybuty-
For
the
offspring
of
hypertensive
and
normotensive
esterified
free
fatty
acids
in
offspring
of
hypertensive
and
parents
duing
euglycaemic
glucose
clamip.
Insulin
parents
in
the
present
study
the
figures
were
295
O
(6
5)
1imol/kg/min
and
40-1
(8
6)
,umol/kg/min
BMJ
VOLUME
307
10
JULY
1993
94
respectively.
Although
we
cannot
be
certain
that
the
offspring
of
hypertensive
parents
in
the
present
study
will
become
hypertensive,
our
data
are
consistent
with
the
view
that
a
stable
degree
of
insulin
resistance
may
be
present
for
many
years
before
the
start
of
clinical
hypertension.
Several
theories
have
been
proposed
to
explain
how
insulin
resistance
and
consequent
hyperinsulinaemia
can
cause
elevated
blood
pressure.
One
possible
explanation
is
the
effect
of
hyperinsulinaemia
on
hormones
that
regulate
blood
pressure.
We
have
previously
shown
that
short
term
physiological
hyper-
insulinaemia
increases
the
circulating
concentrations
of
renin
angiotensin
and
noradrenaline
and
increases
systolic
blood
pressure."
Secondly,
insulin
may
pro-
mote
retention
of
sodium
by
the
kidney.9
Thirdly,
insulin
is
known
to
have
direct
and
indirect
effects
on
a
variety
of
membrane
cation
transport
systems,
particu-
larly
sodium-potassium
ATPase
and
sodium-hydrogen
exchange.29
Even
relatively
small
increases
in
insulin
might
initiate
the
processes
outlined
above.
In
our
subjects,
however,
a
minor
increase
of
blood
pressure
was
already
present
at
the
time
of
study,
and
when
differences
in
insulin
action
were
adjusted
for
blood
pressure
they
were
no
longer
significant.
It
is
therefore
possible
that insulin
resistance
arose
after
these
minor
elevations
of
blood
pressure,
perhaps
through
haemodynamically
induced
alterations
to
the
microcirculation,
leading
to
reduced blood
flow
and
glucose
uptake.30
The
familial
connection
with
insulin
resistance
suggested
by
our
results
is
intriguing.
The
predispo-
sition
to
elevated
blood
pressure
in
people
with
a
parental
history
of
hypertension
is
already
well
estab-
lished,
although
it
is
likely
to
be
multifactorial
with
about
5-10%
of
the
overall
variance
in
blood
pressure
being
due
to
the
shared
family
environment.'2-'4
3'
Current
data
suggest
that
more
than
half
of
those
with
essential
hypertension
will
have
at
least
one
other
first
degree
relative
with
hypertension.'2
We
also
know
that
insulin
sensitivity
varies
widely
in
normal
subjects,32
33
and
it
may
be
determined
as
a
familial
characteristic.3433
Insulin
resistance
being
present
in
offspring
of
hyper-
tensive
parents
is
consistent
with
it
being
a
familially
determined
pathogenetic
mechanism
for
development
of
hypertension.
There
are
many
possible
sites
for
genetic
control
of
insulin
resistance
including
the
insulin
gene,
the
insulin
receptor
gene,
and
the
glucose
transporter
gene.
All
have
been
subjects
of
extensive
study
in
non-insulin
dependent
diabetes
without
a
consistent
abnormality
being
identified.
36-38
We
found
that
the
offspring
of
hypertensive
parents
had
reduced
high
density
lipoprotein
cholesterol
con-
centrations.
Several
recent
studies
have
supported
the
view
that
hypertensive
patients
often
carry
several
risk
factors
for
vascular
disease
and
that
these
may
have
a
familial
component.P
39
Reaven
suggested
that,
because
insulin
resistance
is
associated
with
hypertension,
hypertriglyceridaemia,
and
non-insulin
dependent
diabetes,
it
may
contribute
to
the
development
of
these
abnormalities
and,
as
a
consequence,
vascular
disease.40
This
hypothesis
remains
controversial.4'
Our
data
do
not
allow
speculation
beyond
a
role
for
insulin
resist-
ance
in
essential
hypertension.
It
should
be
noted,
however,
that
we
excluded
subjects
with
a
family
history
of
diabetes
mellitus
from
our
study,
which
would
suggest
that,
if
Reaven's
view
is
correct,
several
different
determinants
of
insulin
action
may
be
involved.
We
have
shown
that
insulin
resistance
is
present
at
an
early
stage
in
the
offspring
of
hypertensive
parents
and
is
associated
with
dyslipidaemia.
The
extent
of
insulin
resistance
in
subjects
with
an
increased
risk
of
developing
hypertension
is
similar
to
that
in
older
patients
with
established
clinical
hypertension.
It
Clinical
implications
*
Essential
hypertension
is
associated
with
insulin
resistance
*
Offspring
of
hypertensive
parents
who
are
at
increased
risk
of
hypertension
but
who
are
not
yet
hypertensive
show
reduced
insulin
sensitivity
compared
with
normotensive
offspring
of
normotensive
parents
*
Insulin
resistance
precedes
clinical
hyper-
tension
and
may
be
important
in
its
aetiology
seems
that
the
risk
of
a
person
developing
essential
hypertension
is
associated
with
reduced
insulin
sensi-
tivity
and
that
this
may
be
determined
in
part
by
familial
factors.
We
thank
Mr
C
N
Ennis
and
Mr
N
P
Bell
for
expert
technical
assistance,
Mr
C
Patterson
for
statistical
advice,
and
Mrs
Marie
Loughran
for
typing
the
manuscript.
OLB
was
supported
by
a
Royal
Victoria
Hospital
Research
Fellowship.
I
Shen
DC,
Shieh
SM,
Fuh
MT,
Wu
DA,
Chen
YDI,
Reaven
GM.
Resistance
to
insulin
stimulated
glucose
uptake
in
patients
with
hypertension.
J
C/in
EndocrinolMetab
1988;66:580-3.
2
Swislocki
AL,
Hoffman
BB,
Reaven
GM.
Insulin
resistance,
glucose
intoler-
ance
and
hyperinsulinemia
in
patients
with
hypertension.
Am
Jf
Hypertens
1989;2:419-23.
3
Modan
M,
Halkin
H,
Almog
S,
Lusky
A,
Eshkol
A,
Shefi
M,
et
al.
Hyperinsulinemia,
a
link
between
hypertension,
obesity
and
glucose
intolerance.
]
ClGn
Invest
1985;75:809-17.
4
Pollare
T,
Lithell
H,
Selinus
I,
Beme
C.
Application
of
prazosin
is
associated
with
an
increase
of
insulin
sensitivity
in
obese
patients
with
hypertension.
Diabetologia
1988;31:415-20.
5
Pollare
T,
Lithell
H,
Beme
C.
A
comparison
of
the
effects
of
hydrochlorthia-
zide
and
captopril
on
glucose
and
lipid
metabolism
in
patients
with
hypertension.
NEngl7Med
1989;321:868-73.
6
Pollare
T,
Lithell
H,
Selinus
I,
Beme
C.
Sensitivity
to
insulin
during
treatment
with
atenolol
and
metoprolol:
a
randomised,
double
blind
study
of
effects
of
carbohydrate
and
lipoprotein
metabolism
in
hypertensive
patients.
BMJ
1989;298:
1152-7.
7
Ferrannini
E,
Buzzigoli
G,
Bonadonna
R,
Giorico
MA,
Oleggini
M,
Graziadei
L,
et
al.
Insulin
resistance
in
essential
hypertension.
N
Engl
J
Med
1987;317:350-7.
8
Rooney
DP,
Neely
RDG,
Ennis
CN,
Bell
NP,
Sheridan
B,
Atkinson
AB,
et
al.
Insulin
action
and
hepatic
glucose
cycling
in
essential
hypertension.
Metabolism
1992;41:317-24.
9
De
Fronzo
RA.
The
effect
of
insulin
on
renal
sodium
metabolism.
Diabetologia
1981;21:165-7
1.
10
Rowe
JW,
Young
JB,
Minaker
KL,
Stevens
AL,
Pallotta
J,
Landsberg
L.
Effect
of
insulin
and
glucose
infusions
on
sympathetic
nervous
system
activity
in
normal
man.
Diabetes
1981;30:219-25.
11
Rooney
DP,
Edgar
JDM,
Sheridan
B,
Atkinson
AB,
Bell
PM.
The
effects
of
low
dose
insulin
infusions
on
the
renin
angiotensin
and
sympathetic
nervous
systems
in
normal
man.
EurjClin
Invest
1991;21:430-5.
12
Stamler
R,
Stamler
J,
Riedlinger
WF,
Algera
G,
Roberts
RH.
Family
(parental)
history
and
prevalence
of
hypertension.
JAMA
1979;241:43-6.
13
Watt
G.
Design
and
interpretation
of
studies
comparing
individuals
with
and
without
a
family
history
of
high
blood
pressure.
J
Hypertens
1986;4:1-7.
14
Munger
RG,
Prineas
RJ,
Gomez-Marin
0.
Persistent
elevation
of
blood
pressure
among
offspring
with
a
family
history
of
hypertension:
the
Minneapolis
offspring's
blood
pressure
study.
JHypertens
1988;6:647-53.
15
Challenge
for
the
90's-the
change
of
heart
baseline
clinical
survey.
Belfast:
Department
of
Epidemiological
and
Public
Health,
Queen's
University
of
Belfast,
1990.
(Belfast
MONICA
report.)
16
Saltin
B,
Grimby
G.
Physiological
analysis
of
middle-aged
and
old
former
athletes.
Circulation
1968;381104-15.
17
Valdes
CT,
Elkind-Hirsch
KE.
Intravenous
glucose
tolerance
test-derived
insulin
sensitivity
changes
during
the
menstrual
cycle.
J
Clin
Endocrinol
Metab
1991;72:642-6.
18
De
Fronzo
RA,
Tobin
JD,
Andres
R.
Glucose
clamp
technique:
a
method
for
quantifying
insulin
secretion
and
resistance.
Am
J
Physiol
1979;273:
E214-23.
19
Hales
CN,
Randle
PJ.
Immunoassay
of
insulin
with
insulin
antibody
precipi-
tate.
Biochem3
1963;88:137-46.
20
Friedewald
WT,
Levy
RI,
Fredrickson
DS.
Estimation
of
the
concentration
of
low-density
lipoprotein
cholesterol
in
plasma
without
the
use
of
the
preparative
ultracentrifuge.
Clin
Chem
1972;18:499-502.
21
Rizza
RA,
Mandarino
LJ,
Gerich
JE.
Mechanism
and
significance
of
insulin
resistance
in
non-insulin-dependent
diabetes
mellitus.
Diabetes
1981;30:
990-5.
22
Kolterman
OG,
Insel
J,
Saekow
M,
Olefsky
JM.
Mechanisms
of
insulin
resistance
in
human
obesity.
Evidence
for
receptor
and
postreceptor
defects.
JClin
Invest
1980;65:1272-84.
23
De
Fronzo
RA.
Insulin
secretion,
insulin
resistance
and
obesity.
Int
J
Obes
1982;6(suppl
1):73-82.
24
Natali
A,
Santoro
D,
Palombo
C,
Cerri
M,
Ghione
S,
Ferrannini
E.
Impaired
insulin
action
on
skeletal
muscle
metabolism
in
essential
hypertension.
Hypertension
1991;17:170-8.
25
Laakso
M,
Edelman
SV,
Brechtel
G,
Baron
AD.
Decreased
effect
of
insulin
to
stimulate
skeletal
muscle
blood
flow
in
obese
man:
a
novel
mechanism
for
insulin
resistance.
J7Clin
Invest
1990;85:1844-52.
26
Laakso
M,
Edelman
S,
Brechtel
G,
Baron
A.
Decreased
insulin
mediated
BMJ
VOLUME
307
10
JuLY
1993
95
glucose
uptake
(IMGU)
in
NIDDM
subjects:
the
role
of
blood
flow.
Diabetes
1991;40(suppl
1):1
OA.
27
Ferrari
P,
Weidmann
P,
Shaw
S,
Giachino
D,
Riesen
W,
Allemann
Y,
et
al.
Altered
insulin
sensitivity,
hyperinsulinemia
and
dyslipidemia
in
indivi-
duals
with
a
hypertensive
parent.
Am3rMed
1991;91:589-96.
28
Randle
PJ,
Garland
PB,
Hales
CN,
Newsholme
EA.
The
glucose
fatty
acid
cycle:
its
role
in
insulin
sensitivity
and
the
metabolic
disturbances
of
diabetes
mellitus.
Lancet
1963;i:785-9.
29
Moore
RD.
Effects
of
insulin
upon
ion
transport.
Biochirm
Biophys
Acta
1983;737:
1-49.
30
Julius
S,
Gudbrandsson
T,
Jamerson
K,
Shahab
ST,
Andersson
0.
The
haemodynamic
link
between
insulin
resistance
and
hypertension.
Jf
Hyper-
tens
1991;9:983-6.
31
Williams
RR,
Hunt
SC,
Hasstedt
SJ,
Hopkins
PN,
Wu
LW,
Berry
TD,
et
al.
Current
knowledge
regarding
the
genetics
of
human
hypertension.
JHvpertens
1989;7(suppl
6):8-13.
32
Bogardus
C,
Lillioja
S,
Howard
BV,
Reaven
G,
Mott
D.
Relationships
between
insulin
secretion,
insulin
action
and
fasting
plasma
glucose
concentration
in
nondiabetic
and
non-insulin-dependent
diabetic
subjects.
JClin
Invest
1984;74:1238-46.
33
Reaven
G,
Miller
R.
Study
of
the
relationship
between
glucose
and
insulin
responses
to
an
oral
glucose
load
in
man.
Diabetes
1968;17:560-9.
34
Bogardus
C,
Lillioja
S,
Nyomba
BL,
Zurlo
F,
Swinbum
B,
Esposito-Del
Puente
A,
et
al.
Distribution
of
in
vivo
insulin
action
in
Pima
Indians
as
mixture
of
three
normal
distributions.
Diabetes
1989;38:1423-32.
35
Lillioja
S,
Mott
DM,
Zawadzki
JK,
Young
AA,
Abbott
WGH,
Knowler
WC,
et
al.
In
vivo
insulin
action
is
familial
characteristic
in
nondiabetic
Pima
Indians.
Diabetes
1987;36:1329-35.
36
Raben
N,
Barbetti
F,
Cama
A,
Lesniak
MA,
Lillioja
S,
Zimmet
P,
et
al.
Normal
coding
sequence
of
insulin
gene
in
Pima
Indians
and
Nauruans,
two
groups
with
highest
prevalence
of
type
II
diabetes.
Diabetes
1991-40:
118-22.
37
Oelbaum
RS,
Bouloux
PM,
Li
SR,
Baroni
MG,
Stocks
J,
Galton
DJ.
Insulin
receptor
gene
polymorphisms
in
type
2
(non-insulin-dependent)
diabetes
mellitus.
Diabetologia
1991;34:260-4.
38
Kusari
J,
Berma
US,
Buse
JB,
Henry
RR,
Olefsky
JM.
Analysis
of
the
gene
sequences
of
the
insulin
receptor
and
the
insulin
sensitive
glucose
transporter
(GLUT-4)
in
patients
with
common
type
non-insulin-dependent
diabetes
mellitus.
J7
Clin
Invest
1991;88:1323-30.
39
Williams
RR,
Hunt
SC,
Hopkins
PN,
Stults
BM,
Wu
L,
Hasstedt
S,
et
al.
Familial
dyslipidemic
hypertension:
evidence
from
58
Utah
families
for
a
syndrome
present
in
approximately
12%
of
patients
with
essential
hyper-
tension.
JAMA
1988;259:3579-86.
40
Reaven
GM.
Role
of
insulin
resistance
in
human
disease.
Diabetes
1988;37:
1595-607.
41
Jarrett
RJ.
In
defence
of
insulin:
a
critique
of
syndrome
X.
Lancet
1992;340:
469-71.
(Accepted
11
May
1993)
A
decade
of
diabetes:
keeping
children
out
of
hospital
P
G
F
Swift,
J
R
Heamshaw,
J
L
Botha,
G
Wright,
N
T
Raymond,
K
F
Jamieson
Leicester
Royal
Infirmary,
Leicester
LEI
SWW
P
G
F
Swift,
consultant
paediatrician
J
R
Heamshaw,
consultant
physician
in
diabetes
Department
of
Epidemiology
and
Public
Health,
Leicester
University,
Leicester
J
L
Botha,
senior
lecturer
G
Wright,
research
assistant
N
T
Raymond,
statistician
K
F
Jamieson,
medical
student
Correspondence
to:
Dr
Swift.
BMJ
1993;307:96-8
Abstract
Objectives-To
document
the
number
of
children
aged
less
than
15
years
who
developed
diabetes
and
were
managed
within
one
large
health
district,
and
to
evaluate
the
outcome
of
those
children
managed
without
hospital
admission
at
diagnosis.
Design-A
retrospective
study
over
1979-88,
when
a
paediatrician
and
a
physician
with
special
interests
in
childhood
diabetes
initiated
joint
clinics.
Data
collected
from
the
district
diabetes
register
and
files
of
consultants
and
health
visitors
specialising
in
diabetes.
Setting-Referral
of
children
to
consultants
in
Leicestershire
(total
population
863
000).
Main
outcome
measures-The
proportion
of
children
managed
without
hospital
admission,
comparison
of
readmission
rates
and
glycated
haemoglobin
concentrations
between
children
admitted
and
those
not
admitted.
Results-Over
10
years
236
children
aged
10-14
years
developed
diabetes
(annual
incidence
rate
12-8/100
000
child
population
(95%
confidence
interval
11'3
to
14.7)).
In
total
138
were
not
admitted
to
hospital
but,
received
supervised
management
based
at
home.
Admitted
children
were
younger
or
acidotic
or
their
family
doctors
did
not
contact
the
diabetes
team.
Duration
of
admission
declined
from
seven
days
in
1979-80
to
three
days
in
1987-8.
Ninety
two
were
not
admitted
to
hospital
during
the
10
years
for
any
reason.
Significantly
fewer
children
who
received
management
at
home
were
readmitted
for
reasons
related
to
diabetes
than
the
group
treated
in
hospital
(30
(22%)
v
40
(41%);
p=
0004).
Concen-
trations
of
glycated
haemoglobin
were
no
different
between
the
two
groups.
Conclusions-Children
with
newly
diagnosed
dia-
betes
may
be
safely
and
effectively
managed
out
of
hospital.
Domiciliary
or
community
based
manage-
ment
depends
on
the
commitment
of
consultants
specialising
in
diabetes
working
in
close
cooperation
with
general
practitioners,
specialist
nurses
in
diabetes,
and
dietitians.
Introduction
The
United
Kingdom
has
a
comprehensive
primary
and
community
health
care
system,
including
the
widespread
availability
of
specialist
nurses
in
diabetes
in
at
least
81%
of
health
districts.'
Yet
children
with
newly
diagnosed
diabetes
are
still
routinely
admitted
to
hospital.2
The
British
Paediatric
Association's
working
party
on
children's
diabetes
services
found
that
87%
of
paediatricians
reported
that
virtually
all
children
were
admitted
at
the
time
of
diagnosis.'
In
1988,
1600
children
under
15
years
of
age
living
in
the
British
Isles
developed
diabetes.3
A
subsequent
survey
of
these
children
confirmed
that
95%
were
admitted
to
hospital,
42%
for
more
than
seven
days.4
In
the
United
States
a
position
statement
in
1990
by
the
American
Diabetes
Association
accepted
that
inpatient
care
was
most
appropriate
for
children
and
adolescents
when
diabetes
was
diagnosed.5
Supervised
outpatient
management
of
children
was
described
over
40
years
ago
in
the
United
Kingdom2
6
and
since
the
1970s
in
Israel78
and
the
United
States.9
There
is
no
published
work
showing
that
hospital
admission
for
children
who
do
not
require
intravenous
treatment
is
necessary
or
beneficial.
Indeed
several
studies
assume
that
there
are
benefits
from
a
shorter
duration
of
admission
if
the
initiation
of
insulin
treatment
and
basic
education
can
be
accomplished
by
an
organised
specialist
team,"'
"
particularly
when
specialist
nurses
in
diabetes
are
available."
12
The
present
study
spanning
the
decade
1979-88
documents
the
number
of
children
developing
diabetes
who
were
managed
within
a
large
NHS
district
(total
population
863
000);
describes
the
management
at
diagnosis,
drawing
particular
attention
to
the
propor-
tion
of
children
not
admitted
to
hospital;
and
evaluates
the
short
and
medium
term
efficacy
of
inpatient
and
outpatient
management.
Subjects
and
methods
Names
were
identified
of
children
aged
0-14
years
who
had
developed
insulin
dependent
diabetes
between
1
January
1979
and
31
December
1988
from
the
Leicestershire
diabetes
register
of
all
diabetic
patients
who
were
taking
insulin
(95-100%
complete
for
childhood
diabetes'3)
and
from
consultants'
card
indexes.
Data
retrieved
from
the
hospital
notes
of
the
children
included
date
of
diagnosis,
age,
duration
of
admission,
where
and
by
whom
initially
managed,
readmissions
to
hospital,
and
reasons
for
readmissions.
Analysis
was
made
of
all
glycated
haemoglobin
concentrations
during
the
10
years
of
study.
Compari-
96
BMJ
VOLUME
307
10
JULY
1993
